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Synthesis, characterization and in-silico assessment of novel thiazolidinone derivatives for cyclin-dependent kinases-2 inhibitors
Abstract
This work aims to synthesize thiazolidinone derivatives using a rapid, safe and solvent-free grinding assisted approach. The newly synthesized compounds have been targeted due to their bioactivity in wide pharmaceutical uses, especially, as anti-proliferative agents. Two thiazolidinone derivatives having a diverse set of crucial functional groups were diagnosed with melting point (m.p), FT-IR, 1 H NMR, 13 C NMR, GC-Mass and CHNS. High outputs (98% and 96%) of thiazolidinone derivatives were offered by the grinding method and the final product was produced over short reaction times (5 min). This simple strategy would potentially be promising for the preparation of thiazolidinone derivatives in abundance. Followed by synthesis both of our molecules were considered for molecular docking study against the Cyclin-Dependent Kinase 2 (CDK2) protein. A number of potential binding interactions in terms of hydrogen and hydrophobic bonds were observed with the ligand-binding amino acid of CDK2 protein. The behavior of both molecules inside the CDK2 was explored through all-atoms molecular dynamics (MD) simulations. Several parameters calculated from the MD simulation were revealed that both molecules retained inside the receptor cavity of CDK2. Hence, green synthesized both compounds were found to show strong potentiality against the CDK2 and may have significant interests in the field of pharmaceutical chemistry.
... Thiazolidinone derivatives have a five-membered heterocyclic ring with one sulfur, one nitrogen, and three carbon atoms Thiazolidinones are one of the most essential heterocyclic compounds [8], and their derivatives, which have a carbonyl group in the fourth position, are an integral part of many synthetic pharmaceuticals with diverse biological activities [9,10] 4-Imidazolidinones are a class of nitrogen-rich saturated lactams with medicinal applications [11]. Imidazolidinone derivatives are currently of interest as organocatalysts in modern organic synthesis [12]. ...
... All of the produced compounds (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) were either as active as the ordinary ascorbic acid or somewhat less active. The quantities of 50, 100, and 150 g /ml were used in a (2,2-diphenyl-1-picrylhydrazyl) test. ...
... Antioxidant activity was highest for component (11) at a concentration of (150 g/ml), as was out by reviewing the various results. An illustration of the newly synthesized compound's DPPH scavenging activity (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) is shown in Figure 27. ...
In this study, a new series of 1,3-dimethyl-6-(amino aceto hydrazine) pyrimidine-2,4- dione-6-yl with 4-substituted benzyldehyde, The compound (1-5) was synthesized in a single pot that cyclization by the addition of sodium azide, 2-mercapto acid & 2-amino acetic acid to produce five-membered heterocyclic rings includes: tetrazoline-1yl (6-10), thiazolidin-4-one (11-15) and imidazolidin-4-one (16-20) derivatives respectively. These compounds were characterized using spectral methods [FTIR and 1HNMR, 13C-NMR for some of them] evaluations, measurements, and analyses of their physical qualities. Each molecule was evaluated for antioxidant activity in vitro to use the DPPH and phosphomolybdenum methods. When compared to the standard drug Ascorbic acid, (1-20) demonstrated promising antioxidant activity among the bioactive molecules synthesized. Furthermore, molecular docking against, substances showed superiority over the standard medication Exemestane in tests of the Aromatase enzyme.
... In terms of FT-IR, there was the disappearance of the absorption band of NH 2 at (3441-3200) cm -1 and appeared the clear vibrational bands such as those that were assigned for N-H symmetric stretching at (3286-3282) cm -1 and C=O vibrational band at (1654-1620) cm -1 , which is in agreement with other studies. (29,30) Regarding 1 H-NMR spectra of compounds (2a-d), it has appeared the amide N-H as a singlet peak, which was overlapped with the benzylic C-H at (8.54-8.51) ppm. ...
... ppm, which is in coinciding with another research. (29) The another evidence of the synthesis of 4-thiazolidinone comes from 13 C-NMR spectra. It newly formed C-S bond has been shown at chemical shift (37.33-33.01) ...
... It has a multiple signal at (122.99-152.65) ppm attributed to the aromatic ring's carbons in addition to the same ring linked to the aromatic ring [17] as in Figure 4. ...
... It has a multiple signal at (122.99-152.65) ppm attributed to the aromatic ring's carbons in addition to the same ring linked to the aromatic ring [17] as in Figure 4. ...
... Heterocyclic compounds are aromatic and/or cyclic molecules that have multiple heteroatoms, such as oxygen, sulphur, nitrogen and so on, arranged in rings. Despite the importance of heterocyclic compounds in medicine, there is still much to learn about them (Abdullah et al., 2021). Medicinal chemistry is highly interested in fused heterocyclic compounds, which usually consist of five or six members, because of their diverse pharmacological and therapeutic implications. ...
One of the promising classes of compounds in medicinal chemistry and drug design is those with azomethine linkages.
The Chalcone-Schiff base hybrids contain this linkage and some heteroatoms, which are versatile molecules, play a vital
role in drug discovery and development with enormous therapeutic applications. In this view, the present work deals
with the investigation of the in silico biological potential of the Chalcone-Schiff base hybrids based on the network
pharmacology approach. From the results obtained from network pharmacology, the Cyclin-dependent kinase (CDK)
isoforms were identified as the potential targets and the CDK inhibitory activity of the compounds was investigated
using molecular docking studies. The in silico pharmacokinetic, metabolic and theoretical studies at DFT level were
performed. Molecular docking studies revealed that the compounds have better CDK inhibitory potential with better
binding affinity and interaction profile. Among the tested compounds, (Z)-2-((4,6-diphenyl-5,6-dihydro-4H-1,3-
thiazin-2-yl)imino)-2,3-dihydro-1H-inden-1-one was found to be the most active compound than the standards,
palbociclib and dinaciclib against the CDK isoforms (CDK1, CDK2 and CDK4) with the binding energies of -9.9, -10.3
and -10 Kcal/Mol, respectively. Also, this compound exhibited better pharmacokinetic and metabolic properties along
with better solubility. The theoretical studies at the DFT level also indicate that the compound has better metabolic
stability and the electron transfer from HOMO to LUMO was observed. Thus, the tested Chalcone-Schiff base hybrids
can be used effectively for the inhibition of CDK isoforms.
... [37] Singh et al. revealed that the substitution of the antibacterial activities of some new thiazolidinone hybrids (9) against dihydrofolate reductase enzyme (DHFR) (Fig. 23). [38,39] The enzyme known as dihydrofolate reductase (DHFR), by using NADPH as an electron donor turns dihydrofolate into tetrahydrofolate, which can then be changed into the different kinds of cofactors of tetrahydrofolate. The DHFR gene in humans encodes the DHFR enzyme. ...
... The prime module of Schrödinger was used to estimate the theoretical binding free energies of the hits obtained from XP docking, based on the glide scores, were utilised for MM-GBSA (Molecular Mechanical-Generalized Born Surface Area) analysis [57]. The energy properties of free ligand, free protein, and protein-ligand complex were utilised for the estimation of binding free energies [58]. ...
The outbreak of novel Coronavirus, an enduring pandemic declared by WHO, has consequences to an alarming ongoing public health menace which has already claimed several million human lives. In addition to numerous vaccinations and medications for mild to moderate COVID-19 infection, lack of promising medication or therapeutic pharmaceuticals remains a serious concern to counter the ongoing coronavirus infections and to hinder its dreadful spread. Global health emergencies have called for urgency for potential drug discovery and time is the biggest constraint apart from the financial and human resources required for the high throughput drug screening. However, computational screening or in-silico approaches appeared to be an effective and faster approach to discover potential molecules without sacrificing the model animals. Accumulated shreds of evidence on computational studies against viral diseases have revealed significance of in-silico drug discovery approaches especially in the time of urgency. The central role of RdRp in SARS-CoV-2 replication makes it promising drug target to curtain on going infection and its spread. The present study aimed to employ E-pharmacophore-based virtual screening to reveal potent inhibitors of RdRp as potential leads to block the viral replication. An energy-optimised pharmacophore model was generated to screen the Enamine REAL DataBase (RDB). Then, ADME/T profiles were determined to validate the pharmacokinetics and pharmacodynamics properties of the hit compounds. Moreover, High Throughput Virtual Screening (HTVS) and molecular docking (SP & XP) were employed to screen the top hits from pharmacophore-based virtual screening and ADME/T screen. The binding free energies of the top hits were calculated by conducting MM-GBSA analysis followed by MD simulations to determine the stability of molecular interactions between top hits and RdRp protein. These virtual investigations revealed six compounds having binding free energies of -57.498, -45.776, -46.248, -35.67, -25.15 and -24.90 kcal/mol respectively as calculated by the MM-GBSA method. The MD simulation studies confirmed the stability of protein ligand complexes, hence, indicating as potent RdRp inhibitors and are promising candidate drugs to be further validated and translated into clinics in future.
