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Click Chelators – The Behavior of Platinum and Palladium Complexes in the Presence of Guanosine and DNA
European Journal of Inorganic Chemistry
Abstract
Triazole chelators, synthesized by click chemistry, are convenient ligands for palladium(II) and platinum(II). Conformational changes induced by the complexation of these PdII and PtII complexes with guanosine are similar to those of cisplatin. In addition, these complexes behave like cisplatin with regard to the relaxation of supercoiled plasmid DNA
... We reasoned that these ligands should react with Fe(II) ions to generate metallosupramolecular helicates of a similar size and shape to 1 and 2. Given the wide substrate scope of the CuAAC " click " reaction used to construct the ligands, it should be possible to prepare a library of helicates that would enable convenient structure-activity studies. Herein we report the synthesis and biological properties60616263646566676869 of a small family of Fe(II) " click " helicates. ...
A series of metallosupramolecular [Fe2L3](BF4)4 "click" cylinders have been synthesized in excellent yields (90%-95%) from [Fe(H2O)6](BF4)2 and bis(bidentate) pyridyl-1,2,3-triazole ligands. All complexes were characterized by elemental analysis, IR, UV-vis, 1H-, 13C- and DOSY-NMR spectroscopies and, in four cases, the structures confirmed by X-ray crystallography. Molecular modeling indicated that some of these "click" complexes were of similar size and shape to related biologically active pyridylimine-based iron(II) helicates and suggested that the "click" complexes may bind both duplex and triplex DNA. Cell-based agarose diffusion assays showed that the metallosupramolecular [Fe2L3](BF4)4 "click" cylinders display no antifungal activity against S. cerevisiae. This observed lack of antifungal activity appears to be due to the poor stability of the "click" complexes in DMSO and biological media.
As a spectroscopic method, nuclear magnetic resonance (NMR) has seen spectacular growth, both as a technique and in its applications. Today's applications of NMR span a wide range of scientific disciplines, from physics to biology to medicine. Each volume of Nuclear Magnetic Resonance comprises a combination of annual and biennial reports which together provide comprehensive coverage of the literature on this topic. This Specialist Periodical Report reflects the growing volume of published work involving NMR techniques and applications, in particular NMR of natural macromolecules, which is covered in two reports: NMR of Proteins and Nucleic Acids and NMR of Carbohydrates, Lipids and Membranes. In his foreword to the first volume, the then editor, Professor Robin Harris announced that the series would be a discussion on the phenomena of NMR and that articles will be critical surveys of the literature. This has certainly remained the case throughout the series, and in line with its predecessors, Volume 40 aims to provide a comprehensive coverage of the relevant NMR literature. For the current volume this relates to publications appearing between June 2009 and May 2010 (the nominal period of coverage in volume 1 was July 1970 to June 1971). Compared to the previous volume there are some new members of the reporting team. Theoretical Aspects of Spin-Spin Couplings are covered by J. Jazwinski, while E. Swiezewska and J.Wojcik provide an account of NMR of Carbohydrates, Lipids and Membranes.
A series of binuclear metallosupramolecular helices [Ni2L3]⁴⁺ has been synthesized from Ni(II) salts and bis(bidentate) pyridyltriazole or aminomethyltriazole ligands, separated by ortho- (o-xpt and o-xamt, respectively), meta- (m-xpt, m-xamt), and para-xylylene (p-xpt, p-xamt) spacers. All complexes were characterized by elemental analysis, ESI-MS, and in four cases, the structures confirmed by X-ray crystallography. The xpt and xamt ligands, derived by “click” reactions, exhibit similar bonding behavior regardless of modifications in their coordination pockets and spacer groups, forming triple-helical binuclear complexes with pseudo-octahedral geometry at Ni. The crystallographically characterized complexes show shorter Ni···Ni separations with the ortho spacer ([Ni2(o-xpt)3]⁴⁺, 9.332(2); [Ni2(o-xamt)3]⁴⁺, 8.9718(10) Å) than with the para spacer ([Ni2(p-xpt)3]⁴⁺, 11.574(2); [Ni2(p-xamt)3]⁴⁺, 11.899(2), 11.924(2) Å).
Pd(salicylaldimine)2 (ONNO-Pd)(C1 and C2), Pd(salicylaldimine)Cl (ONN-Pd) (C3) and methionine derived ONS donor ligand based (ONS-Pd) Pd(salicylaldimine methionine ethyl ester)Cl (C4) complexes were prepared and structurally characterized by ¹H, ¹³C NMR spectroscopy, high-resolution electrospray mass spectrometry and single crystal X-ray analyses (C1, C2 and C4). In C1 and C2 two ON-donor salicylaldimine ligands completed four coordinates of Pd(II) while in C4 these coordinate were completed by ONS-donor atoms of salicylaldimine and one Cl ancillary ligand. In vitro cytotoxicity assays were performed for these complexes in non-small cell lung (A549) and hepatocellular (HepG2) cancer cells. MTT assay showed that these Pd complexes suppress cancer cells viability and inhibited cell growth in dose and time-dependent manner. Cell cycle analysis was performed in A549 cells. To check the interaction of these complexes with DNA gel electrophoresis study was performed that revealed stronger binding affinity of these complexes with DNA.
Bis-NHC and mixed NHC/PR3 copper(I) complexes (NHC = N-heterocyclic carbene) were found to be efficient catalysts enabling the azide–alkyne cycloaddition reaction leading to the formation of 1,2,3-sulfonyltriazoles under Click conditions. The mechanism of this transformation was probed and decoordination of the NHC ligand (even in the NHC/PR3 mixed ligand systems) during the catalytic transformation was observed.
Complexes of the type cis-[PdX2(imzt)(PPh3)] {imzt = imidazolidine-2-thione; PPh3 = triphenylphosphine; X = Cl (1), Br (2), I (3), SCN (4)} have been synthesized and characterized by elemental analyses, molar conductance, IR and ¹H NMR spectroscopies. The complex 1·MeOH was obtained from the reaction of [PdCl2(CH3CN)2], imidazolidine-2-thione and triphenylphosphine in CHCl3/CH3OH. Complexes 2·MeOH, 3 and 4 were prepared by metathesis of the chlorido ligands in 1 with bromide, iodide and thiocyanate, respectively. Elemental analyses showed good agreement with the expected mononuclear compositions, while the molar conductivities of the complexes in DMF were consistent with their nonelectrolytic nature. NMR spectra confirmed coordination of the imidazolidine-2-thione and triphenylphosphine ligands. Single-crystal X-ray diffraction determination of 1·CH3OH showed that the coordination geometry around PdII is nearly square planar, with the chlorido ligands in a cis configuration. All four complexes have been tested in vitro by XTT assay for their cytotoxicity against human glioblastoma cell line (U87MG). The binding of 1 with guanosine was studied by ¹H NMR spectroscopy, revealing that the coordination takes place via N7.
The synthesis and characterization of the complexes [PdX(PPh3)(4-MeT)]X (4-MeT = 4-methyl-3-thiosemicarbazide; PPh3 = triphenylphosphine; X = Cl, Br, I, SCN) have been described. The complexes were evaluated for in vitro activity as cytotoxic agents on tumor cells and also as cathepsin B and topoisomerase I and II inhibitors.
DNA is considered to be one of the major targets of anticancer drugs. Cisplatin and its analogues exert their activity by forming covalent bonds with the DNA base pairs. However, the DNA structure enables its interaction with metal complexes in many different modes and intercalation is often observed. Particularly, metallointercalators stand out as a class of potential antitumour agents that could circumvent problems such cellular resistance since their mechanism of action is different from that of cisplatin. The interaction complex-DNA can be studied by various techniques, including reaction with guanosine, electrophoretic mobility shift assay (EMSA), viscosity measurements, spectrocphotometric titration for determination of Kb, DNA thermal denaturation and fluorescence spectroscopy.
