In Vitro and In Silico Studies of Human Tyrosyl-DNA Phosphodiesterase 1 (Tdp1) Inhibition by Stereoisomeric Forms of Lipophilic Nucleosides: The Role of Carbohydrate Stereochemistry in Ligand-Enzyme Interactions

Inhibition of human DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (Tdp1) by different chiral lipophilic nucleoside derivatives was studied. New Tdp1 inhibitors were found in the series of the studied compounds with IC₅₀ = 2.7–6.7 μM. It was shown that D-lipophilic nucleoside derivatives manifested higher inhibition activity than their L-analogs, and configuration of the carbohydrate moiety can influence the mechanism of Tdp1 inhibition.     

Novel Tdp1 Inhibitors Based on Adamantane Connected with Monoterpene Moieties via Heterocyclic Fragments

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a promising target for anticancer therapy due to its ability to counter the effects topoisomerase 1 (Top1) poison, such as topotecan, thus, decreasing their efficacy. Compounds containing adamantane and monoterpenoid residues connected via 1,2,4-triazole or 1,3,4-thiadiazole linkers were synthesized and tested against Tdp1. All the derivatives exhibited inhibition at low micromolar or nanomolar concentrations with the most potent inhibitors having IC₅₀ values in the 0.35–0.57 µM range. The cytotoxicity was determined in the HeLa, HCT-116 and SW837 cancer cell lines; moderate CC₅₀ (µM) values were seen from the mid-teens to no effect at 100 µM. Furthermore, citral derivative 20c, α-pinene-derived compounds 20f, 20g and 25c, and the citronellic acid derivative 25b were found to have a sensitizing effect in conjunction with topotecan in the HeLa cervical cancer and colon adenocarcinoma HCT-116 cell lines. The ligands are predicted to bind in the catalytic pocket of Tdp1 and have favorable physicochemical properties for further development as a potential adjunct therapy with Top1 poisons.     

Topo I inhibition,DNA photocleavage,Molecular docking and cytotoxicities of two new phenanthroline-based ruthenium complexes

Two ruthenium complexes containing a new phenanthroline-based ligand pai (pai = 2-(5-(1, 10- phenanthroline))-1H-acenaphtho[1′,2′:4,5]imidazole) were synthesized and characterized. Two ruthenium complexes were found to cleave DNA under irradiation, interact with CT-DNA by intercalation. Furthermore, DNA topoisomerase inhibition experiments indicated that complex 2 exhibited higher topoisomerase I inhibition activity (IC₅₀ = 10 μM) than complex 1 (IC₅₀ = 40 μM). Molecular modeling studies revealed that complex 2 stabilized Top1cc complex via π-π interaction and the formation of hydrogen bond. The cytotoxicity of complexes 1 and 2 against Eca-109 and A549 cells was also evaluate by MTT method, indicating that complex 2 exhibited good anticancer activity against Eca-109 cells (IC₅₀ = 17.23 ± 0.22 μM), but two ruthenium complexes displayed weak anticancer activity against A549 cells.     

Podophyllotoxin aza-analogue, a novel DNA topoisomerase II inhibitor

The pendant E-ring moiety of the podophyllotoxin aza-analogue 1 that is a potent inhibitor of microtubule assembly was modified in order to acquire inhibitory activity of DNA topoisomerase II. The monophenolic analogue 2 did not exhibit human topoisomerase II inhibition, while the ortho-quinone 3 that was obtained by oxidation of 2 inhibited its catalytic activity (decatenation) in a dose-dependent manner and stimulated double strand DNA breaks in supercoiled circular plasmid DNA, resulting in the production of linear DNA. These results showed that the topoisomerase II inhibition of the ortho-quinone 3 is due to stabilization of the topoisomerase II-DNA covalent binary complex. On the other hand, the ortho-quinone 3 did not inhibit the relaxation process of supercoiled DNA by topoisomerase I at concentrations up to 400 microM, nor was intercalation observed in unwinding measurements of 3. Therefore, the ortho-quinone 3 was shown to be a novel nonintercalative topoisomerase II specific inhibitor that stabilizes the cleavable complex. The present results suggest that the 4'-free hydroxyl group on the E-ring and the sugar moiety on the C-ring are not a prerequisite for topoisomerase II inhibition by podophyllotoxin derivatives.     