... Finally, using Swiss ADME online, the prepared complex was effective on drug-likeness criteria derived from the rules of Lipinski, Ghosh, and Veber. [31] µ ε ε ...
In this research, a derivative of L-ascorbic acid (L) as a ligand was synthesized from the reaction of this acid with acetone compound in an acidic medium, and then, a complex reaction was carried out between the synthesized derivatives with zinc chloride salt using ethanol as a solvent. This is a novel attempt to use 5,6-O-isopropylidene-L-ascorbic acid as a derivative of L-ascorbic acid in the synthesis of zinc complex [Zn(L)Cl 2 ]. Thin-layer chromatography was used to determine the time required for the completion of the reactions. The formation of the derivative (L) was confirmed by m.p, Rf, Fourier transform infrared (FT-IR), 1 H-nuclear magnetic resonance, and mass spectra, and the synthesis of [Zn(L)Cl 2 ] was proved by m.p, Rf, FT-IR, and mass spectra. The biological activity of the fabricated complex was evaluated against three human cancer cell lines, including prostate cancer cell line (PC-3), colon cancer cell line (Caco-2), and breast cancer cell line (MCF-7). The [Zn(L)Cl 2 ] exhibited a good reduction in cell viability in a dose-dependent system, where cell viability is reduced by increasing the concentration of the complex. In addition, its antioxidant activity was investigated and demonstrated significant activity at concentrations of 100 and 200 g/mL. Hence, this complex has the potential to be a promising drug for the treatment of PC-3, Caco-2, and MCF-7.
... In the present study, the binding free energy was calculated using the molecular mechanics-generalized born surface area (MM-GBSA) method [55] using the last 10000 frames of each system. The same approach was used in our previous published work [56]. In particular, the following mathematical derivation was followed for MM-GBSA based binding free energy estimation for the protein-ligand complexes. ...
The current ongoing pandemic of COVID-19 urges immediate treatment measures for controlling the highly contagious SARS-CoV-2 infections. The papain-like protease (PLpro), which is released from nsp3, is presently being evaluated as a significant anti-viral drug target for COVID-19 therapy development. Particularly, PLpro is implicated in the cleavage of viral polyproteins and antagonizes the host innate immune response through its deubiquitinating and deISGylating actions, thus making it a high-profile antiviral therapeutic target. The present study reports a few specific food compounds that can bind tightly with the SARS-CoV-2 PLpro protein identified through extensive computational screening techniques. Precisely, extensive advanced computational approaches combining target-based virtual screening, particularly employing sub-structure based similarity search, molecular docking, molecular dynamics (MD) simulations, and MM-GBSA based binding free energy calculations have been employed for the identification of the most promising food compounds with substantial functional implications as SARS-CoV-2 PLpro protein inhibitors/modulators. Observations from the present research investigation also provide a deeper understanding of the binding modes of the proposed four food compounds with SARS-CoV-2 PLpro protein. In docking analyses, all compounds have established essential inter-molecular interaction profiles at the active site cavity of the SARS-CoV-2 PLpro protein. Similarly, the long-range 100 ns conventional MD simulation studies also provided an in-depth understanding of probable interactions and dynamic behaviour of the SARS-CoV-2 PLpro protein-food compound complexes. Binding free energies of all molecular systems revealed a strong interaction affinity of food compounds towards the SARS-CoV-2 PLpro protein. Moreover, clear-cut comparative analyses against the known standard inhibitor also suggest that proposed food compounds may act as potential active chemical entities for modulating the action of the SARS-CoV-2 PLpro protein.
... Also, they have excellent properties such as high strength, lightweight, rich hydroxyl groups that can be modified, excellent mechanical properties, biodegradability and natural properties that are environmental friendliness (Phanthong et al., 2018). The greater attention is being paid to the importance of environmentally friendly chemical products and easy processing design (Abdul-Hadi et al., 2020;Abdullah et al., 2021;Habibi et al., 2010;Owaid et al., 2019;Rabeea et al., 2020a). In recent years, much research has been achieved on the preparation of nanoparticles from cellulose materials, such as wood pulp, cotton fiber, recycled pulp, flax fiber, and grass fiber by using topdown technologies (Chen et al., 2016). ...
... Further, the binding free energy of each polyphenol was obtained through the MD simulation data of the last ~ 10,000 frames of each MD simulation trajectory using the MM-GBSA method. The detailed mathematical expression of the MM-GBSA method is described in our previous publications [80,81]. ...
In this study, a set of dietary polyphenols was comprehensively studied for the selective identification of the potential inhibitors/modulators for galectin-1. Galectin-1 is a potent prognostic indicator of tumor progression and a highly regarded therapeutic target for various pathological conditions. This indicator is composed of a highly conserved carbohydrate recognition domain (CRD) that accounts for the binding affinity of β-galactosides. Although some small molecules have been identified as galectin-1 inhibitors/modulators, there are limited studies on the identification of novel compounds against this attractive therapeutic target. The extensive computational techniques include potential drug binding site recognition on galectin-1, binding affinity predictions of ~ 500 polyphenols, molecular docking, and dynamic simulations of galectin-1 with selective dietary polyphenol modulators, followed by the estimation of binding free energy for the identification of dietary polyphenol-based galectin-1 modulators. Initially, a deep neural network-based algorithm was utilized for the prediction of the druggable binding site and binding affinity. Thereafter, the intermolecular interactions of the polyphenol compounds with galectin-1 were critically explored through the extra-precision docking technique. Further, the stability of the interaction was evaluated through the conventional atomistic 100 ns dynamic simulation study. The docking analyses indicated the high interaction affinity of different amino acids at the CRD region of galectin-1 with the proposed five polyphenols. Strong and consistent interaction stability was suggested from the simulation trajectories of the selected dietary polyphenol under the dynamic conditions. Also, the conserved residue (His44, Asn46, Arg48, Val59, Asn61, Trp68, Glu71, and Arg73) associations suggest high affinity and selectivity of polyphenols toward galectin-1 protein.
Graphic Abstract
... Also, they have excellent properties such as high strength, lightweight, rich hydroxyl groups that can be modified, excellent mechanical properties, biodegradability and natural properties that are environmental friendliness (Phanthong et al., 2018). The greater attention is being paid to the importance of environmentally friendly chemical products and easy processing design (Abdul-Hadi et al., 2020;Abdullah et al., 2021;Habibi et al., 2010;Owaid et al., 2019;Rabeea et al., 2020a). In recent years, much research has been achieved on the preparation of nanoparticles from cellulose materials, such as wood pulp, cotton fiber, recycled pulp, flax fiber, and grass fiber by using topdown technologies (Chen et al., 2016). ...
... The organometallic compounds are important synthesized compounds in organic chemistry [1][2][3] .The nitrogen atom of ligands (Imine compounds) have the ability to form complex [4,5]. The Condensation reaction is considered one of the most important and common methods of preparing amine compounds, which it occurs by the direct condensation between primary aromatic amines and aldehydes or ketones, the reaction is done by using glacial acetic acid as a catalyst, leading to displacement of the water molecule to produce imine compound [6][7][8][9][10] below in scheme 1: ...
... Also, they have excellent properties such as high strength, lightweight, rich hydroxyl groups that can be modified, excellent mechanical properties, biodegradability and natural properties that are environmental friendliness (Phanthong et al., 2018). The greater attention is being paid to the importance of environmentally friendly chemical products and easy processing design (Abdul-Hadi et al., 2020;Abdullah et al., 2021;Habibi et al., 2010;Owaid et al., 2019;Rabeea et al., 2020a). In recent years, much research has been achieved on the preparation of nanoparticles from cellulose materials, such as wood pulp, cotton fiber, recycled pulp, flax fiber, and grass fiber by using topdown technologies (Chen et al., 2016). ...
In this work, chemical hydrolysis and ball milling (chemical-hydrolysis-ball-milling) were combined to produce cellulose acetate nanoparticles (CA-NPs). This method has been exhibiting more efficiency to synthesize CA-NPs. CA-NPs were successfully obtained using chemical-hydrolysis-ball-milling of Iraqi cotton through three stages namely bleaching, cellulose esterification, and milling. Cellulose acetate membranes (CA-NPs-membrane) were prepared by expanded of a saturated solution of cellulose acetate nanoparticles onto a glass surface. Cross-flow filtrations mode was carried out to evaluate membrane performance in removing salt from water. CA-NPs and CA-NPs-membrane were characterized via FTIR, TEM, and FE-SEM. Electrical conductivity (EC) was used to evaluate the performance of the synthesized CA-NP-membrane to remove salts from their aqueous solution. The characterization showed that the CA-NPs have a non-uniform spherical shape with an average diameter of less than 40 nm. The conductivity of water passing through the CA-NPs-membrane reduced from 984 to 1.8 μs at a flow rate of 0.7 liters/min. Wherefore, CA-NPs-membrane can be used efficiently for desalination applications due to its good characteristics.
... The pharmacokinetic analysis ensured the druglikeness of both the derivatives. The molecular dynamic simulation confirmed the stability of complexes of both the compounds with CDK-2 protein [30]. ...