Triazole ring containing three nitrogen atoms, is a quite important five-member heterocycle and possesses aromaticity and rich electrons. This unique structure endows triazole moiety to readily accept protons and coordinate with various metal ions. Therefore, triazole compounds easily form supramolecular aggregates via non-covalent interaction such as coordination bonds, hydrogen bonds, ion-dipole, cation-π, π-π stacking, hydrophobic effect, van der Waals force and so on. These triazole derivatives exhibit various special properties and biological activities, and display a wide range of potential application as artificial ion receptors, materials and medicinal agents. In recent years, the related researches of triazole-based supramolecular chemistry and medicinal drugs have been becoming an extremely active, quite rapidly developing and attracting highlight area. Combining with authors' researches and referring other works from literatures in recent 5 years, this work for the first time systematically reviewed the recent advances of the whole range of triazole-based compounds as cation and anion receptors and triazole supermolecules as luminescent and magnetic materials as well as medicinal drugs majoring in antibacterial, antifungal, anticancer agents. Hopefully, this review would be helpful for the further researches and development of the triazole-based supramolecular chemistry and medicinal drugs.
The coordination of the diazenecarboxamides, which were functionalized with the 1-(2-picolyl)-1H-1,2,3-triazole moiety 1, to platinum(II) were studied, where K2[PtCl4] and cis-[PtCl2(DMSO)2] were used as the platinum sources. The picolyl-triazole (pictri) binding unit enabled chelation to the metal centre through the 1,2,3-triazole N2 and the pyridyl nitrogen atoms under mild reaction conditions. When cis-[PtCl2(DMSO)2] was used, with CH2Cl2 or CH3CN as the reaction solvents, the pure, stable diamminedichloridoplatinum(II) complexes 2 were isolated by filtration in 39 to 83 % yield. The products were structurally characterized in solution by 1H, 13C and 195Pt NMR spectroscopy. The 195Pt NMR chemical shifts for 2 appear in the region of –2203 to –2207 ppm. The structure of complex 2a was confirmed by single-crystal X-ray crystallography. The formation of the platinum complexes 2 was monitored using NMR spectroscopy. The complexation with cis-[PtCl2(DMSO)2] in [D7]dmf proceeded through several intermediates, as indicated by the 195Pt NMR spectra with resonances in the range of –3055 to –2907 ppm. Similarly, the reaction of cis-[PtCl2(DMSO)2] with diazenecarboxamide, which was functionalized with the nonchelating 1-(2-aminoethyl)-1,2,3-triazole derivative, was examined by NMR spectroscopy.
The first examples of heteroleptic bis-N-heterocyclic carbene (NHC) copper(I) complexes and a mixed NHC–phosphine Cu complex are reported. These complexes are easily synthesized from the reaction of [Cu(OH)(NHC)] with various imidazol(idin)ium or phosphonium tetrafluoroborate salts. These cationic heteroleptic bis-NHC Cu complexes are highly active systems for the azide–alkyne cycloaddition leading to the formation of 1,2,3-triazoles. The mechanism of this transformation was investigated, and information gathered suggests that only one NHC remains coordinated to the metal center during catalysis.
The compounds [Ru(bpy)2(L(1))](ClO4)2 ((ClO4)2), [Ru(bpy)2(L(2))](ClO4)2 ((ClO4)2), [Ru(bpy)2(L(3))](ClO4)2 ((ClO4)2), [Ru(bpy)2(L(4))](ClO4)2 ((ClO4)2), [Ru(bpy)2(L(5))](ClO4)2 ((ClO4)2), and [Ru(bpy)2(L(6))](ClO4)2(ClO4)2 (bpy = 2,2'-bipyridine, L(1) = 1-(4-isopropyl-phenyl)-4-(2-pyridyl)-1,2,3-triazole, L(2) = 1-(4-butoxy-phenyl)-4-(2-pyridyl)-1,2,3-triazole, L(3) = 1-(2-trifluoromethyl-phenyl)-4-(2-pyridyl)-1,2,3-triazole, L(4) = 4,4'-bis-{1-(2,6-diisopropyl-phenyl)}-1,2,3-triazole, L(5) = 4,4'-bis-{(1-phenyl)}-1,2,3-triazole, L(6) = 4,4'-bis-{1-(2-trifluoromethyl-phenyl)}-1,2,3-triazole) were synthesized from [Ru(bpy)2(EtOH)2](ClO4)2 and the corresponding "click"-derived pyridyl-triazole or bis-triazole ligands, and characterized by (1)H-NMR spectroscopy, elemental analysis, mass spectrometry and X-ray crystallography. Structural analysis showed a distorted octahedral coordination environment about the Ru(ii) centers, and shorter Ru-N(triazole) bond distances compared to Ru-N(pyridine) distances in complexes of mixed-donor ligands. All the complexes were subjected to cyclic voltammetric studies, and the results were compared to the well-known [Ru(bpy)3](2+) compound. The oxidation and reduction potentials were found to be largely uninfluenced by ligand changes, with all the investigated complexes showing their oxidation and reduction steps at rather similar potentials. A combined UV-vis-NIR and EPR spectroelectrochemical investigation, together with DFT calculations, was used to determine the site of electron transfer in these complexes. These results provided insights into their electronic structures in the various investigated redox states, showed subtle differences in the spectroscopic signatures of these complexes despite their similar electrochemical properties, and provided clues to the unperturbed redox potentials in these complexes with respect to ligand substitutions. The reduced forms of the complexes display structured absorption bands in the NIR region. Additionally, we also present new synthetic routes for the ligands presented here using Cu-abnormal carbene catalysts.
Since the introduction of cisplatin to oncology in 1978, Pt(II) and Pd(II) compounds have been intensively studied with a view to develop the improved anticancer agents. Polynuclear polyamine complexes, in particular, have attracted special attention, since they were found to yield DNA adducts not available to conventional drugs (through long-distance intra- and interstrand cross-links) and to often circumvent acquired cisplatin resistance. Moreover, the cytotoxic potency of these polyamine-bridged chelates is strictly regulated by their structural characteristics, which renders this series of compounds worth investigating and their synthesis being carefully tailored in order to develop third-generation drugs coupling an increased spectrum of activity to a lower toxicity. The present paper addresses the latest developments in the design of novel antitumor agents based on platinum and palladium, particularly polynuclear chelates with variable length aliphatic polyamines as bridging ligands, highlighting the close relationship between their structural preferences and cytotoxic ability. In particular, studies by vibrational spectroscopy techniques are emphasised, allowing to elucidate the structure-activity relationships (SARs) ruling anticancer activity.
Complexes of the type [PdX(PPh3)(1)]X [1 = 4-phenyl-3-thiosemicarbazide; X = Cl- (2), Br- (3), I- (4), and SCN- (5)] have been synthesized and characterized by elemental analyses and IR, UV/Vis, and H-1 and C-13 NMR spectroscopy. The molecular structure of complex 4 was determined by single-crystal X-ray diffraction. The binding of the complexes with a purine base (guanosine) was investigated by H-1 NMR spectroscopy and mass spectrometry, which showed the complexes to coordinate to guanosine through N7. A gel electrophoresis assay demonstrated the ability of 2-5 to cleave DNA plasmid. All the complexes were tested in vitro by means of the MTT assay for their cytotoxicity against two murine cell lines, LM3 (mammary adenocarcinoma) and LP07 (lung adenocarcinoma), and compared with cisplatin. Complexes 2-5 exhibited good cytotoxicity that surpasses that of cisplatin in the case of LM3.
This chapter, divided into three sections, reviews the literature reported during 2010 in the field of interaction of metal complexes with nucleic acids and complex formation between metals and coordinating moieties within nucleic acids. The first two sections focus on the interaction of metal complexes and ions with DNA and RNA, respectively, and are organised by mode of interaction. In the last section examples where transition metals occupy coordination sites covalently incorporated within nucleic acids strands' are discussed. Highlights A series of achiral copper(II) complexes, when bound to duplex DNA, perform catalytic enantioselective hydration of enones. 1 The X-ray structure of a RNA polymerase II transcribing complex stalled at the monofunctional pyriplatin site has been resolved, providing an insight into the mechanism of transcription inhibition. 2 The first structural characterisation of a nucleic acid with a continuous run of metal modified base pairs has been reported. 3 A polyacrylamide hydrogel functionalised with a thymine rich DNA strand has been developed to detect and simultaneously remove toxic Hg II ions from water. 4 The first gold complex to interact with quadruplex DNA has been reported. 5 Cu II –salen metal–base pairs have been introduced inside the double helix of DNA; the stacked copper(II) square planar complexes display antiferromagnetic coupling. 6
The discovery of copper(I) species as excellent catalysts for the regioselective cycloaddition reactions of azides and alkynes served as proof-of-concept of the importance of Click chemistry and opened a broad field of research that has found numerous ramifications in biochemistry, materials and medicinal science, for instance. The use of ligands in this context not only serves to stabilize the oxidation state of copper, but has also been shown to increase and modulate its reactivity. Still, efforts focused on developing more efficient catalytic systems for this transformation remain limited. Herein, the catalytic activities of ligated copper systems are reviewed in a way intended inspirational for further developments.
