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![-Scheme of the reaction pathway leading to the formation of adducts between cisplatin (a) and DNA. One chloride ligand is displaced by water to form the aquacomplex [PtCl(H 2 O)(NH 3 ) 2 ] + (b) which interacts with DNA forming the monofunctional adduct [PtCl(DNA)(NH 3 ) 2 ] + (c). This last might exchange the chloride ligand with one molecule of water forming the hydrated monofunctional adduct [Pt(H 2 O)(DNA)(NH 3 ) 2 ] 2+ (d). Both the monofunctional adduct (c) and its hydrated form (d) lead to the formation of the bifunctional adduct [Pt(H 2 O)(DNA)(NH 3 ) 2 ] 2+ (e).](profile/Petr-Vanhara/publication/274142046/figure/fig7/AS:1099393923067905@1639127345463/Scheme-of-the-reaction-pathway-leading-to-the-formation-of-adducts-between-cisplatin-a.png)
-Scheme of the reaction pathway leading to the formation of adducts between cisplatin (a) and DNA. One chloride ligand is displaced by water to form the aquacomplex [PtCl(H 2 O)(NH 3 ) 2 ] + (b) which interacts with DNA forming the monofunctional adduct [PtCl(DNA)(NH 3 ) 2 ] + (c). This last might exchange the chloride ligand with one molecule of water forming the hydrated monofunctional adduct [Pt(H 2 O)(DNA)(NH 3 ) 2 ] 2+ (d). Both the monofunctional adduct (c) and its hydrated form (d) lead to the formation of the bifunctional adduct [Pt(H 2 O)(DNA)(NH 3 ) 2 ] 2+ (e).
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Metal-based coordination compounds have been used throughout the history of human medicine to treat various diseases, including cancer. Since the discovery of cisplatin in 1965, a great number of metal coordination complexes, such as platinum, ruthenium, gold or copper have been designed, synthesized and tested in order to develop clinically effect...
Citations
... [1] The medical community encounters numerous challenges in addressing cancer, especially when it has metastasized. [2] Before 1960, surgery stood as the primary approach, but the advent of radiation therapy brought about a valuable weapon in the battle against cancer. [3] The modern era of chemotherapy emerged when nitrogen mustards were discovered, proving to be effective treatments for metastatic cancer cases that could not be adequately managed through surgery or radiation alone. ...
In this study, we present the re‐synthesis of a series of twelve bis‐ureido‐substituted benzenesulfonamides, focusing on their potential as antibacterial, anticholinesterase, and cytotoxic agents. First, the antibacterial assessment of these compounds indicated varying activity levels across different bacterial strains, with S. aureus displaying resistance to all compounds, while compounds 9 and 11 exhibited promise against E. faecalis with a MIC value of 31.25 μg/mL. Additionally, P. aeruginosa showed resistance to compounds containing 4‐aminobenzene sulfonamides, whereas derivatives such as (8–11) and compound 19 displayed notable activity against E. coli, comparable to Ampicillin. Second, their anticholinesterase activities were examined, with a focus on their potential role in addressing neurological disorders, particularly Alzheimer′s disease. The findings indicated that all synthesized compounds showed a significant inhibitory effect on both AChE and BChE enzymes. Compound 11 demonstrated the most effective inhibition on the AChE enzyme with an IC50 value of 0.2160±0.09 nM, while compound 18 exhibited the most potent inhibition on the BChE enzyme with an IC50 value of 0.2257±0.06 nM. Finally, cytotoxicity studies were conducted across various cell lines, including breast, lung, and prostate cancer cells and normal cells. The results revealed that compound 12 emerged as the most potent tested compound against breast cancer cells with no cytotoxic effect on CRL‐4010 normal breast epithelial cells. The research presented here not only highlights the multifaceted pharmacological potential of bis‐ureido‐substituted benzenesulfonamides, but also indicates their potential as versatile compounds for antibacterial, anticholinesterase, and cytotoxicity applications, opening up new avenues for drug discovery and development.
