Structure-activity relationship on DNA binding and anticancer activities of a family of mixed-ligand oxidovanadium(V) hydrazone complexes

The title family of mixed-ligand oxidovanadium(V) hydrazone complexes are [V^VO(HL¹)(hq)] (1) and [V^VO(HL²)(hq)] (2), where (HL¹)^2? and (HL²)^2? are the dinegative form of 2-hydroxybenzoylhydrazone of acetylacetone (H₃L¹) and benzoylacetone (H₃L²), respectively, and hq^? is the mononegative form of 8-hydroxyquinoline (Hhq). Complexes were used to determine their binding constant with CT DNA using various spectroscopic techniques namely, electronic absorption, fluorescence and circular dichroism spectroscopy. The binding constant values suggest the intercalative mode of binding with the CT DNA and follow the order: 2 > 1. The bulky size as well as electron withdrawing property of the phenyl group (which is present in the β-diketone part of the hydrazone moiety in complex 2 in place of a CH₃ group in complex 1) is responsible for the higher activity of 2 than 1. Complexes were screened for cytotoxic activity on cervical cancer cells and were found to be potentially active (IC₅₀ value for 1 and 2 is 33 and 29 μM, respectively), even better than the widely used cis-platin (IC₅₀ = 63.5 μM) and carboplatin (IC₅₀ = > 200 μM) which is evident from the respective IC₅₀ value. Nuclear staining experiment suggests that these complexes kill the SiHa cancer cells through apoptotic mode. The molecular docking study also suggested the intercalative mode of binding of these complexes with CT DNA and HPV 18 DNA.     

Evolution of 1, 3, 5-trisubstituted bipyrazole scaffold based platinum(II) complexes as a biological active agent

Abstract

Square planar mononuclear platinum(II) complexes having general formula [Pt(Lⁿ)Cl₂], (where, Lⁿ?=?L^1–4) were synthesized with neutral bidentate heterocyclic 1,3,5-trisubstituted bipyrazole based ligands. The synthesized compounds were characterized by physicochemical method such as TGA, molar conductance, micro-elemental analysis and magnetic moment, and spectroscopic method such as, FT-IR, UV–vis, ¹H NMR, ¹³C NMR and mass spectrometry. Biological applications of the compounds were carried out using in vitro brine shrimp lethality bioassay, in vitro antimicrobial study against five different pathogens, and cellular level cytotoxicity against Schizosaccharomyces pombe (S. Pombe) cells. Pt(II) complexes were tested for DNA interaction activities using electronic absorption titration, viscosity measurements study, fluorescence quenching technique and molecular docking assay. Binding constants (K_b) of ligands and complexes were observed in the range of 0.23–1.07?×?10⁵?M^?1 and 0.51–3.13?×?10⁵?M^?1, respectively. Pt(II) complexes (I–IV) display an excellent binding tendency to biomolecule (DNA) and possess comparatively high binding constant (K_b) values than the ligands. The DNA binding study indicate partial intercalative mode of binding in complex-DNA. The gel electrophoresis activity was carried out to examine DNA nuclease property of pUC19 plasmid DNA.     

Synthesis and spectroscopic characterization study of new palladium complexes containing bioactive O,O-chelated ligands: evaluation of the DNA/protein BSA interaction,in vitro antitumoural activity and molecular docking