Using the ‘Click Protocol’ the new ligands 1-(cyclohexyl)-4-(2-pyridyl)-1,2,3-triazole (1), 1-(2-trifluoromethyl phenyl)-4-(2-pyridyl)-1,2,3-triazole (2), 1-(4-hexyl phenyl)-4-(2-pyridyl)-1,2,3-triazole (3), 1-(2-mercaptomethyl phenyl)-4-(2-pyridyl)-1,2,3-triazole (4) and 1-(4-N,N-dimethylamino phenyl)-4-(2-pyridyl)-1,2,3-triazole (5) were prepared by reacting 2-ethynylpyridine with the corresponding azides. In the next step the ligands were reacted with suitable palladium and platinum precursors to yield the cis-dichloro-palladium complexes 1a–4a and platinum complexes 1b–4b. Investigation of the molecular structure of the free ligands 1 and 5 reveals the formation of infinite chains in the D structure which are governed by hydrogen bonds between the triazole units. Likewise the D structure of 1a shows infinite chains which are held together by multiple remarkably short C–H⋯Cl–Pd contacts. Electrochemical investigation of the free ligands by cyclic voltammetry showed irreversible reduction processes at highly negative potential. Upon metal complexation huge anodic shifts of the reduction potential were observed. To further characterize the electronic properties of all the compounds UV–Vis spectra were also analyzed.
The coordination complexes of Ni(II) with the tripodal ligands tpta (tris[(1-phenyl-1H-1,2,3-triazol-4-yl)methyl]amine), tbta ([(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine), and tdta (tris[(1-(2,6-diisopropyl-phenyl)-1H-1,2,3-triazol-4-yl)methyl]amine) and the bidentate ligand pyta (1-(2,6-diisopropylphenyl)-4-(2-pyridyl)-1,2,3-triazole), [Ni(tpta)2](BF4)2 (1), [Ni(tbta)2](BF4)2 (2), [Ni(tdta)2](BF4)2 (3), and [Ni(pyta)3](BF4)2 (4), were synthesized from Ni(BF4)2·6H2O and the corresponding ligands. Complexes 2 and 4 were also characterized structurally using X-ray diffraction and magnetically via susceptibility measurements. Structural characterization of 2 that contains the potentially tetradentate, tripodal tbta ligand revealed that the Ni(II) center in that complex is in a distorted octahedral environment, being surrounded by two of the tripodal ligands. Each of those ligands coordinate to the Ni(II) center through the central amine nitrogen atom and two of the triazole nitrogen donors; the Ni-N(amine) distances being longer than Ni-N(triazole) distances. In case of 4, three of the bidentate ligands pyta bind to the Ni(II) center with the binding of the triazole nitrogen atoms being stronger than those of the pyridine. Temperature dependent susceptibility measurements on 2 and 4 revealed a room temperature χMT value of 1.18 and 1.20 cm(3) K mol(-1), respectively, indicative of S = 1 systems. High-frequency and -field EPR (HFEPR) measurements were performed on all the complexes to accurately determine their g-tensors and the all-important zero-field splitting (zfs) parameters D and E. Interpretation of the optical d-d absorption spectra using ligand field theory revealed the B and Dq values for these complexes. Quantum chemical calculations based on the X-ray and DFT optimized geometries and their ligand field analysis have been used to characterize the metal-ligand bonding and its influence on the magnitude and sign of the zfs parameters. This is the first time that such extensive HFEPR, LFT, and advanced computational studies are being reported on a series of mononuclear, distorted octahedral Ni(II) complexes containing different kinds of nitrogen donating ligands in the same complex.
Triazole compounds containing three nitrogen atoms in the five-membered aromatic azole ring are readily able to bind with a variety of enzymes and receptors in biological system via diverse non-covalent interactions, and thus display versatile biological activities. The related researches in triazole-based derivatives as medicinal drugs have been an extremely active topic, and numerous excellent achievements have been acquired. Noticeably, a large number of triazole compounds as clinical drugs or candidates have been frequently employed for the treatment of various types of diseases, which have shown their large development value and wide potential as medicinal agents. This work systematically reviewed the recent researches and developments of the whole range of triazole compounds as medicinal drugs, including antifungal, anticancer, antibacterial, antitubercular, antiviral, anti-inflammatory and analgesic, anticonvulsant, antiparasitic, antidiabetic, anti-obesitic, antihistaminic, anti-neuropathic, antihypertensive as well as other biological activities. The perspectives of the foreseeable future in the research and development of triazole-based compounds as medicinal drugs are also presented. It is hoped that this review will serve as a stimulant for new thoughts in the quest for rational designs of more active and less toxic triazole medicinal drugs.
Readily synthesised and functionalised di-1,2,3-triazole "click" ligands are shown to self-assemble into coordinatively saturated, quadruply stranded helical [Pd(2)L(4)](BF(4))(4) cages with Pd(II) ions. The cages have been fully characterised by elemental analysis, HR-ESMS, IR, (1)H, (13)C and DOSY NMR, DFT calculations, and in one case by X-ray crystallography. By exploiting the CuAAC "click" reaction we were able to rapidly generate a small family of di-1,2,3-triazole ligands with different core spacer units and peripheral substituents and examine how these structural modifications affected the formation of the [Pd(2)L(4)](BF(4))(4) cages. The use of both flexible (1,3-propyl) and rigid (1,3-phenyl) core spacer units led to the formation of discrete [Pd(2)L(4)](BF(4))(4) cage complexes. However, when the spacer unit of the di-1,2,3-triazole ligand was a 1,4-substituted-phenyl group steric interactions led to the formation of an oligomeric/polymeric species. By keeping the 1,3-phenyl core spacer constant the effect of altering the "click" ligands' peripheral substituents was also examined. It was shown that ligands with alkyl, phenyl, electron-rich and electron-poor benzyl substituents all quantitatively formed [Pd(2)L(4)](BF(4))(4) cage complexes. The results suggest that a wide range of functionalised palladium(II) "click" cages could be rapidly generated. These novel molecules may potentially find uses in catalysis, molecular recognition and drug delivery.
The Cu(I)-catalyzed 1,3-cycloaddition of organic azides with terminal alkynes, the CuAAC "click" reaction is currently receiving considerable attention as a mild, modular method for the generation of functionalized ligand scaffolds. Herein we show that mild one-pot "click" methods can be used to readily and rapidly synthesize a family of functionalized bidentate 2-pyridyl-1,2,3-triazole ligands, containing electrochemically, photochemically, and biologically active functional groups in good to excellent yields (47-94%). The new ligands have been fully characterized by elemental analysis, HR-ESI-MS, IR, (1)H and (13)C NMR and in three cases by X-ray crystallography. Furthermore we have demonstrated that this family of functionalized "click" ligands readily form bis-bidentate Pd(II) complexes. Solution studies, X-ray crystallography, and density functional theory (DFT) calculations indicate that the Pd(II) complexes formed with the 2-(1-R-1H-1,2,3-triazol-4-yl)pyridine series of ligands are more stable than those formed with the [4-R-1H-1,2,3-triazol-1-yl)methyl]pyridine "click" ligands.
A new coupling constant-torsion angle relation for the three-bond 1H-1H spin-spin coupling constant is formulated. The relation includes a correction for the electronegativity of substituents. The correction term is written as a function of the electronegativity, the H-C-C-H torsion angle, and the orientation of each substituent relative to the coupled protons. A dataset consisting of 315 experimental coupling constants was used to derive six empirical parameters by means of an iterative least-squares minimization procedure. The precision of the proposed equation, expressed as the root-mean-square deviation (0.48 Hz), is superior to any hitherto reported. It is shown that separate treatment of CH2CH2, CH2CH and CHCH fragments even improves this precision. An application in the field of monosubstituted cyclohexanes is given.