... Examples of metals with cytotoxicity against tumor cells include platinum (Pt II or Pt IV ), copper (Cu II ), iron (Fe II or Fe III ), gold (Au I or Au III ), ruthenium (Ru II or Ru III ), titanium (Ti IV ), and others. However, water solubility, efficacy, possible adverse effects, and tumor resistance should be considered since they are limiting factors for this class of drugs [117][118][119]. ...
Colorectal cancer (CRC) is the third most common worldwide cancer with high mortality. Factors such as more effective screening programs and improvements in treatment modalities have favored a decrease in the incidence and mortality rate of colorectal cancer in the last three decades. Metastatic CRC is incurable in most cases, and therapy using multiple drugs can increase patients' life expectancy by 2 to 3 years. Chemotherapy is the primary treatment, and fluoropyrimidines correspond to the first treatment line. They can be used in monotherapy or therapeutic schemes of oxaliplatin, FOLFOX (intravenous fluorouracil, leucovorin, and oxaliplatin), and CAPOX (oral capecitabine and oxaliplatin) or regimens based on Irinotecan, such FOLFIRI (fluorouracil, leucovorin, and Irinotecan) and CAPIRI (capecitabine and Irinotecan). Like Camptothecin, irinotecan and other analogs have a mechanism of action based on forming a ternary complex with Topoisomerase I and DNA by reversibly binding, providing DNA damage and consequent cell death. This way, topoisomerases are vital enzymes for DNA maintenance and cell viability. Thus, here we will review the main works demonstrating the correlation between the inhibition of different isoforms of topoisomerases and the in vitro cytotoxic activity in colon cancer. The findings revealed that natural compounds, semi-synthetic and synthetic analogs showed potential cytotoxicity against several colon cancer cell lines in vitro and that this activity was often accompanied by the ability to inhibit type I and II topoisomerases, demonstrating that these enzymes can be promising drug targets for the development of new chemotherapeutics against colon cancer.
... Therefore, this effort has been dedicated to synthesize compounds that have a broad spectrum of action and less toxicity than the known compounds; thereby, metal complexes like those of ruthenium, gold and copper, are promising. 11,12 Among the few metal-nitrosyls being synthesized and evaluated as exogenous NO donors, [13][14][15][16] nitrosyl ruthenium complexes have attained remarkable progress and are recognized as promising exogenous NO donors 8,[17][18][19] that have vasodilation activity. 7,[20][21][22][23] These complexes are also promising antimicrobial agents by aggregating the recognized microbicidal and microbiostatic effects of the nitric oxide (NO). ...
The synthesized complexes, cis-[Ru(NO)(NO2)(phen)2](PF6)2 (NONO2P) and cis-[Ru(NO)(NO2)(bpy)2](PF6)2 (NONO2B), were characterized by using elemental analysis, voltammetry and electronic and vibrational spectroscopy. Under electrochemical and photochemical stimulation in an aqueous medium, there are indications of the formation of complexes, which suggests that the nitro and nitrosyl groups are converted into nitric oxide. Both compounds do not show cytotoxic activity against human umbilical vein endothelial cells (HUVECs). The cis-[Ru(NO)(NO2)(phen)2](PF6)2 complex presented vasorelaxation activity in superior mesenteric arteries from Wistar rats: the biphasic concentration-response curve indicates two sites of action. In the presence of NO scavengers, we observed an impaired relaxing effect induced by NONO2P, suggesting that the vasorelaxant effect is due to NO production from this compound.
... Several other platinumbased compounds have been reported, some of which have gained clinical approval, but they are either less effective or they treat different cancer types [12,13]. These outcomes have encouraged the study of other metal complexes as potential chemotherapeutic agents [14][15][16]. ...