Background
Cancer can be considered as a genetic as well as a metabolic disorder. Current cancer treatment scenario looks like aggravating tumor cell metabolism, causing the disease to progress even with greater intensity. The cancer therapy is restricted to limitations of poor patient compliance due to toxicities to normal tissues and multi-drug resistance development. There is an emerging need for cancer therapy to be more focused on the better understanding of genetic, epigenetic and transcriptional changes resulting in cancer progression and their relationship with treatment sensitivity.
Objective
The 4-thiazolidinone nucleus possesses marked anticancer potential towards different biotargets, thus targeting different cancer types like breast, prostate, lung, colorectal and colon cancers, renal cell adenocarcinomas and gliomas. Therefore, conjugating the 4-thiazolidinone scaffold with other promising moieties or by directing the therapy towards targeted drug delivery systems like the use of nanocarrier systems, can provide the gateway for optimizing the anticancer efficiency and minimizing the adverse effects and drug resistance development, thus providing stimulus for personalized pharmacotherapy.
Methods
An exhaustive literature survey has been carried out to give an insight into the anticancer potential of the 4-thiazolidinone nucleus either alone or in conjugation with other active moieties, with the mechanisms involved in preventing proliferation and metastasis of cancer covering a vast range of publications of repute.
Conclusion
This review aims to summarise the work reported on anticancer activity of 4-thiazolidinone derivatives covering various cancer biomarkers and pathways involved, citing the data from 2005 till now, which may be beneficial to the researchers for future development of more efficient 4-thiazolidinone derivatives.
... Both models calculate binding free energies by combining molecular mechanics calculations and continuum solvation models. Both approaches are used in a number of interesting studies [55][56][57][58] included by our research group [59][60][61]. Hou et al. [62] considered both the approaches and calculated binding free energy of several ligands. It was concluded that MM/ GBSA gives better correlations than MM/PBSA in most systems. ...
Transmembrane protease serine-2 (TMPRSS2) is a cell-surface protein expressed by epithelial cells of specific tissues including those in the aerodigestive tract. It helps the entry of novel coronavirus (n-CoV) or Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in the host cell. Successful inhibition of the TMPRSS2 can be one of the crucial strategies to stop the SARS-CoV-2 infection. In the present study, a set of bioactive molecules from Morus alba Linn. were screened against the TMPRSS2 through two widely used molecular docking engines such as Autodock vina and Glide. Molecules having a higher binding affinity toward the TMPRSS2 compared to Camostat and Ambroxol were considered for in-silico pharmacokinetic analyses. Based on acceptable pharmacokinetic parameters and drug-likeness, finally, five molecules were found to be important for the TMPRSS2 inhibition. A number of bonding interactions in terms of hydrogen bond and hydrophobic interactions were observed between the proposed molecules and ligand-interacting amino acids of the TMPRSS2. The dynamic behavior and stability of best-docked complex between TRMPRSS2 and proposed molecules were assessed through molecular dynamics (MD) simulation. Several parameters from MD simulation have suggested the stability between the protein and ligands. Binding free energy of each molecule calculated through MM-GBSA approach from the MD simulation trajectory suggested strong affection toward the TMPRSS2. Hence, proposed molecules might be crucial chemical components for the TMPRSS2 inhibition.
Graphic abstract
... The last 10,000 frames of each MD simulation trajectory were used to estimate the binding free energy through the well-known and widely used molecular mechanics-generalized born surface area (MM-GBSA) approach (Genheden & Ryde, 2015). The detailed procedure and expressions can be found in our previous publications (Abdullah et al., 2021;Chikhale et al., 2020). ...
This research is a recent effort to explore some new heterocyclic compounds as novel and potential nonstructural protein-16-nonstructural protein-10 (Nsp16-Nsp10) inhibitors for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) inhibition. The SARS-CoV-2 is causative agent of coronavirus disease 2019 (COVID-19) pandemic. A set of 58 molecules belongs to the naphthyridine and quinoline derivatives have been recently synthesized and considered for structure-based virtual screening against Nsp16-Nsp10. Molecular docking was virtually performed to screen for anti-SARS-CoV-2 activity against Nsp16-Nsp10. Fourteen out of fifty-eight compounds were exhibited binding affinity higher than co-crystal bound ligand s-adenosylmethionine (SAM) toward Nsp16-Nsp10. Further, the in silico pharmacokinetics assessment was carried out and it was found that two molecules possess the acceptable pharmacokinetic profile, hence considered promising Nsp16-Nsp10 inhibitors. The binding interaction analysis was revealed some crucial binding interactions between the final selected two molecules and ligand-binding amino acid residues of Nsp16-Nsp10 protein. In order to explore the characteristics of the protein–ligand complex and how selected small molecules retained inside the receptor cavity in dynamic states, all-atoms conventional molecular dynamics (MD) simulation was performed. Several factors were obtained from the MD simulation trajectory evidently suggested the potentiality of the molecules and stability of the protein–ligand complex. Finally, the binding affinity of both molecules and SAM was explored through the MM-GBSA approach which explained that both molecules possess strong affection towards the Nsp16-Nsp10. Hence, from the pharmacoinformatics assessment, it can be concluded that both heterocyclic compounds might be crucial for SARS-CoV-2 inhibition, subjected to experimental validation.
Communicated by Ramaswamy H. Sarma
Using 2-(9 H -fluoren-9-ylidene)hydrazinyl)thiazol-4(5 H )-one and substituted benzaldehydes, a new library of fluorenone–thiazolidine-4-one scaffolds (5a–u) were synthesized and characterized using FT-IR, ¹ H NMR, ¹³ C NMR and mass spectral data.
Penicillin bioactivity is continuously decreased due to the misuses by people which resulted in an antibiotics resistance. However, B-lactam ring is still an effect group the attack bacterial infection. In this study, we aimed to synthesize compounds with triple B-lactam rings and study in vitro their bioactivity. Schiff bases were followed to form two effective ligands involving triple B-lactam rings that were also docked against Penicillin binding protein to show their abilities through computational simulation studies. The synthesis of the compounds was mainly performed in two major steps: the first step was to form three Schiff bases of the compound named as BTTP compound and the second step to perform a cyclisation to produce triple B-lactam rings named as BTTCDP compounds. The prepared compounds were then confirmed using various routinely spectroscopic methods such as FTIR, NMR and CHN techniques. In vitro study showed (MIC in µg ml⁻¹) ranged from (0.254 and 0.568), respectively for both ligands. However, no inhibition was shown against fungus which could be considered as specific antibacterial. The molecular docking study showed the pockets of the binding with minimum free energy about -8.9 and -9.0 kcal/mol. All to gather, the two novel compounds containing triple B-lactam rings showed an effective bioactivity that are promising for in vivo studies in future.
Histone deacetylase 8 (HDAC8) has emerged as a promising drug target for cancer therapeutics development. HDAC8 has been reported to regulate cancer cell proliferation, invasion and promote metastasis through modulation of cell cycle associated proteins. Of late, phytocompounds have been demonstrated to exhibit anticancer and anti-HDAC8 activity. Here, we have shown the HDAC8 inhibitory potential of an active phytocompound from HC9 (herbal composition-9), a polyherbal anticancer formulation based on the traditional Ayurvedic drug, Stanya Shodhan Kashaya. HC9 was recently reported to exhibit anticancer activity against breast cancer cells through induction of cell cycle arrest, decrease in migration and invasion as well as regulation of inflammation and chromatin modulators. In silico studies such as molecular docking, molecular dynamics (MD) simulation and binding free energy analyses showed greater binding energy values and interaction stability of MA with HDAC8 compared to other phytocompounds of HC9. Interestingly, in vitro validation confirmed the anti-HDAC8 activity of MA. Further, in vitro studies showed that MA significantly decreased the viability of breast and prostate cancer cell lines, thereby confirming its anticancer potential.
Ion channels of viruses (viroporins) represent a common type of protein targets for drugs. The relative simplicity of channel architecture allows convenient computational modeling and enables virtual search for new inhibitors. In this review, we analyze the data published over the last 10 years on known ion channels of viruses that cause socially significant diseases. The effectiveness of inhibition by various types of heterocyclic compounds of the viroporins of influenza virus, hepatitis С virus, human immunodeficiency virus, human papillomaviruses, coronaviruses, and respiratory syncytial virus is discussed. The presented material highlights the promise held by the search for heterocyclic antiviral compounds that act by inhibition of viroporins.
An iodine/DMSO catalyzed selective cyclization of N-tosylhydrazones with sulfur without adding external oxidant was developed for the synthesis of 4-aryl-1,2,3-thiadiazoles. In this reaction, oxidation of HI by using DMSO as dual oxidant and solvent is the key, which allowed the regeneration of I2, ensuring thus the success of the synthesis. This protocol features by simple operation, high step-economy (one-pot fashion), broad substrate scope as well as scale-up ability.