Complete synthetic, structural, and biomedical studies of two Pd complexes as well as Au and Ag complexes of 1-benzyl-3-tert-butylimidazol-2-ylidene are reported. Specifically, trans-[1-benzyl-3-tert-butylimidazol-2-ylidene]Pd(pyridine)Cl2 (1a) was synthesized from the reaction of 1-benzyl-3-tert-butylimidazolium chloride (1) with PdCl2 in the presence of K2CO3 as a base. The other palladium complex, [1-benzyl-3-tert-butylimidazol-2-ylidene]2PdCl2 (1b), and a gold complex, [1-benzyl-3-tert-butylimidazol-2-ylidene]AuCl (1c), were synthesized by following a transmetallation route from the silver complex, [1-benzyl-3-tert-butylimidazol-2-ylidene]AgCl (1d), by treatment with (COD)PdCl2 and (SMe2)AuCl, respectively. The silver complex 1d in turn was synthesized by the reaction of 1 with Ag2O. The molecular structures of 1a-d have been determined by X-ray diffraction studies. Biomedical studies revealed that, while the palladium complexes 1a and 1b displayed potent anticancer activity, the gold (1c) and silver (1d) complexes exhibited significant antimicrobial properties. Specifically, 1b showed strong antiproliferative activity against three types of human tumor cells, namely, cervical cancer (HeLa), breast cancer (MCF-7), and colon adenocarcinoma (HCT 116), in culture. The antiproliferative activity of 1b was found to be considerably stronger than that of cisplatin. The 1b complex inhibited tumor cell proliferation by arresting the cell cycle progression at the G2 phase, preventing the mitotic entry of the cell. We present evidence suggesting that the treated cells underwent programmed cell death through a p53-dependent pathway. Though both the gold (1c) and silver (1d) complexes showed antimicrobial activity toward Bacillus subtilis, 1c was found to be ca. 2 times more potent than 1d.
The crystal and molecular structure of aminoguanidine dinitrate, CN4H82+·(NO3-)2, was determined with the aid of single-crystal X-ray diffraction. In the compound, aminoguanidine dication exists in the form of one tautomer only. One of the positive charges is localized at the terminal nitrogen atom of the hydrazine part of the dication, while the other one is delocalized at the other three nitrogens and obviously also the carbon atom. The dication is remarkably planar. The structure is compared to the corresponding sulphate salt and effects of hydrogen bonding on the planarity of the dication are discussed.
Absorption effects usually present the most serious source of systematic error in the determination of structure factors from single-crystal X-ray diffraction measurements if the crystal is not ground to a sphere or cylinder. A novel method is proposed for the correction of these effects for data collected on a diffractometer. The method works from the premise that the manifestation of systematic errors due to absorption, unlike most other sources of systematic error, will not be evenly distributed through reciprocal space, but will be localized. A Fourier series in the polar angles of the incident and diffracted beam paths is used to model an absorption surface for the difference between the observed and calculated structure factors. Knowledge of crystal dimensions or linear absorption coefficient is not required, and the method does not necessitate the measurement of azimuthal scans or any extra data beyond the unique set. Moreover, application of the correction is not dependent upon the Laue symmetry of the crystal or the geometry of the diffractometer. The method is compared with other commonly used corrections and results are presented which demonstrate its potential.
From a knowledge of the Hartree-Fock and exact non-relativistic energies of atoms, the correlation energy Ec, as defined by Lowdin, may be calculated. For atoms this correlation is defined as dynamic correlation. The separate like-spin and unlike-spin contributions, Ecσσ, Ecαβ, may be calculated as a sum of pair energies from quantum chemistry; we have used the unrestricted Møller-Plesset second-order algorithm, and then scaled them to give Ec. These three values may also be computed using dynamic correlation functionals, with the Stoll partitioning. The VWN, LYP and P91 functionals were studied for the atoms from H to Ar. Although the total correlation energies of LYP and P91 are similar, only P91 gives a semi-sensible breakdown into the Ecσσ, and Ecαβ components. It is immediately apparent that a new functional, OPTC, derived from the P91 components as 0.6625 x Ecσσ, + 1. 1015 x Ecαβ is an improvement (its mean absolute error is only 0.006 Eh). Using the recently introduced improved exchange functional OPTX (obtained through a fit to the HF energies of atoms), Kohn-Sham calculations were performed on the atoms using the OPT(=OPTX + OPTC) functional. The total energies have a mean absolute error of 0.006 Eh. The study then moves to molecules. First it is shown that the dynamic correlation energy contribution to the dissociation energies is very similar (within 2kcalmol in most cases), whether it is calculated with LYP, P91 or OPTC. A calculation is then made of the HF contribution, the dynamic contribution through OPTC and the left-right contribution through OPTX, to molecular binding. In many cases the sum agrees with the observed value, but in some cases the prediction is significantly in error, e.g. O2 is overbound by 10 kcal mol. Thus either OPTX or OPTC or both are inadequate. An attempt was made to determine improved local exchange and correlation functionals by fitting to both atomic and molecular data, but this was unsuccessful. The conclusion is that the method is close to the limit of accuracy achievable from separately optimized local exchange and correlation functionals. Finally, a new hybrid functional O3LYP, which is a substantial improvement on B3LYP, is presented.
2 complexation to 2-deoxyguanosine 3,5-bis(ethyl hydrogen phosphate) 1 and its ribo analogue 3 which mimic the central nucleotide moiety in a trinucleoside diphosphate in the complete absence of intramolecular base-base stacking interactions. The N S pseudorotational equilibrium shifts towards N-type conformers by 17 and 21 percentage points at 298 K, respectively, thereby showing that free energy of platination is transmitted to drive the sugar conformation. The increase in the population of N-type conformers was rationalized with the strengthening of the anomeric effect in both 2-deoxy and ribo nucleotides upon the formation of the Pt-N7 bond which promotes nO4 → σ*C1-N9 orbital interactions due to the reduction of π-electron density in the imidazole part of guanine. The additional stabilization of N-type conformers in Pt 2 complexes of ribonucleotides is due to the tuning of the gauche effect of the (N9-C1-C2-O2) fragment, which is absent in 2-deoxy-ribo counterparts. The platination of N7 favours N1 deprotonation in 2 and 4 by ∆pKa of 0.7 and 0.9 units in comparison with parent nucleotides 1 and 3, respectively. The N S pseudorotational equilibrium in 1-4 showed classical sigmoidal dependence as a function of pH with pKa-values at the inflection points. The population of S-type conformers has increased upon N1 deprotonation in 1-4 because the anomeric effect weakened due to the increased π-electron density in the imidazole part of the guanine moiety. The formation of the Pt-N7 bond in bifunctional complexes 2 and 4 simultaneously causes a shift of the syn anti equilibrium towards anti by 43 and 63 percentage points, and the increase in the population of ε t,N conformers by 20 and 32 percentage points at 278 K, respectively. Only a minor conformational redistribution along β, γ, β 1 and ε 1 torsion angles has been observed, which suggests their weak conformational cooperativity with the N S pseudorotational equilibrium as a result of platination to guanine. In comparison with nucleotide phosphodiesters, apurinic 3,5-bis(ethyl hydrogen phosphate) sugars 5 and 6 showed no interaction with Pt 2 and therefore no conformational changes.
A mixed-ligand complex [Pd(Phen)(Phe)]ClH2O (Phen-o-phenantroline, Phe-L-phenylalanine) is synthesized and structurally characterized by elemental analyses and single-crystal
X-ray diffraction. Diffraction data: C21H19ClN3O3Pd, monoclinic, P21/n, a = 9.478(4) , b = 22.395(9) , c = 9.528 (4) , β = 104.358(11), V = 1959.3(14) 3, Z = 4. The Pd atom has planar-square coordination geometry and is surrounded by the Phen and Phe ligand to form a monovalent
complex cation, Cl− is filled in the crystal lattice as a counterion. The Cl atom is bonded to the complex cation through an electrostatic interaction
and has a very weak hydrogen bond with a water molecule. Hydrogen bonding interactions and π-π stacking interactions stabilize
the crystal lattice. The anti-cancer activity of the complex increases with the increasing concentration of the complex, which
shows that the complex has strong anti-cancer activity.