[Pd{(C,N)–C₆H₄CH₂NH(Et) (Qu)] (2) and [Pd{(C,N)–C₆H₄CH₂NH(Et) (Nar)] (3) (Qu = Quercetin, Nar = Naringin) mononuclear palladium (II) complexes have been synthesized and characterized using elemental analysis, IR and electronic spectroscopy. The interaction of the prepared complexes with calf thymus DNA and bovine serum albumin (BSA), monitored by UV–visible and fluorescence titrations, respectively, have been carried out to better understand the mode of their action under biological conditions. Intercalative binding mode between the complexes and DNA is suggested by the binding constant (K_b) values of 2.5 × 10⁶ and 3.2 × 10⁶ for complexes 2 and 3, respectively. In particular, the in vitro cytotoxicity of the complexes on two cancer cells lines (bladder carcinoma TCC and breast cancer MCF7) showed that the compounds had broad spectrum, anti-cancer activity with low IC₅₀ values and the order of in vitro anticancer activities is consistent with the DNA-binding affinities. In the meantime, the quenching of tryptophan emission with the addition of complexes using BSA as a model protein indicated the protein binding ability. The quenching mechanisms of BSA by the complexes were static processes, according to the results obtained. The competitive binding using Warfarin, Digoxin and Ibuprofen site markers, which contain definite biding sites, demonstrated that the complexes bind to site I on BSA. Ultimately, the binding sites of DNA and BSA with the complexes have been determined by molecular modelling studies.     

Synthesis,DNA/BSA binding studies and in vitro biological assay of nickel(II) complexes incorporating tridentate aroylhydrazone and triphenylphosphine ligands

Abstract

Two new nickel (II) triphenylphosphine complexes derived from tridentate aroylhydrazone ligands [H₂L¹ = 2-hydroxy-3-methoxybenzylidene)benzohydrazone and H₂L² = N′-(2-hydroxy-3-methoxybenzylidene)-2-hydroxybenzoylhydrazone] and triphenylphosphine were prepared and their molecular structures were determined by single crystal X-ray diffraction analysis. Both nickel(II) complexes showed slightly distorted square planar geometry with one tridentate aroylhydrazone ligand coordinated through ONO donor atoms and one triphenylphosphine ligand coordinated to the nickel center through the phosphorus atom. DNA interaction studies indicated that both complexes possessed higher affinity to herring sperm DNA (HS-DNA) than the corresponding free aroylhydrazone ligand. Molecular docking investigations showed that both complexes could bind to DNA through intercalation of the phenyl rings between adjacent base pairs in the double helix. Meanwhile, bovine serum albumin (BSA) binding studies revealed the complexes could effectively interact with BSA and change the secondary structure of BSA. Further pharmacological evaluations of the synthesized complexes by in vitro antioxidant assays demonstrated high antioxidant activity against NO· and O₂˙^? radicals. The anticancer activity of each complex was assessed through in vitro cytotoxicity assays (CCK-8 kit) toward A549 and MCF-7 cancer cell and normal L-02 cell lines. Significantly, the Ni(II) complex derived from H₂L¹ ligand was found to be more effective cytotoxic toward MCF-7cancerous cell with the IC₅₀ value equaled 9.7?μM, which showed potent cytotoxic activity over standard drug cisplatin.

Abbreviations A549 human lung carcinoma cell

BSA bovine serum albumin

CCK-8 Cell Counting Kit-8

DFT density functional theory

DNA deoxyribonucleic acid

DPPH˙ 2,2-diphenyl-1-picrylhydrazyl

H₂L¹ 2-hydroxy-3-methoxybenzylidene)benzohydrazone N′-(2-hydroxy-3-methoxybenzylidene)-2-hydroxybenzoylhydrazone

H₂L² N′-(2-hydroxy-3-methoxybenzylidene)-2-hydroxybenzoylhydrazone

HOMO highest occupied molecular orbital

IC₅₀ the 50% activity

L-02 human normal liver cell

LOMO lowest unoccupied molecular orbital (LUMO)

MCF-7 human breast carcinoma cell

NO˙ nitric oxide

O₂˙^? superoxide anion

SOD superoxide dismutase

Communicated by Ramaswamy H. Sarma     

Effects of Geissoschizine Methyl Ether, an Indole Alkaloid in Uncaria Hook, a Constituent of Yokukansan, on Human Recombinant Serotonin7 Receptor