Photolysis is one of the main transformation pathways for 2,4,6-trinitrotoluene (TNT) released into the environment. Upon exposure to sunlight, TNT is known to undergo both oxidation and reduction reactions with release of nitrite, nitrate, and ammonium ions, followed by condensation reactions of the oxidation and reduction products. In this study, compound classes of transformation products from the aqueous and solid phase photodegradation of 2,4,6-trinitrotoluene (TNT) have been identified by liquid and solid state 13C and 15N NMR. Aqueous phase experiments were performed on saturated solutions of T15NT in deionized water, natural pond water (pH = 8.3, DOC = 3.0 mg/L), pH 8.0 buffer solution, and in the presence of Suwannee River Natural Organic Matter (SRNOM; pH = 3.7), using a Pyrex-filtered medium pressure mercury lamp. Natural sunlight irradiations were performed on TNT in the solid phase and dissolved in the pond water. In deionized water, carboxylic acid, aldehyde, aromatic amine, primary amide, azoxy, nitrosophenol, and azo compounds were formed. 15N NMR spectra exhibited major peaks centered at 128 to 138 ppm, which are in the range of phenylhydroxylamine and secondary amide nitrogens. The secondary amides are proposed to represent benzanilides, which would arise from photochemical rearrangement of nitrones formed from the condensation of benzaldehyde and phenylhydroxylamine derivatives of TNT. The same compound classes were formed from sunlight irradiation of TNT in the solid phase. Whereas carboxylic acids, aldehydes, aromatic amines, phenylhydroxylamines, and amides were also formed from irradiation of TNT in pond water and in pH 8 buffer solution, azoxy and azo compound formation was inhibited. Solid state 15N NMR spectra of photolysates from the lamp irradiation of unlabeled 2,6-dinitrotoluene in deionized water also demonstrated the formation of aromatic amine, phenylhydroxylamine/ 2° amide, azoxy, and azo nitrogens.
In this study, we successfully explored the effect of steric hindrance on the one-pot reaction of different aryl aldehydes with malononitrile and N-substituted 2-cyanoacetamide in the presence of piperidinium acetate as the catalyst. It involved the Knoevenagel condensation of the aldehyde and malononitrile to produce arylidene malononitrile as an intermediate, which was further treated with N-substituted 2-cyanoacetamide to give 6-amino-2-pyridone-3,5-dicarbonitrile derivatives when the less steric bulky group was involved. High steric hindrance changed the earlier reaction route and gave N-substituted 2-cyanoacrylamides via a slower route.
This review focuses on the intramolecular cyclization of molecules through C–O, C–N and C–S bonds forming C–H functionalizations with an emphasis on the literature after 2000. Intramolecular C–H functionalization reactions attract much interest because of the ease of reaction due to the proximity of reacting centers and favorable entropy over intermolecular reactions. Less by-product formation, high atom economy, ease of purification, and avoidance of prefunctionalization of substrates are the additional advantages. Hence, a number of research articles have been published in this field, but no review is available so far. This review includes the synthesis of various heterocycles involving C–O, C–N and C–S bond creation. This is the first review on the current topic which will motivate the readers to work in this area further.
Herein, we established a straightforward synthetic route for biological relevant [1,2,4]triazolo[5,1‐b]quinazolin‐8(4H)one scaffolds using the group‐assisted purification (GAP) chemistry via one‐pot and three component reaction of 3‐Amino‐5‐methylthio‐1H‐1,2,4‐triazole (1), Aryl aldehyde(2 a–g), and 1,3‐cyclodione (3 a–b) using L‐proline and aqueous ethanol (1:1, v/v) as green catalyst and reaction media respectively. This work shows some key features such as practical low Environment factor (E‐factor) values, excellent atom economy, reaction mass efficiency, mild reaction condition, metal‐free synthesis, and no use of column chromatography. In preliminary biological screening, the compounds, 2‐(methylthio)‐9‐(4‐nitrophenyl)‐5,6,7,9‐tetrahydro‐[1,2,4]triazolo[5,1‐b]quinazolin‐8(4H)‐one (4 i) and 6,6‐dimethyl‐2‐(methylthio)‐9‐(pyridin‐4‐yl)‐5,6,7,9‐tetrahydro‐[1,2,4]triazolo[5,1‐b]quinazolin‐8(4H)‐one (4 l) were found most potent against Gram‐negative bacteria (E. coli) than the standard drugs ampicillin and chloramphenicol. Moreover, compounds 2‐(methylthio)‐9‐phenyl‐5,6,7,9‐tetrahydro‐[1,2,4]triazolo[5,1‐b]quinazolin‐8(4H)‐one (4 a) and 9‐(4‐methoxyphenyl)‐6,6‐dimethyl‐2‐(methylthio)‐5,6,7,9‐tetrahydro‐[1,2,4]triazolo[5,1‐b]quinazolin‐8(4H)‐one (4 f) exhibited excellent potency in comparison with the standard drugs ampicillin, chloramphenicol, and ciprofloxacin against Gram‐positive bacteria (S. aeruginosa and S. pneumoniae). In antifungal screening compounds, 9‐(4‐methoxyphenyl)‐2‐(methylthio)‐5,6,7,9‐tetrahydro‐[1,2,4]triazolo[5,1‐b]quinazolin‐8(4H)‐one (4 e) and 2‐(methylthio)‐9‐(4‐nitrophenyl)‐5,6,7,9‐tetrahydro‐[1,2,4]triazolo[5,1‐b]quinazolin‐8(4H)‐one (4 i) efficiently inhibited C. albicans fungi strain than that of standard drug griseofulvin. Noteworthy compounds 6,6‐dimethyl‐2‐(methylthio)‐9‐phenyl‐5,6,7,9‐tetrahydro‐[1,2,4]triazolo[5,1‐b]quinazolin‐8(4H)‐one (4 b), 9‐(4‐chlorophenyl)‐6,6‐dimethyl‐2‐(methylthio)‐5,6,7,9‐tetrahydro‐[1,2,4]triazolo[5,1‐b]quinazolin‐8(4H)‐one (4 d), and 2‐(methylthio)‐9‐(pyridin‐4‐yl)‐5,6,7,9‐tetrahydro‐[1,2,4]triazolo[5,1‐b]quinazolin‐8(4H)‐one (4 k) were exhibited better potency against M. Tuberculosis.
Herein our team explored a promising synthetic trail to Functionalized pyrazolodihydropyridine core using hydroxyl alkyl ammonium ionic liquid via one-pot fusion of 3-methyl-1-phenyl-1H-pyrazole-5-amine, different heterocyclic aldehydes and 1, 3-Cyclic diones. The aimed compounds were obtained by Domino-Knoevenagel condensation and Michael addition followed by cyclization. The reaction transformation involves the formation of two C–C and one C–N bond formation. The perspective of the present work is selectively approached to Functionalized pyrazolodihydropyridine core excluding other potential parallel reactions under environmentally benign reaction condition. The present protocol show features such as the low E-factor, ambiphilic behavior of ionic liquid during reaction transformation, scale-up to a multigram scale, reusability of the ionic liquid, mild reaction condition, and produce water as a byproduct. All newly derived compounds were evaluated for their in vitro biological activities. In preliminary biological studies compound, 4c showed better potency than the standard drug ampicillin against Gram-negative bacteria (E. coli); the compound 4i exhibited outstanding activity against S. aeruginosa which is far better than ampicillin, chloramphenicol, and ciprofloxacin. The compound 4m was found more potent against C. albicans, than that of griseofulvin and show equipotency to nystatin whereas, in preliminary antitubercular screening, compound 4o was exhibited more potency than rifampicin. Noteworthy compounds 4f and 4i were found most active in antiproliferative screening.
Background:
Dinaciclib is a potent inhibitor of cell cycle and transcriptional cyclin-dependent kinases. This Phase 1 study evaluated the safety, tolerability and pharmacokinetics of various dosing schedules of dinaciclib in advanced solid tumour patients and assessed Pharmacodynamic and preliminary anti-tumour activity.
Methods:
In part 1, patients were enrolled in escalating cohorts of 2-h infusions administered once every 3 weeks, utilising an accelerated titration design until a recommended phase 2 dose (RP2D) was defined. In part 2, 8- and 24-h infusions were evaluated. Pharmacokinetic parameters were determined for all schedules. Pharmacodynamic effects were assessed with an ex vivo stimulated lymphocyte proliferation assay performed in whole blood.Effects of dinaciclib on retinoblastoma (Rb) phosphorylation and other CDK targets were evaluated in skin and tumour biopsies. In addition to tumour size, metabolic response was evaluated by 18F-fluorodeoxyglucose-positron emission tomography.
Results:
Sixty-one patients were enrolled to parts 1 and 2. The RP2Ds were 50, 7.4 and 10.4 mg m(-2) as 2- 8- and 24-hour infusions, respectively. Dose-limiting toxicities included pancytopenia, neutropenic fever, elevated transaminases, hyperuricemia and hypotension. Pharmacokinetics demonstrated rapid distribution and a short plasma half-life. Dinaciclib suppressed proliferation of stimulated lymphocytes. In skin and tumour biopsies, dinaciclib reduced Rb phosphorylation at CDK2 phospho-sites and modulated expression of cyclin D1 and p53, suggestive of CDK9 inhibition. Although there were no RECIST responses, eight patients had prolonged stable disease and received between 6 and 30 cycles. Early metabolic responses occurred.