Synthesis and characterization of Ru(II)-DMSO-Cl-chalcone complexes: DNA binding, nuclease, and topoisomerase II inhibitory activity

The complexes of type cis-[Ru(S-DMSO)(3)(R-CO-CH═CH-R')Cl] (R = 2-hydroxyphenyl for all, R' = phenyl 1, naphthyl 2, anthracenyl 3, thiophene 4, 3-methyl thiophene 5) are synthesized and characterized using spectroscopic (IR, (1)H and (13)C NMR, and UV-vis) and single crystal X-ray diffraction techniques. Their crystal structures show the formation of both intermolecular and intramolecular H-bonding. The molecular assembly of complex 5 using secondary interactions provides a butterfly structure. The binding of complexes with calf thymus DNA is monitored using UV-vis spectral titrations. The binding interaction of complexes 1, 2, and 3 with DNA increases with increasing conjugation of aromatic rings. However, complexes 4 and 5 interact with DNA strongly. The emission from ethidium bromide (EB) bound DNA recorded in phosphate buffer solution (pH = 7.2) decreases by incremental addition of solution of the complexes. The complexes 4 and 5 (100 μM) bind with the minor groove of DNA and cleave double-stranded pBR322 DNA significantly even in the absence of an activator. In the presence of H(2)O(2), they cleave supercoiled DNA via oxidative pathway even at lower concentration (20 μM). Both complexes 4 and 5 inhibit topoisomerase II activity with IC(50) values of 18 and 13. These values suggest that 4 and 5 are potential topoisomerase II inhibitors as compared to some of known inhibitors like novobiocin and etoposide.     

New designed DNA light switch Ruthenium complexes as DNA photocleavers and Topoisomerase I inhibitors

Two ruthenium complexes containing a new ligand phipz (phipz = 2‐(1,10‐phenanthroline)‐1H‐imidazo[4,5‐b]phenazine) were designed and synthesized. These complexes were found to inhibit the DNA supercoiled relaxation mediated by topoisomerase I (topo I), cleave DNA under irradiation and bind to calf thymus DNA through intercalative mode. Furthermore, complex 2 shows higher photocleavage activity, topo I inhibition activity and DNA affinity than complex 1 . Additionally, introduction of phenazine unit may be the reason that two complexes exhibit DNA ‘light switch’ behavior. The present work shows that two complexes might be potential as new DNA ‘light switches’, DNA photocleavers and topo I inhibitors.     

TCM active ingredient oxoglaucine metal complexes: crystal structure, cytotoxicity, and interaction with DNA