... IR (cm − 1 ): 1455 ν(C--C), 1630 ν(C--N aromatic), 3261 ν(NH). 1 4.02 (q, J HH = 7.0, 2H, CH 2 ), 1.31 (t, J HH = 7.0, 3H, CH 3 ). 13 C NMR (DMSO) δ: 161.7 (C 7 ), 160.3 (C 5 ), 154.7 (C 9 ), 149.7 (C 1 ), 148.6 (C 10 ), 139.4 (C 2 ), 126.4 (C 3 ), 123.7 (C 8 ), 121.1 (C 4 ), 120.3 (C 13 ), 117.8 (C 12 ), 114.3 (C 11 ), 66.6 (C 6 ), 63.9 (CH 2 ), 14 3.00 (q, J HH = 5.6, 2H, CH 2 ), 1.08 (t, J HH = 6.9, 3H, CH 3 ). 13 ...
Tridentate ligands of the type N^{N^{OH }}were obtained from the reactions between salicylaldehyde derivatives (3-ethoxy, 4-diethylamino, 4-hydroxy) and primary amines (2-picolylamine or N-phenylethylenediamine), and were used to synthesize a set of five palladium complexes of the general formula Pd(N^{NO})Cl. The new complexes were characterized by NMR spectroscopy and mass spectrometry; further confirmation of the structure of Pd-Py-OEt was provided by single-crystal XRD. A DNA-binding study confirmed the importance of the ligand on the mode of binding with ct-DNA. Four complexes possess apparent binding constants in the same range, and all are higher than that of Pd-EN-NEt2. The BSA-binding proceeds via the formation of BSA-compound adducts, with higher binding constants for the ethylene-containing example due to the more flexible ligand. Molecular docking studies identified the binding site at the cleft of BSA. Anticancer properties of the palladium complexes are poorer than those of their platinum analogues, although Pd-Py-OEt and Pd-Py-NEt2 exhibit cytotoxicity similar to that of cisplatin, and significantly better cytotoxicity towards the cancer cell line over a normal cell line. Flow cytometry analysis suggests a late apoptotic cell death pathway for Pd-Py-OEt. Pd-Py-OEt; they afford different cell cycle accumulation patterns compared to Pt-Py-OEt and cisplatin, which suggests mechanistic differences in their anticancer activities.
... Complexation data on the metal-based compounds resulting from these interactions are important for a wide range of applications in many fields, including pharmaceutical and medical applications, as well as improving and designing more biologically active drugs [5][6][7][8][9][10][11][12]. For example, several platinum-based compounds have been approved as broad-spectrum drugs for the treatment of solid tumors of the testicles, ovaries, and bladder [13][14][15][16]. Unfortunately, resistance can be acquired to some of these drugs, and some have severe side effects [17][18][19]. ...
... Complexation data on the metal-based compounds resulting from these interactions are important for a wide range of applications in many fields, including pharmaceutical and medical applications, as well as improving and designing more biologically active drugs [5][6][7][8][9][10][11][12]. For example, several platinum-based compounds have been approved as broadspectrum drugs for the treatment of solid tumors of the testicles, ovaries, and bladder [13][14][15][16]. Unfortunately, resistance can be acquired to some of these drugs, and some have severe side effects [17][18][19]. ...