A wide variety of Platinum(II) complexes have been investigated for antitumor activity against Sarcoma 180 in Swiss white female mice. In general, only neutral complexes exhibit activity while charged species are inactive and relatively nontoxic. A series of complexes of the type cis-[PtA2X2] (where A2 is either two monodentate or one bidentate amine ligand and X2 is either two monodentate or one bidentate anionic ligand) have been studied with A and X being systematically varied. This has resulted in the identification of at least ten potentially active antitumor drugs. Trans isomers are inactive in comparison with active cis complexes and the presence of cis-reactive ligands appears to be a necessary parameter for antitumor activity. Complexes with highly reactive ligands such as cis-[Pt(NH3)2(H3O)2] (NO3)2 are highly toxic. Palladium(II) complexes, which are analogs of the active Platinum(II) compounds, have been found to be inactive.
The 1D 1H NOE difference spectra of 50 base- and/or sugar-modified nucleosides were measured in (CD3)2SO with irradiation of various protons. The resulting NOE data were used for a conformational analysis with respect to their syn-anti conformer equilibrium. Irradiation of H-8 [purine numbering (purine and pyrimidine numbering has been used for all nucleosides throughout the paper)] of the conformationally fixed compounds 25β and 41β resulted in NOE values at H-1′, Hβ-2′, and Hβ-3′, respectively, which were used to establish a calibration graph for a semiquantitative estimation of syn and anti conformer populations of β-D nucleosides. Moreover, the preferred conformations of a number of α-D nucleosides were qualitatively deduced from their 1D 1H NOE difference spectra. Measurement of the NOE spectra of sterically hindered nucleosides implied that both the chemical properties as well as the van der Waals radius of a nucleobase substituent are of decisive importance for the conformation around the N-glycosylic bond.
Aminoguanidine (AG) is a prototype therapeutic agent for the prevention of formation of advanced glycation endproducts. It reacts rapidly with alpha,beta-dicarbonyl compounds such as methylglyoxal, glyoxal, and 3-deoxyglucosone to prevent the formation of advanced glycation endproducts (AGEs). The adducts formed are substituted 3-amino-1,2,4-triazine derivatives. Inhibition of disease mechanisms, particularly vascular complications in experimental diabetes, by AG has provided evidence that accumulation of AGEs is a risk factor for disease progression. AG has other pharmacological activities, inhibition of nitric oxide synthase and semicarbazide-sensitive amine oxidase (SSAO), at pharmacological concentrations achieved in vivo for which controls are required in anti-glycation studies. AG is a highly reactive nucleophilic reagent that reacts with many biological molecules (pyridoxal phosphate, pyruvate, glucose, malondialdehyde, and others). Use of high concentrations of AG in vitro brings these reactions and related effects into play. It is unadvisable to use concentrations of AG in excess of 500 microM if selective prevention of AGE formation is desired. The peak plasma concentration of AG in clinical therapy was ca. 50 microM. Clinical trial of AG to prevent progression of diabetic nephropathy was terminated early due to safety concerns and apparent lack of efficacy. Pharmacological scavenging of alpha-oxoaldehydes or stimulation of host alpha-oxoaldehyde detoxification remains a worthy therapeutic strategy to prevent diabetic complications and other AGE-related disorders.
WinGX is a suite of Microsoft Windows™ programs for the processing, solution, refinement and publication of single-crystal diffraction data.
In modern cancer therapy the clinical application of platinum-based drugs is more and more limited by the occurrence of intrinsic or acquired resistances. In this context the potential use of dinuclear platinum complexes in chemotherapy is increasingly relevant. The novel complexes Pd(Bzdpa)Cl2, Pd2(C4H8(dpa)2)Cl4, and Pt2(C4H8(dpa)2)Cl4 allow a direct comparison of mono- and dinuclear palladium and platinum complexes respectively deriving from a 2,2′-dipyridylamine (Hdpa) ligand system. They were characterized by single crystal X-ray analysis as well as infrared spectroscopy and elemental analysis. The cisplatin analogous mononuclear palladium complex Pd(Bzdpa)Cl2 (1) (Bzdpa: (2,2′-dipyridylbenzyl)amine) belongs to a range of 2,2′-dipyridylamine-based compounds which were extensively studied in our laboratories. 1 crystallizes in the orthorhombic space group Pna21 with a = 13.722(3), b = 13.457(3), c = 9.483(2), V = 1751.1(6) Å3, and Z = 4. The metal binding motif of 1 was expanded by a flexible butyl-linker to form the tetradentate C4H8(dpa)2 ligand. The resulting isotypic dinuclear complexes Pd2(C4H8(dpa)2)Cl4·2CH3CN (2) and Pt2(C4H8(dpa)2)Cl4·2CH3CN (3) crystallize in the triclinic space group with a = 7.8427(2), b = 8.7940(2), c = 11.7645 (3), α = 79.219(2)°, β = 84.033(2)°, γ = 87.744(2)°, V = 792.58(3) Å3 (2) and a = 7.831(5), b = 8.814(5), c = 11.817(5), α = 79.271(5)°, β = 83.571(5)°, γ = 88.063(5)°, V = 796.3(8) Å3 (3), both with one centrosymmetrical molecule in the unit cell.
Metalloproteins are of utmost importance for nearly all biological processes. Valuable information about their functionalities came from mutagenesis studies and led to the de novo design of artificial proteins. Advances in peptide chemistry enable the total synthesis of complete proteins and allow the incorporation of non-proteinogenic amino acids. Chelating amino acids utilized to introduce artificial metal-binding sites into proteins should mimic the side chains of the natural residues in order to minimize structural consequences within the target proteins. In this paper a synthetic method is described for the preparation of amino acids bearing a metal ligand system connected to the β-carbon via triazole formation. Thereby, a histidine isoster is generated with an additional metal-binding site in proximity to the peptide backbone. Two representative building blocks bearing the ligands triazacyclononane (tacn) and bis(picoloyl)-amine (bpa) were synthesized and incorporated into model peptides.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
Triazoles from “click chemistry” are convenient ligands for the formation of platinum complexes bearing combined triazole–amine or triazole–carboxylate moieties. Striking differences in the chelation modes are observed between the two series. One of the triazole–amine platinum complexes exhibits selective cytotoxicity against breast cancer cells lines. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)
Some 2-[(methyleneamino)oxy]-N-(guanidino)ethaneimines (10a-g) were synthesized as analogs of guanabenz-type benzylideneaminoguanidine α2-agonists (9) in which the aryl portion (Ar) is substituted by the [(methyleneamino)oxy]methyl moiety (MAOMM). The α2-adrenergic activity of compounds 10a-g was evaluated by functional tests on guinea-pig ileum. The MAOM-derivatives 10a-g exhibited an α2-adrenergic stimulating activity fairly similar to that of the benzylideneaminoguanidine reference drug guanabenz, thus supporting the hypothesis of the existence of a bioisoster-like relationship between the MAOMM and the Ar in the class of guanabenz-type α2-adrenergic agonists.
Examination of nature's favorite molecules reveals a striking preference for making carbon–heteroatom bonds over carbon–carbon bonds—surely no surprise given that carbon dioxide is nature's starting material and that most reactions are performed in water. Nucleic acids, proteins, and polysaccharides are condensation polymers of small subunits stitched together by carbon–heteroatom bonds. Even the 35 or so building blocks from which these crucial molecules are made each contain, at most, six contiguous C−C bonds, except for the three aromatic amino acids. Taking our cue from nature's approach, we address here the development of a set of powerful, highly reliable, and selective reactions for the rapid synthesis of useful new compounds and combinatorial libraries through heteroatom links (C−X−C), an approach we call “click chemistry”. Click chemistry is at once defined, enabled, and constrained by a handful of nearly perfect “spring-loaded” reactions. The stringent criteria for a process to earn click chemistry status are described along with examples of the molecular frameworks that are easily made using this spartan, but powerful, synthetic strategy.