The alkaloid oxoglaucine (OG), which is a bioactive component from traditional Chinese medicine (TCM), was synthesized by a two-step reaction and used as the ligand to react with transition metal salts to give four complexes: [OGH][AuCl(4)]·DMSO (1), [Zn(OG)(2)(H(2)O)(2)](NO(3))(2) (2), [Co(OG)(2)(H(2)O)(2)](ClO(4))(2) (3), and [Mn(OG)(2)(H(2)O)(2)](ClO(4))(2) (4). The crystal structures of the metal complexes were confirmed by single crystal X-ray diffraction. Complex 1 is an ionic compound consisting of a charged ligand [OGH](+) and a gold complex [AuCl(4)](-). Complexes 2-4 all have similar structures (inner-spheres), that is, octahedral geometry with two OG coordinating to one metal center and two aqua ligands occupying the two apical positions of the octahedron, and two NO(3)(-) or ClO(4)(-) as counteranions in the outer-sphere. The complexation of OG to metal ion was confirmed by ESI-MS, capillary electrophoresis and fluorescence polarization. The in vitro cytotoxicity of these complexes toward a various tumor cell lines was assayed by the MTT method. The results showed that most of these metal-oxoglaucine complexes exhibited enhanced cytotoxicity compared with oxoglaucine and the corresponding metal salts, with IC(50) values ranging from 1.4 to 32.7 μM for sensitive cancer cells, which clearly implied a positive synergistic effect. Moreover, these complexes appeared to be selectively active against certain cell lines. The interactions of oxoglaucine and its metal complexes with DNA and topoisomerase I were investigated by UV-vis, fluorescence, CD spectroscopy, viscosity, and agarose gel electrophoresis, and the results indicated that these OG-metal complexes interact with DNA mainly via intercalation. Complexes 2-4 are metallointercalators, but complex 1 is not. These metal complexes could effectively inhibit topoisomerase I even at low concentration. Cell cycle analysis revealed that 1-3 caused S-phase cell arrest.     

Synthesis,characterization, DNA binding,topoisomerase I inhibition,and antiproliferation activities of (di-<Emphasis Type="Italic">tert</Emphasis>-butylbipyridine) platinum(II) complexes

Two mononuclear Pt(II) complexes, Pt(dbbpy)Cl₂ (1) and [Pt(dbbpy)₂](PF₆)₂ (2) (dbbpy?=?4,4′-ditertbutyl-2,2′-biyridine) were synthesized and characterized by single-crystal X-ray diffraction analysis, elemental analysis, ¹H NMR, and ESI–MS. Their binding affinities for both double-stranded (DS) calf thymus DNA (ct-DNA) and G-quadruplex DNA (HT21 and BCL-2) were investigated. In addition to structural differences, complex 1 displayed higher binding affinity for DS ct-DNA, whereas positively charged complex 2 was selective for binding to G-quadruplex DNA over DS DNA. The time-dependent cleavage of supercoiled circular plasmid pBR322 DNA by 1 was observed using agarose gel electrophoresis, whereas complex 2 hardly cleaved DS DNA. Stabilization of G-quadruplex HT21 DNA by both complexes was assessed by PCR stop assays. Both complexes exhibited moderate activities for inhibition of topoisomerase I as well as modest antiproliferation activities toward cancer cells in CKK-8 assays.     

Topoisomerase I inhibitory and photocleavage activity of non‐dppz DNA ‘light switches’ based on ruthenium complexes containing nitro group

A new polypyridyl ligand containing a nitro group and two new ruthenium complexes of it were synthesized. The two complexes exhibited non‐dppz DNA ‘light switch’ effects after interaction with calf thymus DNA. Introducing both electron‐withdrawing group (─ NO₂) and electron‐donating group (─ CH₃) may be the reason that the two complexes display DNA ‘light switch’ behaviors. Furthermore, one of the complexes showed higher photocleavage activity, topoisomerase I inhibition activity and DNA affinity than the other. The present work shows that the more active complex can be employed as a non‐dppz DNA ‘light switch’, DNA photocleaver and topoisomerase I inhibitor. In addition, the two complexes have no or weak cytotoxic activities against Eca‐109 and A549 cells.     

Formation and structure of 1:1 complexes between aryl hydroxamic acids and vanadate at neutral pH