Chenodeoxycholic acid (CA) is a naturally occurring bile acid that is produced in the liver from cholesterol. Three CA complexes using Zn(II), Mg(II), and Ca(II) ions were synthesized to examine the chelation tendencies of CA towards these metal ions. The complexation reaction of CA with the metal ions under investigation was conducted with a 1:1 molar ratio (CA to metal) at 60–70 °C in neutralized media, which consisted of a binary solvent of MeOH and H2O (1:1). The resulting CA complexes were characterized using elemental data (metal, H, C, and Cl analysis) and spectral data (UV–visible, FT-IR, and 1H NMR). The results suggested that CA in anion form utilized oxygen atoms of the carboxylate group (-COO−) to capture Zn(II), Mg(II), and Ca(II) ions. This produced complexes with the general compositions of [Zn(CA)(H2O)Cl], [Mg2(CA)2(H2O)4Cl2], and [Ca2(CA)2(H2O)4Cl2]·2H2O, respectively. The Kirby–Bauer disc diffusion assay was then used to explore the bioactivity of the CA complexes toward three fungal species (Aspergillus niger, Candida albicans, and Penicillium sp.), three Gram-positive bacteria (Staphylococcus aureus, Streptococcus pneumoniae, and Bacillus subtilis), and two Gram-negative bacteria (Pseudomonas aeruginosa and Escherichia coli). The Ca(II) and Mg(II) complexes exhibited marked inhibitory effects on the cell growth of the fungal species Aspergillus niger with potency equal to 127 and 116% of the activity of the positive control, respectively. The Zn(II) and Ca(II) complexes strongly inhibited the growth of Penicillium sp., while the Zn(II) and Mg(II) complexes showed strong growth inhibition towards the Gram-negative species Pseudomonas aeruginosa.
... Rohand et al. [27] reported that the antimicrobial activity in vitro reveals that metal complexation increases the complexed ligand's antibacterial activity versus both bacterial strains compared to the free ligand (Complexes' higher activity could be attributed to their increased lipophilicity due to their chelation [28]. Although cisplatin and its derivatives have been widely utilized to treat certain malignancies, their therapeutic efficacy is limited by systemic toxicity and resistance [29][30][31][32]. For these limitations, scientists are searching for and synthesizing novel metal complexes with enhanced anticancer activity while reducing toxicity and resistant properties [33][34][35][36][37][38][39]. ...
Metallic antitumor drugs with heterocyclic ligands, such as novel AMI (amino methyl imidazole) complexes [Pd(AMI)Cl2](1), [Cu(AMI)L¹](2), and [Cu(AMI)L²·2H2O](3) where L¹ = oxalate and L² = malonate, were synthesized and characterized. Assessments included elemental analyses, mass spectrometry, Fourier transform-infrared spectroscopy, ultraviolet–visible spectroscopy, and thermal analysis. The cytotoxicity of AMI complexes compared to cisplatin was assessed using MTT (3-[4,5-dimethylthiazol-2-yl] 2,5diphenyl tetrazolium bromide) assay with breast (MCF-7) and cervical (HeLa) cancer cell lines. After treating these cells with the AMI complexes' IC50 values for 48 h, malondialdehyde levels and catalase activity were used to assess oxidative stress, antioxidant activity was evaluated with DPPH radical scavenging method, comet assays assessed DNA damage, and DNA fragmentation was evaluated using the gel electrophoresis. In vitro, antimicrobial activity was assessed using a disc diffusion method. The anticancer activity results showed that IC50 (half-maximal inhibitory concentration) values of complex one, two, and three against MCF-7 and HeLa cancer cells are 0.156 ± 0.0006, 0.125 ± 0.001, 0.277 ± 0.002 μM respectively for MCF-7 cells and 0.222 ± 0.0005, 0.126 ± 0.0009, 0.152 ± 0.001 μM respectively for HeLa cells. Complex two demonstrated strong anticancer activity against MCF-7 and Hela cells. The study of oxidative stress parameters revealed that Malondialdehyde levels increased in cancer cell lines treated with complexes compared to untreated cells. Catalase activity decreased in cells treated with palladium chelate. The DPPH radical scavenging assay results identified that complex one was a more potent antioxidant in MCF-7 and Hela cells than other complexes with SC50 values of 227.5 ± 0.28 and 361 ± 1.2 μL/mL, respectively. The comet assay results showed that complex two caused significant DNA damage in MCF-7 and HeLa cancer cells treated. Antimicrobial assays identified complex three as the most effective. Copper complexes give better antifungal activity against A. flavus than the palladium complex. We conclude that complex two is the most active in both cell types and might be assessed as a clinically useful drug for breast cancer treatment. The significance of the current study is the synthesis of antitumor drugs containing heterocyclic ligands, such as novel AMI complexes, and the study of their biological activities.