Cu-I-catalyzed alkyne-azide cycloaddition provides 1,4-disubstituted 1,2,3-triazoles with such efficiency and scope that the transformation has been described as "click" chemistry. An overview of the mechanism of this remarkable reaction is presented as a means to explain the myriad of experimental results, particularly the various methods of catalyst generation, solvent and substrate effects, and choice of base or ligand. Both solution-phase and solid-phase results are comprehensively examined. ((c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006).
The crystal and molecular structure of aminoguanidine hemioxalate, a salt in which aminoguanidine exists in the monocation form, was determined by single crystal X-ray diffraction. The salt crystallizes in the monoclinic space group P2(1)/n with unit cell dimensions ofa=4.95,b=10.46,c=10.40 Å, β=92.57°, andZ=4. The structure contains one oxalate ion for every two CN4H
7+ ions, the latter being practically planar. The structure of the monocation is largely similar to those of aminoguanidine dications except that the monocation is devoid of one of the protons attached to the terminal hydrazine nitrogen. This result is of interest considering the synthesis of amidinohydrazones, indicating that the concentration of the active nucleophile is nearly maximal even when aminoguanidine exists in the monocation form. Therefore, the synthesis of amidinohydrazones should be performed in thepH range in which aminoguanidine exists mainly in the monocation form,i.e. at apH higher than 2. There is, however, no need to elevate thepH to values at which a considerable proportion of aminoguanidine exists as the free base.
Two novel dinuclear palladium(II) complexes, {[Pd(en)Cl]2(bpse)}(NO3)2 (1) and {[Pd(en)Cl]2 (bpsu)}(NO3)2 (2), (where en is ethylenediamine; bpse is bis(3-methyl-4-pyridyl) selenide; bpsu is bis(3-methyl-4-pyridyl) sulfide) have been synthesized. The complexes have been characterized by elemental analysis, IR, 1H NMR, and 13C NMR. They have been assayed for antitumor activity in vitro against the mice leukemia L1210 and the human coloadenocarcinoma HCT8 cell lines. The results show that compound 1 has a lower I.D.50 value against the two cancer cell lines as compared to compound 2; the compounds also shows a lower I.D.50 value than cisplatin against the HCT8 cell line, but a higher I.D.50 value than cisplatin against the L1210 cell line. Binding studies indicate that compound 1 possibly interacts with DNA by a nonintercalative mode. Kinetics of binding of the two compounds to DNA are firstly studied using ethidium bromide as a fluorescence probe with stopped-flow spectrophotometer under pseudo-first-order condition. The stronger binding of two steps in the process of the compounds interacting with DNA are observed, and the kobs and Ea of binding of the two steps (where kobs is the observed pseudo-first-order rate constant, Ea is the observed energy of activation) are obtained.
A side-by-side comparison of the synthesis, radiolabeling, and in vitro and in vivo characterization of two new and isostructural (99m)Tc-tricarbonyl folic acid radiotracers comprising either a N(tau)-functionalized histidine (His) chelator or a 1,4-bifunctionalized 1,2,3-triazole His analogue is described. The 1,2,3-triazole-containing folic acid derivative was synthesized in approximately 80% yield by a short reaction sequence including application of click chemistry (the Cu(I)-catalyzed cycloaddition of azides and terminal alkynes). The synthesis of the ligand system and the functionalization of the folic acid derivative were accomplished simultaneously, which prompted us to call this approach "click-to-chelate". In comparison, the reported regioselective synthesis of the N(tau)-His compound provided the final product in only very low yields (<1%). While the efficiency of the syntheses differs considerably, the two isostructural folate derivatives exhibit virtually identical properties with respect to Tc-99m radiolabeling and in vitro and in vivo characteristics as shown by experiments performed with FR-positive KB cells and xenografted mice bearing folate receptor overexpressing tumors. We have demonstrated herein for the first time that a ligand system known to be an excellent chelator for the stable complexation of the organometallic core [M(CO)3] (+) (M = Tc-99m, Re) can be replaced by an isostructural 1,2,3-triazole analogue without influencing the characteristics of the radiometal conjugate. The "click-to-chelate" strategy provides a highly efficient and convenient entry to metal conjugates suitable for diagnostic and potentially therapeutic applications. The described procedures should be readily applicable to any azide-functionalized (bio)molecule and, thus, are likely to represent the method of choice for the future development of radiopharmaceuticals radiolabeled with the organometallic precursors [M(CO)3(H2O)3] (+) (M = (99m)Tc, (188)Re).
The copper(I) catalyzed azide-alkyne cycloaddition (CuAAC) is the premier example of a click reaction. The reaction is modular, reliable and easy to perform, providing easy access to molecular diversity. The majority of reported applications of the reaction employ the 1,2,3-triazole as a stable linkage to connect two chemical/biological components, while the potential for metal coordination of the heterocycle itself has received much less attention. In fact, 1,4-functionalized 1,2,3-triazoles are versatile ligands offering several donor sites for metal coordination, including N3, N2 and C5. In this article, we summarize the areas in which the CuAAC has been applied to the synthesis of novel triazole-containing ligands for transition metals.
A study was conducted to demonstrate copper(I)-NHC catalytic efficiency improvement on Huisgen reaction by adding aromatic nitrogen donors. Several unsaturated nitrogen heterocycles such as l-histidine, a ubiquitous amino acid residue associated to all types of copper enzymes, N-methylimidazole (NMI), 4-dimethylaminopyridine (4-DMAP), phenanthroline (Phen), and bathophenanthroline disulfonic sodium salt (Bathophen) were used to evaluate their influence on the CuAAC catalyzed by [CuCl(SIMes)]. The monitoring of the cycloaddition of benzyl azide and phenyl acetylene in a 2:1 tert-butyl alcohol/water mixture was also performed. It was observed that simple addition of aromatic amines increased CuAAC catalytic activity of [CuCl(SIMes)] at a large range of temperatures, which further accelerated the catalysis process in hydro-alcoholic solvents.
This feature article covers recent reports of work towards the development of (99m)Tc-carbohydrate based agents for use in SPECT imaging, particularly of cancerous tissue. An outline of some of the key biological functions and coordination chemistry of carbohydrates is given, along with an introduction to bioconjugation and molecular imaging. Technetium coordination chemistry and the subset of this involving bioconjugates are discussed before moving into the focus of the article: glycoconjugates of (99m)Tc(v) and the more recently developed [(99m)Tc(I)(CO)(3)](+). Significant work in the last decade has featured the very attractive [(99m)Tc(CO)(3)](+) core, and the ligand sets designed for this core are discussed in detail.
Azoamides, previously established as bioactive intracellular GSH-depleting agents, were decorated with a terminal alkyne moiety to 4 and then were transformed, by copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), into different ligand-arm functionalized azoamides 6. Azides 5 having ligand-arms amenable for binding to platinum(II) were selected for this study. Because, for the fragile azoamides 4, the typically employed reaction conditions for CuAAC failed, several alternative solvents and copper catalysts were tested. Excellent results were obtained with copper(II) sulfate pentahydrate/metallic copper and especially with heterogeneous catalysts, such as copper-in-charcoal, cupric oxide, and cuprous oxide. The heterogeneous catalysts were employed to obtain the desired products in almost quantitative yields by a simple three-step "stir-filter-evaporate" protocol with no or negligible contamination with copper impurities. This is of particular importance because compounds 6 have been designed for coordination.
The copper catalysis in the Huisgen reaction broadly known as the azide/ alkyne reaction or CuAAC reaction has been discussed. This simple and robust reaction, which involves clusters of Cu and ligands, has led to exclusive formation of the 1,4-isomer. It is vital to maintain a good concentration of Cu throughout the reaction medium particularly in the case of less reactive reaction components or dilute reactions. The ligands' role in protecting the copper from oxidation or disproportionation is also important. The ligands also influence the structure and equilibria of copper clusters and may promote the formation of the most catalytically active copper complexes. The CuAAC reaction may be designed to accommodate all types of protecting groups and reactive intermediates.