Conclusions:
Dinaciclib is tolerable at doses demonstrating target engagement in surrogate and tumour tissue.British Journal of Cancer advance online publication, 31 August 2017; doi:10.1038/bjc.2017.288 www.bjcancer.com.
Accumulating evidence indicates that CDK2 promotes hyperproliferation and is associated to poor prognosis in multiple cancer cells. However, the physiological role of CDK2 in GBM and the biological mechanism still remains unclear. In this study, we identified that CDK2 expression was significantly enriched in GBM tumors compared with normal brain. Additionally, CDK2 was functionally required for tumor proliferation and its expression was associated to poor prognosis in GBM patients. Mechanically, CDK2 induced radio resistance in GBM cells and CDK2 knock down increased cell apoptosis when combined with radiotherapy. Therapeutically, we found that CDK2 inhibitor attenuated tumor growth both in vitro and in vivo. Collectively, CDK2 promotes proliferation, induces radio resistance in GBM, and could become a therapeutic target for GBM.
A series of new 4-thiazolidinone derivatives was synthesized, characterized by spectral techniques, and screened for antimicrobial activity. All the compounds were evaluated against five Gram-positive bacteria, two Gram-negative bacteria, and two fungi, at concentrations of 50, 100, 200, 400, 800, and 1600
µ
g/mL, respectively. Minimum inhibitory concentrations of all the compounds were also determined and were found to be in the range of 100–400
µ
g/mL. All the compounds showed moderate-to-good antimicrobial activity. Compounds
4a
[2-(4-fluoro-phenyl)-3-(4-methyl-5,6,7,8-tetrahydro-quinazolin-2-yl)-thiazolidin-4-one] and
4e
[3-(4,6-dimethyl-pyrimidin-2-yl)-2-(2-methoxy-phenyl)-thiazolidin-4-one] were the most potent compounds of the series, exhibiting marked antimicrobial activity against
Pseudomonas fluorescens
,
Staphylococcus aureus,
and the fungal strains. Thus, on the basis of results obtained, it may be concluded that synthesized compounds exhibit a broad spectrum of antimicrobial activity.
The characterization of interactions in protein-ligand complexes is essential for research in structural bioinformatics, drug discovery and biology. However, comprehensive tools are not freely available to the research community. Here, we present the protein-ligand interaction profiler (PLIP), a novel web service for fully automated detection and visualization of relevant non-covalent protein-ligand contacts in 3D structures, freely available at projects.biotec.tu-dresden.de/plip-web. The input is either a Protein Data Bank structure, a protein or ligand name, or a custom protein-ligand complex (e.g. from docking). In contrast to other tools, the rule-based PLIP algorithm does not require any structure preparation. It returns a list of detected interactions on single atom level, covering seven interaction types (hydrogen bonds, hydrophobic contacts, pi-stacking, pi-cation interactions, salt bridges, water bridges and halogen bonds). PLIP stands out by offering publication-ready images, PyMOL session files to generate custom images and parsable result files to facilitate successive data processing. The full python source code is available for download on the website. PLIP's command-line mode allows for high-throughput interaction profiling.
© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.
Introduction:
The molecular mechanics energies combined with the Poisson-Boltzmann or generalized Born and surface area continuum solvation (MM/PBSA and MM/GBSA) methods are popular approaches to estimate the free energy of the binding of small ligands to biological macromolecules. They are typically based on molecular dynamics simulations of the receptor-ligand complex and are therefore intermediate in both accuracy and computational effort between empirical scoring and strict alchemical perturbation methods. They have been applied to a large number of systems with varying success.
Areas covered:
The authors review the use of MM/PBSA and MM/GBSA methods to calculate ligand-binding affinities, with an emphasis on calibration, testing and validation, as well as attempts to improve the methods, rather than on specific applications.
Expert opinion:
MM/PBSA and MM/GBSA are attractive approaches owing to their modular nature and that they do not require calculations on a training set. They have been used successfully to reproduce and rationalize experimental findings and to improve the results of virtual screening and docking. However, they contain several crude and questionable approximations, for example, the lack of conformational entropy and information about the number and free energy of water molecules in the binding site. Moreover, there are many variants of the method and their performance varies strongly with the tested system. Likewise, most attempts to ameliorate the methods with more accurate approaches, for example, quantum-mechanical calculations, polarizable force fields or improved solvation have deteriorated the results.
In this research, a green, easy, and effective solvent-free procedure for the synthesis of heterocyclic fullerene derivatives has been achieved via 1,3-dipolar cycloaddition reaction of C60, substituted arylhydrazones/oximes, and PhI(OAc)2 under grinding as a simple physical-mechanical method. This approach does not involve any hazardous organic solvent and has various advantages including design of safe reaction conditions moderate to good yields and short reaction times.
Background:
AT7519 is a small-molecular inhibitor of multiple cyclin-dependent kinases (CDKs). It shows encouraging anti-cancer activity against multiple cell lines and in tumour xenografts. This phase I study was conducted to evaluate the safety and tolerability of AT7519 given as 1-h intravenous infusion on days 1, 4, 8 and 11 every 3 weeks.
Methods:
Patients with advanced refractory solid tumours or non-Hodgkin's lymphoma were enroled. Dose escalation occurred in a 3+3 manner based on toxicity assessment. Pharmacokinetic samples were collected after first AT7519 infusion, whereas pharmacodynamics (PD) samples were obtained in selected patients.
Results:
Thirty-four patients were enroled, and 32 received study treatments over 4 dose levels. Dose-limiting toxicities included mucositis, febrile neutropenia, rash, fatigue and hypokalemia. The recommended phase II dose (RP2D) was 27.0 mg m(-2). Ten of 19 patients evaluable for efficacy had stable disease as the best response (median duration: 3.3 months; range: 2.5 to 11.1 months). There was no clinically significant QTc prolongation. There was an apparent dose proportional increase in AT7519 exposure. The PD studies showed reduction in markers of CDK activity in selected patients' skin biopsies post treatment.
Conclusions:
AT7519, when administered as an intravenous infusion on days 1, 4, 8 and 11, was well tolerated. The RP2D is 27.0 mg m(-2). At this dose level, plasma AT7519 concentrations were above the biologically active concentrations, and preliminary anti-cancer activity was observed in patients. This dosing schedule is being further evaluated in multiple phase II studies.
In the early 2000s, the anticancer drug imatinib (Glivec®) appeared on the market, exhibiting a new mode of action by selective kinase inhibition. Consequently, kinases became a validated therapeutic target, paving the way for further developments. Although these kinases have been thoroughly studied, none of the compounds commercialized since then target cyclin-dependent kinases (CDKs). Following a recent and
detailed review on the subject by Galons et al., we concentrate our attention on an updated list of compounds under clinical evaluation (phase I/II/III) and discuss their mode of action as ATP-competitive inhibitors. CDK inhibition profiles and clinical development stages are reported for the 14 compounds under clinical evaluation. Also, tentative progress for forthcoming potential ATP non-competitive inhibitors and allosteric inhibitors are briefly described, along with their limitations.
A variety of DNA-binding proteins regulate DNA transactions including DNA replication and DNA damage response. To initiate DNA replication in S phase of the cell cycle, numerous replication proteins must be recruited to the replication origin in order to unwind and synthesize DNA. Some replication factors stay at the origin, while replisome components move with the replication fork. When the replisome encounters DNA damage or other issues during DNA replication, the replication fork stalls and accumulates single-stranded DNA that triggers the ATR-dependent replication checkpoint, in order to slow down S phase and arrest the cell cycle at the G2-M transition. It is also possible that replication forks collapse, leading to double-strand breaks that recruit various DNA damage response proteins to activate cell cycle checkpoints and DNA repair pathways. Therefore, defining the localization of DNA transaction factors during the cell cycle should provide important insights into mechanistic understanding of DNA replication and its related processes. In this chapter, we describe a chromatin immunoprecipitation method to locate replisome components at replication origins in human cells.
Non classical methods (water based reaction, microwave and grindstone chemistry) were used for the preparation of Schiff bases from 3-chloro-4-fluoro aniline and several benzaldehydes. The key raw materials were allowed to react in water, under microwave irradiation and grindstone. These methodologies constitute an energy-efficient and environmentally benign greener chemistry version of the classical condensation reactions for Schiff bases formation.
A series of 5-{[(6-substituted-2-hydroxyquinolin-3-yl)methylidene]/5-[(7-substitutedtetrazolo[1,5-a]quinoline-4-yl)methylidene]}-2-[(4-substitutedphenyl)amino]-1,3-thiazol-4(5H)-one was successfully synthesized under solvent free conditions by microwave irradiation in high yield. Structures of these newly synthesized compounds were established on the basis of spectral and analytical data. These novel compounds were also evaluated for their in vitro antioxidant, antibacterial and antifungal activity.