Although aryl hydroxamic acids are well-known to form coordination complexes with vanadate (V(V)), the nature of these complexes at neutral pH and submillimolar concentrations, the conditions under which such complexes inhibit various serine amidohydrolases, is not well established. A series of qualitative and quantitative experiments, involving UV/vis, (1)H NMR, and (51)V NMR spectroscopies, established that both 1:1 and 1:2 vanadate/hydroxamate complexes form at pH 7.5, with the former dominating at submillimolar concentrations. Formation constants for the complexes of several aryl and alkyl hydroxamic acids were determined; for example, for benzohydroxamic acid, the stepwise formation constants of the 1:1 and 1:2 complexes were 3000 and 400 M(-1), respectively. The (51)V chemical shift of the 1:1 4-nitrobenzohydroxamic acid complex was -497 ppm, and that of its unsubstituted analogue was -498 ppm. A (1)H-(15)N HSQC spectrum of the 4-nitrobenzo-(15)N-hydroxamic acid/vanadate complex indicated the presence of an N-H group with (15)N and (1)H chemical shifts of 115 and 5.83 ppm, respectively. A (13)C NMR spectrum of the complex of 4-nitrobenzo-(13)C-hydroxamic acid with vanadate displayed a resonance at 170.1 ppm and thus a coordination-induced shift (CIS) of +3.8 ppm. In contrast, the CIS value of an established 1:2 complex, thought to contain chelated hydroxamic acid ligands, was +11.9 ppm. These spectral data led to the following structural picture of 1:1 complexes of vanadate and aryl hydroxamic acids. They contain penta- or hexa-coordinated vanadium. The ligand is in the hydroxamate rather than hydroximate form. The ligand is presumably bound to vanadium through the hydroxamic hydroxyl oxygen, but the hydroxamic acid carbonyl oxygen interacts weakly with vanadium. These species are the most likely candidates for the inhibitors of serine amidohydrolases found in vanadate/hydroxamic acid mixtures.     

trans-Dichloro(triphenylarsino)(N,N-dialkylamino)platinum(II) Complexes: In Search of New Scaffolds to Circumvent Cisplatin Resistance

The high incidence of the resistance phenomenon represents one of the most important limitations to the clinical usefulness of cisplatin as an anticancer drug. Notwithstanding the considerable efforts to solve this problem, the circumvention of cisplatin resistance remains a challenge in the treatment of cancer. In this work, the synthesis and characterization of two trans-dichloro(triphenylarsino)(N,N-dialkylamino)platinum(II) complexes (1 and 2) were described. The trypan blue exclusion assay demonstrated an interesting antiproliferative effect for complex 1 in ovarian carcinoma-resistant cells, A2780cis. Quantitative analysis performed by ICP-AES demonstrated a scarce ability to platinate DNA, and a significant intracellular accumulation. The investigation of the mechanism of action highlighted the ability of 1 to inhibit the relaxation of supercoiled plasmid DNA mediated by topoisomerase II and to stabilize the cleavable complex. Cytofluorimetric analyses indicated the activation of the apoptotic pathway and the mitochondrial membrane depolarization. Therefore, topoisomerase II and mitochondria could represent possible intracellular targets. The biological properties of 1 and 2 were compared to those of the related trans-dichloro(triphenylphosphino)(N,N-dialkylamino)platinum(II) complexes in order to draw structure–activity relationships useful to face the resistance phenotype.     

Molecular drug design, synthesis and structure elucidation of a new specific target peptide based metallo drug for cancer chemotherapy as topoisomerase I inhibitor

To evaluate the biological preference of metallopeptide drugs in cancer cells, a new dinuclear copper(II) complex [Cu(2)(glygly)(2)(ppz)(H(2)O)(4)]·2H(2)O (1) (glygly = glycyl glycine anion and ppz = piperazine), was designed and synthesized as topoisomerase I inhibitor. The structural elucidation of the complex was done by elemental analysis, spectroscopic methods and single crystal X-ray diffraction. The in vitro DNA binding studies of complex 1 with CT DNA were carried out by employing different optical methods viz. UV-vis, fluorescence and circular dichroism. The molecular docking technique was also utilized to ascertain the mechanism and mode of action towards the molecular target DNA and enzymes. Complex 1 cleaves pBR322 DNA via an oxidative mechanism and strongly binds to the DNA minor groove. Furthermore, complex 1 exhibits significant inhibitory effects on the catalytic activity of topoisomerase I at a very low concentration, ~12.5 μM, in addition to its excellent SOD mimics (IC(50)~0.086 μM).     