Guanabenz, a centrally acting antihypertensive agent, has been shown to have intestinal antisecretory properties. A series of aromatic aminoguanidine hydrazones was made in an effort to separate the antisecretory and cardiovascular activities. Benzaldehyde, naphthaldehyde, and tetralone derivatives were synthesized. The compounds were evaluated in the cholera toxin treated ligated jejunum of the rat and in the Ussing chamber using a rabbit ileum preparation. A number of compounds, including members of each structural class, were active upon subcutaneous administration in the rat. Active compounds were determined to be alpha 2-adrenergic agonists by yohimbine reversals of their Ussing chamber activities. The compound displaying the best separation of activities was the aminoguanidine hydrazone of 2,6-dimethyl-4-hydroxybenzaldehyde (20).
Torsion angles C-H between the sugar C-H bonds were deduced from X-ray data on 60 nucleosides and nucleoside phosphates with the aid of the pseudorotation model for five-membered rings. Two pseudorotation ranges were considered classified as type N [C(2′)-exo, C(3′)-endo] and type S [C(2′)-endo, C(3′)-exo] conformers, each characterized by a narrow range of the phase angle of pseudorotation P. The various values of φHH along the ring bonds, and hence the corresponding coupling constants, must obey certain interrelationships. It was shown that the coupling J2′3′ as well as the sum J1′2′ + J3′4′ should be practically independent of the position of the N ⇄ S conformational equilibrium; values taken from the literature were then used to extract a set of Karplus parameters valid for the system in question. The effect of pseudorotation (within each of the two ranges of P) on the coupling constants is explored. For all practical purposes, the percentage of S-type conformer in aqueous solution of the common nucleosides and nucleoside phosphates can be calculated by taking 10J1′2′. The purine ribosides show a small conformational preference for the S type conformer (ΔG°av = -0.12 kcal mol-1), whereas the pyrimidine derivatives slightly favor the N-type ribose conformer (ΔG°av = +0.16 kcal mol-1). Published coupling constants of two compounds in which a keto group must lie over the sugar ring, orotidine and β-cyanuric acid ribonucleoside, were reinterpreted as follows: (i) the ribose ring in these compounds is "flatter" than in the normal series, (ii) the N type conformer is favored over the S type by 0.4-0.5 kcal mol-1, and (iii) the N type rings are characterized by a higher P value than normally occurs. On the basis of known coupling cosstants of dinucleoside phosphates at various temperatures, we proposed a three-state dynamic conformational equilibrium model for the common dimers: (i) unstacked S type, (ii) unstacked N type, and (iii) fully stacked N type. The 2′,5′ dimers, A2′p5′A and A2′p5′C, behave in another manner; two stacked forms seem to be present, differing in the conformation of the 2′-ribose residue. The deoxyribose ring in all common deoxyribonucleosides and their 5′-phosphates show equilibrium compositions that are substantially biased toward the S type conformer over a wide temperature range. This preference may be due to an entropy, rather than to an enthalpy, difference.
The amplitude (τm) and phase angle of pseudorotation (P) of the sugar ring in several β-purine and β-pyrimidine nucleosides and nucleotides were calculated from the known endocyclic torsion angles. A statistical classification of the number of compounds for which P falls in a given range shows that only two relatively narrow pseudorotational ranges are preferred by β sugars in the solid, each occupying less than 10% of the total pathway.
A series of N-amino-N-substituted guanidines have been synthesized and evaluated for antiinflammatory activity.
A number of substituted indole carbazimidamides were prepared and evaluated as 5-HT4 receptor agonists by using the isolated field-stimulated guinea pig ileum preparation. Their selectivity for the 5-HT4 receptor was established by examining their affinity for other 5-HT receptors using radioligand-binding techniques. Several selective and highly potent full as well as partial agonists emerged from this study. For example, 1b,d were found to be the most potent, full 5-HT4 receptor agonist described so far (EC50 = 0.5 and 0.8 nM, respectively), being 6 and 4 times more potent than serotonin itself. On the other hand, 5b and 1h appeared as partial 5-HT4 receptor agonists in the nonstimulated guinea pig ileum preparation with potencies, evaluated against serotonin action, respectively similar (5b, Ki = 12 nM) to and 300-fold higher (1h, Ki = 0.04 nM) than serotonin.
Local delivery of serotonin (5-HT) produces a rapid edematous response in soft tissues via increased fluid extravasation which is prevented by 5-HT2 antagonists such as ketanserin or mianserin. Here we report the effects of a new class of aminoguanidine 5-HT2 antagonists, with relative selectivity for 5-HT2A receptors which are potent inhibitors of 5-HT-induced paw edema in the rat. Radioligand binding studies with 125I DOI on human 5-HT2A and 5-HT2C receptors and with 3H-5-HT on human 5-HT2B receptors demonstrated that, LY314228, and LY320954 displayed some selectivity for the 5-HT2A receptor. When compared to binding at other 5-HT2 receptor subtypes, LY314228 had an 18.6-fold greater affinity for the 5-HT2A site over the 5-HT2B site, and 2.6 fold greater at the 5-HT2C site. LY320954 displayed similar preference for 5-HT2A sites. Both compounds also inhibited 5-HT-induced paw swelling in rats, with ED50's of 6.4 and 4.8 mg/kg (for LY314228 and LY320954, respectively). These studies offer evidence for a novel class of pharmacophores for the 5-HT2 receptor family which show greater relative affinities for the 5-HT2A receptor subclass.
3-Guanidinopropionic acid (1) has been demonstrated both to improve insulin sensitivity and to promote weight loss selectively from adipose tissue in animal models of non-insulin-dependent diabetes mellitus (NIDDM). However, 1 has also been shown to be a substrate for both the creatine transporter and creatine kinase, leading to marked accumulation in muscle tissue as the corresponding N-phosphate. The corresponding aminoguanidine analogue 2 was recently discovered to retain the antidiabetic activity of 1 while being markedly less susceptible to creatine-like metabolism, suggesting that it should have less potential to accumulate in muscle. Further structural modification of 2 was undertaken to investigate whether the antidiabetic potency could be augmented while maintaining resistance to creatine-like metabolism. Modifications such as alpha-alkylation, homologation, and bioisosteric replacement of the aminoguanidine all were detrimental to antidiabetic activity. However, the simple regioisomeric aminoguanidinoacetic acid 9 and diaminoguanidinoacetic acid analogue 7 were found to be equipotent to 2, leading eventually to the discovery of the significantly more potent diaminoguanidinoacetic acid regioisomers 52 and 53. Further attempts to modify the more active template represented by 52 led only to reductions in antidiabetic activity. Each of the new active analogues displayed the same resistance to creatine-like metabolism as 2. Further testing of 7, 9, and 53 in obese diabetic ob/ob mice confirmed that weight loss is induced selectively from adipose tissue, similar to the lead 1. Administration of 53 to insulin-resistant rhesus monkeys led to reductions in both fasting and post-prandial plasma glucose levels with concomitant reductions in plasma insulin levels, suggesting that the compound improved the action of endogenous insulin. Compounds 7 and 53 were selected for further preclinical development.
Targeted cellular delivery of drugs to specific tissues is an important goal in biomedical chemistry. Achieving this requires harnessing and applying molecular-level recognition events prevalent in (or specific to) the desired tissue type. Tissues rich in estrogen receptors (ERs), which include many types of breast cancer, accumulate molecules that have high binding affinities for these receptors. Therefore, molecules that (i) bind to the ER, (ii) have favorable cellular transport properties, and (iii) contain a second functionality (such as a center that may be used for diagnostic imaging or medical therapy) are exciting synthetic targets in the field of drug delivery. To this end, we have prepared a range of metallo-estrogens based on 17alpha-ethynylestradiol and examined their binding to the ER both as isolated receptor and in whole cell assays (ER positive MCF-7 cells). Estrogens functionalized with metal binding units are prepared by palladium-catalyzed cross-coupling reactions and a wide range of metal centers introduced readily. All the compounds prepared and tested exhibit effective binding to the estrogen receptor and are delivered across the cell membrane into MCF-7 cells. In the whole cell assays, despite their monocationic nature, the palladium and platinum complexes prepared exhibit similar (and even enhanced) receptor binding affinities compared to their corresponding neutral free ligands. It is unprecedented for a higher ER binding affinity to be observed for a cationic complex than for its metal-free ligand.