A divergent route for the synthesis of new derivatives of 4,11-diaminoanthra[2,3-b]thiophene-5,10-dione was developed based on the introduction of cyclic amines to the terminal positions of 4,11-aminoalkyl groups. Modification of the side chains of anthra[2,3-b]thiophene-5,10-dione increases the affinity of ligands to DNA duplex and decreases the affinity to G-quadruplexes. An analysis of the structure–activity relationship showed that 2-(piperidin-1-yl)ethylamine is the most promising side chain fragment for the development of new double-stranded DNA ligands. The ability of new ligands to bind to DNA duplex correlates with inhibition of tumor cell growth, which indicates the prospects for a further search for new antitumor compounds or chemical probes for duplex-forming nucleic acid sequences among 4,11-diaminoanthra[2,3-b]thiophene-5,10-diones.
The review is devoted to the methods of synthesis of furan, pyran, and thiazole derivatives employing aryltellurium trihalides published in 1983–2019.
The cyclin-dependent kinase-2 (CDK2) belongs to the protein kinase family and its overexpression leads to an unusual regulation of cell-cycle which directly linked with hyperproliferation in many cancer cell types. CDK2 activation spontaneously promotes the cell cycle progression and also involved in a large number of cellular processes including cell cycle regulation, DNA replication, DNA damage response and apoptotic pathways, therefore targeting the CDK2 can be reemerged as a therapeutic boulevard to restrain cancer cell proliferation. For the last two decades, emerging evidence suggested that CDK2 inhibition draws out some antitumor/anticancer activity, which has driven the research possibility for developing next-generation newer or cost-effective inhibitors with greater specificity to CDK2. In the current work, compounds from the FooDB - a world's largest food constituents database was retrieved and curated and followed by multi-pharmacoinformatics approaches adopted to find out potential CDK2 inhibitors. The curated dataset was considered for “Virtual Screening Workflow” (VSW) employed in Schrödinger suite. The numbers of cost-effective food constituents were reduced by removing low potential molecules in terms of interaction affinity and further explored for pharmacokinetics analysis. Based on strong binding interaction profiles with the lowest binding interactions affinity and energy values, four food compounds were proposed as CDK2 inhibitors. A number of key analyzing parameters from MD simulations studies were successfully substantiated that all four proposed food compounds can act as CDK2 inhibitors based on their proficient structural and molecular interactions integrity with CDK2 protein following in the active site cavity. Furthermore, the binding free energy was calculated using the MM-PBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) approach from the entire trajectory frames derived in MD simulation revealed strong interaction affinity. The binding free energy was found to be in the range of −991.831 to −210.452 kJ/mol. High binding free energy was undoubtedly explained that all molecules possess strong affection towards CDK2. Hence, proposed molecules may be crucial to stop the hyperproliferation in cancer cells subjected to experimental validation.
Cyclin-dependent kinase 2 (CDK2) plays a pivotal part in cell cycle regulation and is involved in a range of biological processes. CDK2 interacts with and phosphorylates proteins in pathways such as DNA damage, intracellular transport, protein degradation, signal transduction, DNA and RNA metabolism and translation. CDK2 and its regulatory subunits are deregulated in many human cancers and there is emerging evidence suggesting CDK2 inhibition elicits antitumor activity in a subset of tumors with defined genetic features. Previous CDK2 inhibitors were nonspecific and limited by off-target effects. The development of new-generation CDK2 inhibitors represents a therapeutic opportunity for CDK2-dependent cancers.
An efficient and rapid synthesis of new heterocyclic compounds via reactions of 1,3-diphenyl-1H-pyrazole-4-carbaldehyde thiosemicarbazone with some carbon electrophiles, namely dimethyl acetylenedicar-boxylate, maleic anhydride, and ω-bromoacetophenone, under microwave irradiation has been developed. The structure of the synthesized compounds was confirmed by their analytical and spectral data.
The anthrazolinic core is an important building block for several applications, especially those depending on the effect of light. The synthesis of these compounds evolved much since the first work published based on this diazaheterocycle. Nowadays, methods such as Friedlander reactions and more efficiently multi-component reactions provide faster and less expensive access to these polycyclic structures. Here we show an overview of the evolution in the synthesis and application of these compounds.
Nowadays, synthesis of novel nitrogen-bearing heterocyclic scaffolds is a challenging and demanding task as well. In our present work, we demonstrated a novel one-pot pseudo four-component reaction of 3,4-methylenedioxyaniline, N,N-dimethylbarbituric acid, and aryl/heteroaryl aldehyde for the regioselective construction of functionalized 6,8-dihydro-1'H,5H-spiro[[1,3]dioxolo[4,5-g]quinoline-7,5'-pyrimidine]-2',4',6' (3'H)-trione scaffolds using trimethyl glycine betaine based sustainable catalyst. The titled derivatives achieved through the formation of three new C-C bonds, one C-N bond, and generate two asymmetric carbon centers in final motif. Present protocol works efficiently, tolerate different substituents present in reactants, simple operational procedure, provide excellent reaction yield in short time, use of recyclable catalyst, up to 99.7% purity (HPLC) for the synthesized compounds, high diastereoselectivity (d.r.>50:1(syn:anti)), excellent Atom economy, Reaction mass efficiency, and Effective mass yield.
With renewed interest in free energy methods in contemporary structure-based drug design, there is a pressing need to validate against multiple targets and force fields to assess the overall ability of these methods to accurately predict relative binding free energies. We computed relative binding free energies using graphics processing unit accelerated thermodynamic integration (GPU-TI) on a data set originally assembled by Schrödinger, Inc. Using their GPU free energy code (FEP+) and the OPLS2.1 force field combined with the REST2 enhanced sampling approach, these authors obtained an overall MUE of 0.9 kcal/mol and an overall RMSD of 1.14 kcal/mol. In our study using GPU-TI from AMBER with the AMBER14SB/GAFF1.8 force field but without enhanced sampling, we obtained an overall MUE of 1.17 kcal/mol and an overall RMSD of 1.50 kcal/mol for the 330 perturbations contained in this data set. A more detailed analysis of our results suggested that the observed differences between the two studies arise from differences in sampling protocols along with differences in the force fields employed. Future work should address the problem of establishing benchmark quality results with robust statistical error bars obtained through multiple independent runs and enhanced sampling, which is possible with the GPU-accelerated features in AMBER.
Firstly, triarylmethanes bearing formyl groups (TRAM-CHOs) have been synthesized by the reaction of arenes with aromatic dialdehydes catalyzed by sulfuric acid immobilized on SiO 2 under solvent-free grinding conditions in good yields and short grinding time. Secondly, condensation of TRAM-CHOs with several arenes proceeded rapidly within a few minutes to afford the new corresponding mixed-bistriarylmethanes in excellent yields. TRAM-CHOs were also found to be valuable precursors for the Biginelli reaction to synthesize a variety of 3,4-dihydropyrimidin-2(1H)-one-triarylmethane hybrid derivatives. © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.
Different series of novel pyrazole and pyrazolo[1,5-a] pyrimidine derivatives (2a-g), (3a-c), (7a-d) and (10a-e) were designed, synthesized and evaluated for their ability to inhibit CDK2/cyclin A2 enzyme in vitro. In addition, the cytotoxicity of the newly synthesized compounds was screened against four different human cancer cell lines. The CDK2/cyclin A2 enzyme inhibitory activity revealed that compounds (2d) and (2 g) are among the most active with inhibitory activity values of 60% and 40%, respectively, while compounds (7d) and (10b) exhibited the highest activity among the newly synthesized derivatives against four tumor cell lines (HepG2, MCF-7, A549 and Caco2) with IC50 values 24.24, 14.12, 30.03 and 29.27 μM and 17.12, 10.05, 29.95 and 25.24 μM, respectively. Flow cytometry cell cycle assay was carried for compounds (7d) and (10b) to investigate their apoptotic activity. The obtained results revealed that they induced cell-cycle arrest in the G0-G1phase and reinforced apoptotic DNA fragmentation. Molecular modeling studies have been carried out to gain further understanding the binding mode of the target compounds together with field alignment to define the similar field properties.
In this study, we explored the catalyst‐free one‐pot multi‐component synthesis of 1,4‐dihydropyridine derivatives by following green chemistry protocol. The present approach shows the significant outcomes such as yield up to 94%, catalyst‐free reaction, easy workup procedure and shorter period of reaction time. In this work we also highlighted the comparison of the yields obtained under both neat and solvent media as well. The anti‐proliferative activity of all newly synthesized compounds has been assessed against six human solid tumor cell lines. Seven compounds show good activity against single cell line whereas, compounds having a pyridine scaffold showed significant anti‐proliferative activity. An expedient synthesis of 1,4‐dihydropyridines (DHPs) and pyridines under catalyst‐free condition is explored with excellent reaction yield up to 94%. All newly synthesized compounds were screened for anti‐proliferative activity against different human tumor cell lines. The remarkable results on yield, process, development of DHPs, anti‐proliferative activity, structure determination and single crystal study of DHPs discussed in this article.