... Over the years, numerous metallodrugs have demonstrated their potential pharmaceutical activity, including antiviral, anticancer, and antibacterial properties. They are used as therapeutic agents and chemotherapeutics to treat various human diseases, such as infections, neurological disorders, diabetes, and cancer [1][2][3][4][5][6][7][8]. Furthermore, metallodrugs can be employed to design more biologically active drugs. ...
... Furthermore, metallodrugs can be employed to design more biologically active drugs. Platinum-based metallodrugs, such as carboplatin, oxaliplatin, and cisplatin, are widely used as anticancer drugs for treating solid tumors, including testicular, ovarian, and bladder cancers [5,[9][10][11]. These platinum-based metallodrugs inhibit the division of tumor cells by damaging their DNA and inducing cell death. ...
The chemical reaction between quinolone antibiotic oxolinic acid (OA) and Fe(III), Zn(II), Ca(II), and Mg(II) ions results in the formation of metal-based complexes with the following formulas: [Fe(OA)(H2O)2Cl2]·2H2O, [Zn(OA)(H2O)Cl]·2H2O, [Ca(OA)(H2O)Cl], and [Mg(OA)(H2O)Cl]. We used analytical (C, N, H, Cl, metal analysis) and spectral (FT-IR, 1H NMR, UV-visible) data to structurally characterize the synthesized metal-based complexes of the OA molecule. We found that the OA molecule utilizes the two oxygen atoms of the carboxylate group and the pyridone C=O group to bind the investigated metal ions. The morphological properties of the synthesized OA complexes were assessed using X-ray powder diffractometry (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The biological properties, specifically antibacterial and antifungal activity, of the synthesized complexes were evaluated in vitro using the Kirby–Bauer disc diffusion protocol with five bacterial and three fungal strains. The complex containing Ca(II) ions exhibited remarkable antibacterial and antifungal activity against all tested microbial strains, surpassing or equaling the potency of the standard drugs (streptomycin for antibacterial assays and ketoconazole for antifungal assays).
... Furthermore, metallodrugs can be employed to design more biologically active drugs. Platinum-based metallodrugs, such as carboplatin, oxaliplatin, and cisplatin, are widely used as anticancer drugs for treating solid tumors, including testicular, ovarian, and bladder cancers [9][10][11][12]. These platinum-based metallodrugs inhibit the division of tumor cells by damaging their DNA and inducing cell death. ...
The chemical reaction between the quinolone antibiotic oxolinic acid (OA) and Fe(III), Zn(II), Ca(II), and Mg(II) ions results in the formation of metal-based complexes with the following formulas: [Fe(OA)(H2O)2Cl2]2H2O, [Zn(OA)(H2O)Cl]2H2O, [Ca(OA)(H2O)Cl], and [Mg(OA)(H2O)Cl]. We used analytical (C, N, H, Cl, metal analysis) and spectral (FT-IR, 1H NMR, UV-visible) data to structurally characterize the synthesized metal-based complexes of the OA molecule. We found that the OA molecule utilizes the two oxygen atoms of the carboxylate group and the pyridone C=O group to bind the investigated metal ions. The morphological properties of the synthesized OA complexes were assessed using X-ray powder diffractometry (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The biological properties, specifically antibacterial and antifungal activity, of the synthesized complexes were evaluated in vitro using the Kirby-Bauer disc diffusion protocol with five bacterial and three fungal strains. The complex containing Ca(II) ions exhibited remarkable antibacterial and antifungal activity against all tested microbial strains, surpassing or equaling the potency of the standard drugs (streptomycin for antibacterial assays and ketoconazole for antifungal assays).
... Cytostatics are common drugs which are widely used for the treatment of cancer [1]. Within chemotherapy, cytotoxic drugs are used as active agents to treat rapidly spreading tumor cells by inhibiting proliferation, inducing apoptosis, damaging DNA, or disrupting the cell metabolism [2]. ...