Guanine O6 to carrier ligand hydrogen bonding is a central feature of many hypotheses advanced to explain the anticancer activity of cis-type anticancer drugs, cis-PtA(2)X(2) (A(2) = diamine or two amines). Early structural evidence suggested that cis-Pt(NH(3))(2)(d(GpG)) (the cross-link model for the key cisplatin-DNA adduct) and other cis-PtA(2)(d(GpG)) adducts exist exclusively or mainly as the HH1 conformer with head-to-head (HH) bases. The dynamic motion of the d(GpG) in these adducts is too rapid to permit definitive characterization of both the conformation and the H-bonding. Hence, we use retro models having A(2) ligands designed to slow the motion. Here, we employ Me(2)ppz (N,N'-dimethylpiperazine), which lacks NH groups. Me(2)ppz is unique in having sp(3) N-methyl groups directly in the coordination plane, allowing the coexistence of multiple conformers but hindering dynamic motion in Me(2)ppzPt(d(GpG)) and Me(2)ppzPt(GpG) retro models. Dynamic processes are decreased enough in Me(2)ppzPt(d(GpG)) to permit HPLC separation of three abundant forms. After HPLC separation, the three re-equilibrate, proving that the three forms must be conformers and that Me(2)ppz has little influence on conformer distribution. This marks the first reported characterization of three abundant conformers for one cis-PtA(2)(d(GpG)) adduct. From NMR evidence, the Me(2)ppzPt(d(GpG)) HH1 conformer has uncanted bases. Another conformer, one of two recently discovered conformer types, has head-to-tail (HT) bases with Delta chirality. For this Delta HT1 form, several lines of evidence establish that the dinucleotide moieties have essentially identical structures in d(GpG) (and GpG) adducts of Me(2)ppzPt and other cis-PtA(2) complexes. For example, the shifts of the highly structure-sensitive G H8 NMR signals are almost identical for the Delta HT1 form of all adducts. In previous models, the stabilization of the Delta HT1 form could be attributed to G O6 H-bonding to A(2) NH groups. Such H-bonds are not possible for Me(2)ppz. The unambiguous conclusions are that G O6 H-bonding is weak and that neither canting nor H-bonding is essential in HH forms. These two features are present in almost all other small models but are essentially absent in the cross-link base pair (bp) step in duplexes. We conclude from our work that the forces favoring canting and H-bonding are weak, and we hypothesize that steric effects within the Lippard bp step adjacent to this cross-link bp step easily overcome these forces.
The cycloaddition of azides to alkynes is one of the most important synthetic routes to 1H-[1,2,3]-triazoles. Here a novel regiospecific copper(I)-catalyzed 1,3-dipolar cycloaddition of terminal alkynes to azides on solid-phase is reported. Primary, secondary, and tertiary alkyl azides, aryl azides, and an azido sugar were used successfully in the copper(I)-catalyzed cycloaddition producing diversely 1,4-substituted [1,2,3]-triazoles in peptide backbones or side chains. The reaction conditions were fully compatible with solid-phase peptide synthesis on polar supports. The copper(I) catalysis is mild and efficient (>95% conversion and purity in most cases) and furthermore, the X-ray structure of 2-azido-2-methylpropanoic acid has been solved, to yield structural information on the 1,3-dipoles entering the reaction. Novel Fmoc-protected amino azides derived from Fmoc-amino alcohols were prepared by the Mitsunobu reaction.
Oxaliplatin, a diaminocyclohexane-containing platinum, has a spectrum of activity and mechanisms of action and resistance that appear to be different from those of other platinum-containing compounds, notably cisplatin. The first part of this review describes the differences between oxaliplatin and cisplatin in terms of their spectrum of activity and adduct formation and then goes on to discuss molecular and cellular experimental data that potentially explain them. Particular emphasis is placed on the differential role of DNA repair mechanisms. In addition, the anticancer effects of oxaliplatin are optimized when it is administered in combination with other anticancer agents, such as 5-fluorouracil, gemcitabine, cisplatin, or carboplatin; topoisomerase I inhibitors; and taxanes. In vitro and preclinical combination data that could optimize oxaliplatin-based chemotherapy are also reviewed.
IN an investigation of the possible effects of an electric field on growth processes in bacteria, we have discovered a new and interesting effect. In E. coli, the presence of certain group VIIIb transition metal compounds in concentrations of about 1-10 parts per million of the metal in the culture medium causes an inhibition of the cell division process. The bacteria form long filaments, up to 300 times the normal length, which implies that the growth process is not markedly affected.
Click chemistry is a modular approach that uses only the most practical and reliable chemical transformations. Its applications are increasingly found in all aspects of drug discovery, ranging from lead finding through combinatorial chemistry and target-templated in situ chemistry, to proteomics and DNA research, using bioconjugation reactions. The copper-(I)-catalyzed 1,2,3-triazole formation from azides and terminal acetylenes is a particularly powerful linking reaction, due to its high degree of dependability, complete specificity, and the bio-compatibility of the reactants. The triazole products are more than just passive linkers; they readily associate with biological targets, through hydrogen bonding and dipole interactions.
Click chemistry has been employed for the assembly of novel and efficient triazole-based multidentate chelating systems while simultaneously attaching them to molecules of biological interest. The "click-to-chelate" approach offers a powerful new tool for the modification of (bio)molecules with metal chelators for potential diagnostic and therapeutic applications.
Click chemistry has been utilized to access 2,6-bis(1-aryl-1,2,3-triazol-4-yl)pyridines (BTPs) as versatile extended heteroaromatic building blocks for their exploitation in supramolecular chemistry, in particular foldamer and ligand design. In addition to their high-yielding synthesis using Cu(I)-catalyzed Huisgen-type 1,3-dipolar cycloaddition reactions the formed triazole moieties constitute an integral part of the BTP framework and encode both its pronounced conformational preferences as well as its chelating ability. A diverse set of symmetrical and non-symmetrical BTPs carrying electron-donating and -withdrawing substituents at both terminal aryl and the central pyridine moieties has efficiently been synthesized and could furthermore readily be postfunctionalized with amphiphilic side chains and porphyrin chromophores. In both solution and solid state, the BTP scaffold adopts a highly conserved horseshoe-like anti-anti conformation. Upon protonation or metal coordination, the BTP scaffold switches to the chelating syn-syn conformation. Iron and europium complexes have been prepared, successfully characterized by single-crystal X-ray diffraction analysis, and investigated with regard to their spin state and luminescent properties. The extended heteroaromatic BTP scaffold should prove useful for the design of responsive foldamer backbones and the preparation of new magnetic and emissive materials.
The site-specific conjugation of metal chelating systems to biologically relevant molecules is an important contemporary topic in bioinorganic and bioorganometallic chemistry. In this work, we have used the CuI-catalyzed cycloaddition of azides and terminal alkynes to synthesise novel ligand systems, in which the 1,2,3-triazole is an integral part of the metal chelating system. A diverse set of bidentate alkyne building blocks with different aliphatic and aromatic backbones and various donor groups were prepared. The bidentate alkynes were reacted with benzyl azide in the presence of a catalytic amount of CuI to form tridentate model ligands. The chelators were reacted with [ReBr3(CO)3]2- to form well-defined and stable complexes with different overall charges, structures and hydrophilicities. In all cases tridentate coordination of the ligands, including through N3 of the 1,2,3-triazole ring, was observed. The ligand systems could also be quantitatively radiolabelled with the precursor [99 mTc (H2O)3(CO)3]+ at low ligand concentrations. Similarly the alkynes were reacted with an azido thymidine derivative to form a series of compounds, which could be radiolabelled in situ to form single products. Subsequent incubation of the neutral and cationic organometallic 99 mTc thymidine derivatives with human cytosolic thymidine kinase, a key enzyme in tumour proliferation, revealed that only the neutral compounds maintained substrate activity towards the enzyme. Bioconjugation, radiolabelling and enzymatic reactions were successfully performed in a matter of hours. Thus, click chemistry provides an elegant method for rapidly functionalising a biologically relevant molecule with a variety of efficient metal chelators suitable for (radio)labelling with the M(CO)3 core (M=99 mTc, Re), to offer new potential for technetium-99 m in clinical and preclinical tracer development.
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