An efficient and green strategy is developed to synthesize 2‐amino‐2‐oxospiro [indoline‐3, 4′‐pyran]‐3′‐carbonitriles. The method encompasses a domino multicomponent reaction using isatin or acetanaphthelenequinone, malononitrile or ethylcyanoacetate and enolizable 1, 3‐dicarbonyl compounds without any promoter and catalyst in one pot through hand grinding in excellent yields within minutes.
Aim:
This study aims the potential gene involved in the metastasis of prostate cancer (Pca).
Methods:
PubMed GEO datasets (GSE6605 and GSE6606) were downloaded. We used multiple bioinformatics methods to screen differentially expressed genes in Pca. Gene network was built by STRING and visualized by Cytoscape. All of the hub genes were analyzed by cBioPortal. Inhibition of CDK2 including siRNA, inhibitor and cas9-induced CDK2 knockout was followed by an invasion assay. Downstream genes of CDK2 were analyzed by western blot.
Results:
Sequencing data were analyzed to screen the genes with expression alterations. The top genes were validated in our samples. 11 hub genes were screened out. Among these genes, STAT3 and CDK2 were significantly associated with recurrence. Further study suggested that inhibition of CDK2 reduced invasion of Pca cell lines. The invasion ability was rescued after reintroduction of CDK2.
Conclusion:
These data indicated that CDK2 was a crucial factor in metastasis of Pca and might be a novel therapy target. [Formula: see text].
A fast analytical formula was derived for the calculation of approximate atomic and molecular van der Waals (vdWSA), and solvent-accessible surface areas (SASAs), as well as the first and second derivatives of these quantities with respect to atomic coordinates. This method makes use of linear combinations of terms composed from pairwise overlaps of hard spheres; therefore, we term this the LCPO method for linear combination of pairwise overlaps. For higher performance, neighbor-list reduction (NLR) was applied as a preprocessing step. Eighteen compounds of different sizes (8–2366 atoms) and classes (organic, proteins, DNA, and various complexes) were chosen as representative test cases. LCPO/NLR computed the SASA and first derivatives of penicillopepsin, a protein with 2366 atoms, in 0.87 s (0.22 s for the creation of the neighbor list, 0.35 s for NLR, and 0.30 s for SASA and first derivatives) on an SGI R10000/194 Mhz processor. This appears comparable to or better than timings reported previously for other algorithms. The vdWSAs were in good agreement with the numerical results: relative errors for total molecular surface areas ranged from 0.1 to 2.0% and average absolute atomic surface area deviations from 0.3 to 0.7 Ų. For SASAs without NLR, the LCPO method exhibited relative errors in the range of 0.4–9.2% for total molecular surface areas and average absolute atomic surface area deviations of 2.0–2.7 Ų; with NLR the relative molecular errors ranged from 0.1 to 7.8% and the average absolute atomic surface area deviation from 1.6 to 3.0 Ų. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 217–230, 1999
In the current study, a series of 2,4-disubstituted-1,3-thiazoles linked with pyrazoline scaffolds 3a-o were rationally designed and synthesized. The structures of the title compounds were elucidated by spectroscopic data (UV–Vis, IR, NMR and Mass spectra) and elemental analysis. Single crystal X-Ray diffraction studies revealed that, the compounds 3i and 3k crystallized in monoclinic crystal system with P21/n space group and Z = 4. The molecules 3i and 3k were connected with intermolecular hydrogen bonds N2—H2 … O1, N3[sbnd]H3 … Cl1 and short contacts (C[sbnd]H … π and C[sbnd]Cl … π). Intramolecular hydrogen bonds, N3[sbnd]H3 … N5 and C5[sbnd]H5 ….N1 were also existed. The compounds were evaluated for their anticancer activity against A549 and MCF-7 human cancer cell lines and in vitro antimicrobial activity against pathogenic microbial strains. The compounds bearing chloro atom at the para position of phenyl ring A like 3f, 3j and 3k with the IC50: 7.5, 5.0 and 5.0 μM respectively, exhibited better activity than standard drug Cisplatin (IC50: 10.0 μM). In addition, the compounds 3a, 3f, 3j and 3l have exhibited the similar antimicrobial activity as that of standard drug Ciprofloxacin and Fluconazole. Furthermore, to support the biological potency of the compounds, in silico molecular docking studies were carried out against the E. coli MurB (PDB code: 2MBR) and Jnk1 inhibitor (PDB code: 3v3v) enzymes. The various types of interactions between the compounds and amino acid residue of enzymes were also reported.
Background:
This phase I trial evaluated the safety and tolerability of milciclib, an inhibitor of multiple cyclin-dependent kinases and tropomycin receptor kinase A, in combination with gemcitabine in patients with refractory solid tumors.
Design:
Sixteen patients were enrolled and treated with milciclib at three dose levels (45 mg/m(2)/day, n = 3; 60 mg/m(2)/day, n = 3; and 80 mg/m(2)/day, n = 10) with a fixed dose of gemcitabine (1000 mg/m(2)/day). Milciclib was administered orally once daily for 7 days on/7 days off in a 4-week cycle, and gemcitabine was administered intravenously on days 1, 8 and 15 in a 4-week cycle.
Results:
All 16 enrolled patients were evaluable for safety and toxicity. Dose-limiting toxicities, which occurred in only one out of nine patients treated at the maximum dose tested (milciclib 80 mg/m(2)/day and gemcitabine 1000 mg/m(2)/day), consisted of Grade 4 thrombocytopenia, Grade 3 ataxia and Grade 2 tremors in the same patient. Most frequent treatment-related AEs were neutropenia and thrombocytopenia. Among 14 evaluable patients, one NSCLC patient showed partial response and 4 patients (one each with thyroid, prostatic, pancreatic carcinoma and peritoneal mesothelioma) showed long-term disease stabilization (>6-14 months). Pharmacokinetics of the orally administered milciclib (~t1/2 33 h) was not altered by concomitant treatment with gemcitabine.
Conclusion:
The combination treatment was well tolerated with manageable toxicities. The recommended phase II dose was 80 mg/m(2)/day for milciclib and 1000 mg/m(2)/day for gemcitabine. This combination treatment regimen showed encouraging clinical benefit in ~36% patients, including gemcitabine refractory patients. These results support further development of combination therapies with milciclib in advanced cancer patients.
Eluding the involvement of solvents in organic synthesis and introducing environment friendly procedures can control environmental problems. A facile and an efficient solvent free mechanochemical method (grinding) is achieved to synthesize novel bis-biphenyl substituted thiazolidinones using non-toxic and cheap N-acetyl glycine (NAG). Organocatalytic condensation of a series of Schiff's bases bearing different substituents with thioglycolic acid produces a variety of thiazolidinones derivatives in good to excellent yield. In vitro inhibition studies against mushroom tyrosinase of these thiazolidinone analogues revealed that many of them possessed good to excellent tyrosinase inhibition at low micro-molar concentrations. In particular, six compounds exhibited potent inhibitory potential with IC50 values ranging from 0.61 ± 0.31 to 21.61 ± 0.11 μM as compared with that of standard kojic acid (IC50 6.04 ± 0.11 μM). Further molecular docking studies revealed that the thiazolidinones moiety plays a key role in the inhibition mechanism by well fitting into the enzyme bounding pocket.
Background: The first generation CDK2/7/9 inhibitor seliciclib (CYC202) causes multipolar anaphase and apoptosis in lung cancer cells with supernumerary centrosomes (known as anaphase catastrophe). We investigated a new and potent CDK2/9 inhibitor, CCT68127 (Cyclacel).
Methods: CCT68127 was studied in lung cancer cells (three murine and five human) and control murine pulmonary epithelial and human immortalized bronchial epithelial cells. Robotic CCT68127 cell-based proliferation screens were used. Cells undergoing multipolar anaphase and inhibited centrosome clustering were scored. Reverse phase protein arrays (RPPAs) assessed CCT68127 effects on signaling pathways. The function of PEA15, a growth regulator highlighted by RPPAs, was analyzed. Syngeneic murine lung cancer xenografts (n = 4/group) determined CCT68127 effects on tumorigenicity and circulating tumor cell levels. All statistical tests were two-sided.
Results: CCT68127 inhibited growth up to 88.5% (SD = 6.4%, P < .003) at 1 μM, induced apoptosis up to 42.6% (SD = 5.5%, P < .001) at 2 μM, and caused G1 or G2/M arrest in lung cancer cells with minimal effects on control cells (growth inhibition at 1 μM: 10.6%, SD = 3.6%, P = .32; apoptosis at 2 μM: 8.2%, SD = 1.0%, P = .22). A robotic screen found that lung cancer cells with KRAS mutation were particularly sensitive to CCT68127 (P = .02 for IC50). CCT68127 inhibited supernumerary centrosome clustering and caused anaphase catastrophe by 14.1% (SD = 3.6%, P < .009 at 1 μM). CCT68127 reduced PEA15 phosphorylation by 70% (SD = 3.0%, P = .003). The gain of PEA15 expression antagonized and its loss enhanced CCT68127-mediated growth inhibition. CCT68127 reduced lung cancer growth in vivo (P < .001) and circulating tumor cells (P = .004). Findings were confirmed with another CDK2/9 inhibitor, CYC065.