Cisplatin is a platinum-based cytostatic drug that is widely used for cancer treatment. Mitochondria and mtDNA are important targets for platinum-based cytostatics, which mediates its nephrotoxicity. It is important to develop therapeutic approaches to protect the kidneys from cisplatin during chemotherapy. We showed that the exposure of mitochondria to cisplatin increased the level of lipid peroxidation products in the in vitro experiment. Cisplatin caused strong damage to renal mtDNA, both in the in vivo and in vitro experiments. Cisplatin injections induced oxidative stress by depleting renal antioxidants at the transcriptome level but did not increase the rate of H2O2 production in isolated mitochondria. Methylene blue, on the contrary, induced mitochondrial H2O2 production. We supposed that methylene blue-induced H2O2 production led to activation of the Nrf2/ARE signaling pathway. The consequences of activation of this signaling pathway were manifested in an increase in the expression of some antioxidant genes, which likely caused a decrease in the amount of mtDNA damage. Methylene blue treatment induced an increase in the expression of genes that were involved in the base excision repair (BER) pathway: the main pathway for mtDNA reparation. It is known that the expression of these genes can also be regulated by the Nrf2/ARE signaling pathway. We can assume that the protective effect of methylene blue is related to the activation of Nrf2/ARE signaling pathways, which can activate the expression of genes related to antioxidant defense and mtDNA reparation. Thus, the protection of kidney mitochondria from cisplatin-induced damage using methylene blue can significantly expand its application in medicine.
... Herein, we have changed the ligand environment by adding the electron-donating methyl substituent, which would increase the biological activity. Bearing all these facts in our mind, we have focused on the synthesis of mixed-ligand copper(II) complexes of 5-methylsalicylaldehyde and 2,2'-bipyridyl/1,10-phenanthroline (1)(2)(3)(4)(5)(6). The biological efficacy of the synthesized complexes was tested in terms of antibacterial and DNA binding studies. ...
... Yield UV-Vis data λmax, nm (ε, M -1 cm -1 ) in DMF: 282 (9, 398), 371 (3,893) ...
... The reaction between equimolar amounts of ligands and diimines as co-ligand in the presence of CuCl2.2H2O yielded pendant-armed mixed-ligand copper(II) complexes (1)(2)(3)(4)(5)(6) in good yield with characteristic color (Scheme 1). In Tris-HCl/NaCl buffer, CH3OH, CH3CN, DMF, and DMSO, all of the complexes are soluble. ...
A series of pendant-armed mixed-ligand copper(II) complexes of the type [CuL1-3(diimine)] (1-6) have been synthesized by the reaction of pendant-armed ligands N,N-bis(2-(((E)-2-hydroxy-5-methylbenzylidene)amino)ethyl)benzamide (H2L1), N,N-bis(2-(((E)-2-hydroxy-5-methylbenzylidene)amino)ethyl)-4-nitrobenzamide (H2L2) and N,N-bis(2-(((E)-2-hydroxy-5-methylbenzylidene)amino)ethyl)-3,5-dinitrobenzamide (H2L3) with diimine = 2,2'-bipyridyl (bpy) or 1,10-phenanthroline (phen) in the presence of copper(II) chloride and analyzed using various spectroscopic methods. All the spectroscopic results support that the complexes adopt a pentagonal-bipyramidal shape around the metal ions. Gram-positive and Gram-negative bacteria were used to test all the complexes for antibacterial activity and all the complexes had greater potency against gram-negative pathogens. DNA-binding experiments of complexes with calf thymus DNA revealed a major-groove binding pattern, further supported by molecular docking studies. Complexes have significantly interacted with SARS-CoV-2 receptor via π-π, π-σ, π-alkyl, π-anion, π-cation, alkyl, hydrogen bond, van der Waals, and electrostatic interactions. The estimated binding energy and inhibition constant of these complexes are higher than standard drugs, chloroquine, and molnupiravir.