Adamantane-Monoterpenoid Conjugates Linked via Heterocyclic Linkers Enhance the Cytotoxic Effect of Topotecan

Inhibiting tyrosyl-DNA phosphodiesterase 1 (TDP1) is a promising strategy for increasing the effectiveness of existing antitumor therapy since it can remove the DNA lesions caused by anticancer drugs, which form covalent complexes with topoisomerase 1 (TOP1). Here, new adamantane–monoterpene conjugates with a 1,2,4-triazole or 1,3,4-thiadiazole linker core were synthesized, where (+)-and (−)-campholenic and (+)-camphor derivatives were used as monoterpene fragments. The campholenic derivatives 14a–14b and 15a–b showed activity against TDP1 at a low micromolar range with IC₅₀ ~5–6 μM, whereas camphor-containing compounds 16 and 17 were ineffective. Surprisingly, all the compounds synthesized demonstrated a clear synergy with topotecan, a TOP1 poison, regardless of their ability to inhibit TDP1. These findings imply that different pathways of enhancing topotecan toxicity other than the inhibition of TDP1 can be realized.     

Solution and solid state 13C NMR and X-ray studies of genistein complexes with amines. Potential biological function of the C-7, C-5, and C4'-OH groups

Parent genistein and its new amine complexes with morpholine and piperazine were studied comparatively in the solid and liquid states by X-ray crystallography and 13C and 15N NMR spectroscopy. Biochanine A and its complexes were used as reference. Secondary deuterium isotope effects on 13C chemical shifts in solution were studied in parent isoflavones and their morpholine and piperazine complexes to aid in evaluation of the electronic distribution in both systems. In addition, to quantify the extent of proton transfer as well as to establish strong hydrogen bonding of the 7-OH group in a morpholine complex, proton transfer from the 7-OH group to the piperazine nitrogen atom was also confirmed by 13C NMR in the solid state and by X-ray studies. The effect of 7-OH deprotonation yields a high frequency shift of 7-8 ppm on the C-7 carbon atom of the piperazine complex whereas it is as large as 12 ppm in the morpholine complex in the solid. The former trend is confirmed from solution state concentration studies which also show that the isoflavones have a strong tendency to form complexes with bases. Depending on the pKa difference between the isoflavones and the base this leads either to proton transfer and ion-pair formation or, in the case of a larger pKa difference, to a hydrogen bonded ion pair. The concentration studies show formation of a 1:1 genistein-piperazine complex in DMSO. Addition of water leads to formation of solvent separated ions. The C-5 OH group is involved in strong intramolecular hydrogen bonding leading to a pseudo aromatic ring extending the aromatic part of the drug pharmacophore. The analysis also suggests the way that both the C-7 and C-4' hydroxyl group of genistein may participate in stabilising the ternary inhibitor complexes of tyrosine-specific kinases or DNA topoisomerase II.     

Human topoisomerase I poisoning: docking protoberberines into a structure-based binding site model

Summary Using the X-ray crystal structure of the human topoisomerase I (top1) – DNA cleavable complex and the Sybyl software package, we have developed a general model for the ternary cleavable complex formed with four protoberberine alkaloids differing in the substitution on the terminal phenyl rings and covering a broad range of the top1-poisoning activities. This model has the drug intercalated with its planar chromophore between the −1 and +1 base pairs flanking the cleavage site, with the nonplanar portion pointing into the minor groove. The ternary complexes were geometry-optimized and relative interaction energies, computed by using the Tripos force field, were found to rank in correct order the biological potency of the compounds; in addition, the model is also consistent with the top1-poisoning inactivity of berberine, a major prototype of the protoberberine alkaloids. The model might serve as a rational basis for elaboration of the most active compound as a lead structure, in order to develop more potent top1 poisons as next generation anti-cancer drugs.     

Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors

A new type of berberine derivatives was obtained by the reaction of berberrubine with aliphatic sulfonyl chlorides. The new polycyclic compounds have a sultone ring condensed to C and D rings of a protoberberine core. The reaction conditions were developed to facilitate the formation of sultones with high yields without by-product formation. Thus, it was shown that the order of addition of reagents affects the composition of the reaction products: when sulfochlorides are added to berberrubine, their corresponding 9-O-sulfonates are predominantly formed; when berberrubine is added to pre-generated sulfenes, sultones are the only products. The reaction was shown to proceed stereo-selectively and the cycle configuration was confirmed by 2D NMR spectroscopy. The inhibitory activity of the synthesized sultones and their 12-brominated analogs against the DNA-repair enzyme tyrosyl-DNA phosphodiesterase 1 (Tdp1), an important target for a potential antitumor therapy, was studied. All derivatives were active in the micromolar and submicromolar range, in contrast to the acyclic analogs and 9-O-sulfonates, which were inactive. The significance of the sultone cycle and bromine substituent in binding with the enzyme was confirmed using molecular modeling. The active inhibitors are mostly non-toxic to the HeLa cancer cell line, and several ligands show synergy with topotecan, a topoisomerase 1 poison in clinical use. Thus, novel berberine derivatives can be considered as candidates for adjuvant therapy against cancer.     

Synthesis,physicochemical elucidation,biological screening and molecular docking studies of a Schiff base and its metal(II) complexes

A Schiff base 1-((3-nitrophenylimino)methyl)naphthalen-2-olate (HL) and its two novel complexes with Zn(II) and Co(II) metals were successfully synthesized and characterized by FTIR, ¹H NMR, ¹³C NMR, elemental analysis, magnetic susceptibility, TGA and EIS-MS. Crystal of Schiff base was also characterized by X-ray analysis and experimental parameters were found in line with the theoretical parameters. Quantum mechanical approach was also used to compare structural and calculated parameters and to ensure the geometry of metal complexes. The photometric behaviors of all the synthesized compounds were investigated in a wide pH range using BR buffers. Appearance of isosbestic point suggested the existence of Schiff base molecules in different tautomeric forms. Binding of synthesized complexes with calf thymus DNA was explored by photometric and voltammetric titrations and binding constants were calculated. The results indicated that ligand and its metal complexes bind to DNA by intercalation mode. Docking studies indicate their binding possibilities with topoisomerase II. Moreover, all these prepared compounds were screened for enzyme inhibition, antibacterial, cytotoxic and in vivo antidiabetic activities and found active against one or other activity. This effort just provides preliminary data for some biological properties and which can act as foundation stone for their application in drug development.     

New Potential Pharmacological Targets of Plant-Derived Hydroxyanthraquinones from Rubia spp.

The increased use of polyphenols nowadays poses the need for identification of their new pharmacological targets. Recently, structure similarity-based virtual screening of DrugBank outlined pseudopurpurin, a hydroxyanthraquinone from Rubia cordifolia spp., as similar to gatifloxacin, a synthetic antibacterial agent. This suggested the bacterial DNA gyrase and DNA topoisomerase IV as potential pharmacological targets of pseudopurpurin. In this study, estimation of structural similarity to referent antibacterial agents and molecular docking in the DNA gyrase and DNA topoisomerase IV complexes were performed for a homologous series of four hydroxyanthraquinones. Estimation of shape- and chemical feature-based similarity with (S)-gatifloxacin, a DNA gyrase inhibitor, and (S)-levofloxacin, a DNA topoisomerase IV inhibitor, outlined pseudopurpurin and munjistin as the most similar structures. The docking simulations supported the hypothesis for a plausible antibacterial activity of hydroxyanthraquinones. The predicted docking poses were grouped into 13 binding modes based on spatial similarities in the active site. The simultaneous presence of 1-OH and 3-COOH substituents in the anthraquinone scaffold were emphasized as relevant features for the binding modes’ variability and ability of the compounds to strongly bind in the DNA-enzyme complexes. The results reveal new potential pharmacological targets of the studied polyphenols and help in their prioritization as drug candidates and dietary supplements.     