Conclusions: Next-generation CDK2/9 inhibition elicits marked antineoplastic effects in lung cancer via anaphase catastrophe and reduced PEA15 phosphorylation.
The decarboxylative carbon-carbon bond formation reaction of β-ketoacid derivatives with isatylidene malononitrile derivatives catalyzed by DBU affords adducts in excellent yield. The desired product can be easily isolated using simple filtration method without performing any column chromatography. The decarboxylative adduct was further subjected to reductive-cyclization to obtain biologically important spirooxindoles in 89% yield.
Here we report the discovery of a selective inhibitor of Aurora A, a key regulator of cell division and potential anti-cancer target. We used atom category extended ligand overlap score (xLOS), a 3D ligand based virtual screening method recently developed in our group, to select 437 shape and pharmacophore analogs of reference kinase inhibitors. Biochemical screening uncovered two inhibitor series with scaffolds unprecedented among kinase inhibitors. One of them was successfully optimized by structure-based design to a potent Aurora A inhibitor (IC50 = 2 nM) with very high kinome selectivity for Aurora kinases. This inhibitor locks Aurora A in an inactive conformation and disrupts binding to its activator protein TPX2, which impairs Aurora A localization at the mitotic spindle and induces cell division defects. This phenotype can be rescued by inhibitor-resistant Aurora A mutants. The inhibitor furthermore does not induce Aurora B specific effects in cells.
While there has been an increase in the number of biomolecular computational studies employing graphics processing units (GPU), results describing their use with the molecular dynamics package AMBER with the CUDA implementation are scarce. No information is available comparing MD methodologies pmemd.cuda, pmemd.mpi or sander.mpi, available in AMBER, for generalised Born (GB) simulations or with solvated systems. As part of our current studies with antifreeze proteins (AFP), and for the previous reasons, we present details of our experience comparing performance of MD simulations at varied temperatures between multi-CPU runs using sander.mpi, pmemd.mpi and pmemd.cuda with the AFP from the fish ocean pout (1KDF). We found extremely small differences in total energies between multi-CPU and GPU CUDA implementations of AMBER12 in 1ns production simulations of the solvated system using the TIP3P water model. Additionally, GPU computations achieved typical one order of magnitude speedups when using mixed precision but were similar to CPU speeds when computing with double precision. However, we found that GB calculations were highly sensitive to the choice of initial GB parametrisation regardless of the type of methodology, with substantial differences in total energies.
The features of the chemistry of 4-thiazolidinone and pyrazole/pyrazolines as pharmacologically attractive scaffolds were described in a number of reviews in which the main approaches to the synthesis of mentioned heterocycles and their biological activity were analyzed. However, the pyrazole/pyrazoline-thiazolidine-based hybrids as biologically active compounds is poorly discussed in the context of pharmacophore hybrid approach. Therefore, the purpose of this review is to summarize the data about the synthesis and modification of heterocyclic systems with thiazolidine and pyrazoline or pyrazole fragments in molecules as promising objects of modern bioorganic and medicinal chemistry. The description of biological activity was focused on SAR analysis and mechanistic insights of mentioned hybrids.
Mesoporous MCM-41 supported Schiff base and CuSO4·5H2O shows high catalytic activity in the cyclocondensation of mercaptoacetic acid with imines (or aldehydes and amines) to afford pharmaceutically important thiazolidinone derivatives. The catalytic reactions involving two-components or three-components afforded the desired product in high yields (up to 98% and 99%). Moreover, the catalyst works well with respect to recyclability, giving the product in 85% and 83% yields after recycling six times.
Molecular mechanics is powerful for its speed in atomistic simulations, but an accurate force field is required. The Amber ff99SB force field improved protein secondary structure balance and dynamics from earlier force fields like ff99, but weaknesses in side chain rotamer and backbone secondary structure preferences have been identified. Here, we performed a complete refit of all amino acid side chain dihedral parameters, which had been carried over from ff94. The training set of conformations included multidimensional dihedral scans designed to improve transferability of the parameters. Improvement in all amino acids was obtained as compared to ff99SB. Parameters were also generated for alternate protonation states of ionizable side chains. Average errors in relative energies of pairs of conformations were under 1.0 kcal/mol as compared to QM, reduced 35% from ff99SB. We also took the opportunity to make empirical adjustments to the protein backbone dihedral parameters as compared to ff99SB. Multiple small adjustments of φ and ψ parameters were tested against NMR scalar coupling data and secondary structure content for short peptides. The best results were obtained from a physically motivated adjustment to the φ rotational profile that compensates for lack of ff99SB QM training data in the β-ppII transition region. Together, these backbone and side chain modifications (hereafter called ff14SB) not only better reproduced their benchmarks, but also improved secondary structure content in small peptides and reproduction of NMR χ1 scalar coupling measurements for proteins in solution. We also discuss the Amber ff12SB parameter set, a preliminary version of ff14SB that includes most of its improvements.
We describe PTRAJ and its successor CPPTRAJ, two complementary, portable, and freely available computer programs for the analysis and processing of time series of three-dimensional atomic positions (i.e., coordinate trajectories) and the data therein derived. Common tools include the ability to manipulate the data to convert among trajectory formats, process groups of trajectories generated with ensemble methods (e.g., replica exchange molecular dynamics), image with periodic boundary conditions, create average structures, strip subsets of the system, and perform calculations such as RMS fitting, measuring distances, B-factors, radii of gyration, radial distribution functions, and time correlations, among other actions and analyses. Both the PTRAJ and CPPTRAJ programs and source code are freely available under the GNU General Public License version 3 and are currently distributed within the AmberTools 12 suite of support programs that make up part of the Amber package of computer programs (see http://ambermd.org). This overview describes the general design, features, and history of these two programs, as well as algorithmic improvements and new features available in CPPTRAJ.
Antibiotic resistance has become a problem since the discovery of antibiotics. Not long after
the introduction of penicillin, Staphylococcus aureus, which can be also
transmitted to humans via milk and milk products, began developing penicillin-resistant strains. Therefore,
one approach that has been used for the discovery of new antimicrobial agents from natural sources is based
on the evaluation of traditional plant extracts. Natural products have played a pivotal role in antibiotic
drug innovation and include aminoglycosides, cephalosporins, macrolides, cycloserine, novobiocin, and lipoproteins.
However, only a few antiviral agents are available on the market. To this purpose, we have screened
a great number of herbal extracts along with some pure natural substances and obtained interesting
findings. This chapter covers the results of our rigorous search for new antiviral and antimicrobial alternative
compounds from a number of Turkish plants.
An improved green Knoevenagel condensation of various aromatic aldehydes with 4-thiazolidinones in the
presence of anhydrous ammonium acetate can be achieved by grinding at room temperature in the absence of solvents. This process is simple, efficient, economical, and environmentally benign compared to classical reactions.
New series of 4-methyl and 3,4-dimethyl-7-oxycoumarin derivatives (oxadiazoles, thiadiazoles, triazoles and thiazolidinones) were designed, synthesized and evaluated for their monoamine oxidase (MAO) A and B inhibiting effect. All the synthesized compounds showed in vitro high affinity and selectivity towards MAO-A isoenzyme, compared to clorgyline and moclobemide, with Ki values on the picomolar range. Moreover, most of the tested compounds displayed MAO inhibitory effect when tested in vivo. The docking experiments carried out on MAO-A and MAO-B structures proved new information about the enzyme-inhibitor interaction and the potential therapeutic application of 7-oxycoumarin scaffold.
The synthesis and antitumor activity screening of novel 3-[2-(3,5-diaryl-4,5-dihydropyrazol-1-yl)-4-oxo-4,5-dihydro-1,3-thiazol-5-ylidene]-2,3-dihydro-1H-indol-2-ones 1-23 and 3-(3,5-diarylpyrazol-1-yl)-2,3-dihydro-1H-indol-2-ones 24-39 are performed. In vitro anticancer activity of the synthesized compounds was tested by the National Cancer Institute. Most of them displayed anticancer activity on leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate, and breast cancers cell lines. The structure-activity relationship is discussed. The most effective anticancer compound 10 was found to be active with mean GI(50) and TGI values of 0.071 μM and 0.76 μM, respectively. It demonstrated the highest antiproliferative influence on the non-small-cell lung cancer cell line HOP-92 (GI(50) < 0.01 μM), colon cancer line HCT-116 (GI(50) = 0.018 μM), CNS cancer cell line SNB-75 (GI(50) = 0.0159 μM), ovarian cancer cell line NCI/ADR-RES (GI(50) = 0.0169 μM), and renal cancer cell line RXF 393 (GI(50) = 0.0197 μM).