Transition state analogues for nucleotidyl transfer reactions: Structure and stability of pentavalent vanadate and phosphate ester dianions

The structures and energy of phosphate dimethyl ester and vanadate dimethyl ester have been calculated using B3LYP/TZVP density functional quantum chemical methods and polarized continuum (PCM) and Langevin dipoles solvation models. These calculations were carried out to obtain fundamental information on the ability of vanadate esters to function as transition state analogues for the nucleotidyl transfer reaction catalyzed by DNA polymerases. Base-catalyzed methanolysis of the phosphate and vanadate dimethyl esters were the model reactions examined in this study. The structures of the phosphate and vanadate dimethyl esters and pentavalent intermediates in aqueous solution were optimized and evaluated at the PCM/B3LYP/TZVP level. The three-dimensional free energy surfaces for the studied reactions were determined at the PCM/B3LYP/TZVP//B3LYP/TZVP level. Comparison with experimental structural data obtained from the Cambridge Structural Database and with the observed kinetics of phosphate diester hydrolysis demonstrated that the level of theory chosen for these studies was appropriate. The results showed that structurally and electrostatically the vanadate dimethylester and a five-coordinate nearly trigonal bipyramidal intermediate were reasonable analogues for the parent phosphorus systems. Despite these similarities in structure, the energetics of the two systems were different, and the transition states of the two model reactions were found on different areas of the potential energy surface. When the binding energy of a transition state-DNA polymerase complex was extrapolated to a transition state analogue-DNA polymerase complex, the formation of a simple dianionic pentavalent vanadate ester adduct in the enzyme active site was not found to be sufficiently favorable. This finding suggests that additional stabilization of this adduct is needed before this type of transition state analogue will be likely to yield stable adducts with this class of enzymes. New possible candidates for such complexes are suggested.     

Biocatalysis,DNA–protein interactions,cytotoxicity and molecular docking of Cu(II), Ni(II), Zn(II) and V(IV) Schiff base complexes

Four mononuclear metal complexes (Cu(II) ( 1 ), Ni(II) ( 2 ), Zn(II) ( 3 ) and V(IV) ( 4 )) were synthesized using the Schiff base ligand 2,2′‐{cyclohexane‐1,2‐diylbis[nitrilo(1E )eth‐1‐yl‐1‐ylidine]}bis[5‐(prop‐2‐yn‐1‐yloxy)phenol] and structurally characterized by various spectral techniques. The catecholase‐mimicking activities of 1 – 4 were investigated and the results reveal that all the complexes have ability to oxidize 3,5‐di‐tert ‐butylcatechol (3,5‐DTBC) to 3,5‐di‐tert ‐butylquinone in aerobic conditions. Electrospray ionization mass spectrometry studies were performed for 1 – 4 in the presence of 3,5‐DTBC to determine the possible complex–substrate intermediates. X‐band electron paramagnetic resonance spectroscopy results indicate that the metal centres are involved in the catecholase activity. Ligand‐centred radical generation was further confirmed by density functional theory calculation. The phosphatase‐like activity of 1 – 4 was investigated using 4‐nitrophenylphosphate as a model substrate. All the complexes exhibit excellent phosphatase activity in acetonitrile medium. The interactions of 1 – 4 with calf thymus DNA (CT‐DNA) and bovine serum albumin (BSA) protein were investigated using absorption and fluorescence titration methods. All the complexes strongly interact with CT‐DNA and BSA protein. The complexes exhibit significant hydrolytic cleavage of supercoiled pUC19 DNA. Complexes 1 – 4 exhibit significant in vitro cytotoxicity against MCF7 (human breast cancer) and MIA‐PA‐CA‐2 (human pancreatic cancer) cell lines. Moreover, the molecular docking technique was employed to determine the binding affinity with DNA and protein molecules.