Effects of seven alkaloids, geissoschizine methyl ether (GM), hirsutine, hirsuteine, rhynchophylline, isorhynchophylline, corynoxeine and isocorynoxeine, in Uncaria hook, a constituent of the kampo medicine yokukansan, on serotonin₇ (5-HT₇) receptor were investigated using Chinese hamster ovary (CHO) cell membranes and human embryonic kidney 293 (HEK293) cells stably expressing the human recombinant 5-HT₇ receptor. A competitive binding assay using CHO membranes showed that GM (IC₅₀ = 0.034 μM) more strongly inhibited the binding of the radioligand [³H] LSD to 5-HT₇ receptor than the other alkaloids, suggesting that GM is bound to 5-HT₇ receptor. Agonistic/antagonistic effects of GM (1–50 μM) on the receptor were evaluated by measuring intracellular cAMP levels in HEK239 cells. GM (IC₅₀ = 6.0 μM) inhibited 5-HT-induced cAMP production in a concentration-dependent manner, as well as the specific 5-HT₇ receptor antagonist SB-269970 (0.1–1 μM). However, GM did not induce intracellular cAMP production as 5-HT did. These results suggest that GM has an antagonistic effect on 5-HT₇ receptor.     

Toxicity, transformation and accumulation of inorganic arsenic species in a microalga Scenedesmus sp. isolated from soil

Arsenic speciation and cycling in the natural environment are highly impacted via biological processes. Since arsenic is ubiquitous in the environment, microorganisms have developed resistance mechanisms and detoxification pathways to overcome the arsenic toxicity. This study has evaluated the toxicity, transformation and accumulation of arsenic in a soil microalga Scenedesmus sp. The alga showed high tolerance to arsenite. The 72-h 50 % growth inhibitory concentrations (IC₅₀ values) of the alga exposed to arsenite and arsenate in low-phosphate growth medium were 196.5 and 20.6 mg? L^?1, respectively. When treated with up to 7.5 mg? L^?1 arsenite, Scenedesmus sp. oxidised all arsenite to arsenate in solution. However, only 50 % of the total arsenic remained in the solution while the rest was accumulated in the cells. Thus, this alga has accumulated arsenic as much as 606 and 761 μg? g^?1 dry weight when exposed to 750 μg? L^?1 arsenite and arsenate, respectively, for 8 days. To our knowledge, this is the first report of biotransformation of arsenic by a soil alga. The ability of this alga to oxidise arsenite and accumulate arsenic could be used in bioremediation of arsenic from contaminated water and soil.     

Transition metal complexes (M = Cu, Ni and Mn) of Schiff-base ligands: Syntheses, crystal structures, and inhibitory bioactivities against urease and xanthine oxidase

Six new transition metal complexes (M = Cu(II), Ni(II) and Mn(III)) of tridentate (H₂L¹, HL²) and/or bidentate (HL³, HL⁴) Schiff-base ligands, obtained from the condensation of salicylaldehyde with glycine, N-(2-aminoethyl)morpholine, 4-(2-aminoethyl)phenylic acid and 4-(2-aminoethyl)benzsulfamide, respectively, were synthesized and structurally determined by single-crystal X-ray analysis. Complexes 1-6 were evaluated for their effect on the jack bean urease and xanthine oxidase (XO). Copper(II) complexes 1-3 (IC₅₀ = 0.43-2.25 μM) showed potent inhibitory activity against jack bean urease, comparable with acetohydroxamicacid (IC₅₀ = 42.12 μM), which is a positive reference. And these copper(II) complexes (IC₅₀ = 10.26-15.82 μM) also exhibited strong ability to inhibit activity of XO, comparable to allopurinol (IC₅₀ = 10.37 μM), which was used as a positive reference. Nickel(II) and manganese(III) complexes 4-6 showed weak inhibitory activity to jack bean urease (IC₅₀ = 4.36-8.25 μM) and no ability to inhibit XO (IC₅₀ > 100 μM).     

Synthesis,characterization, DNA interaction,and cytotoxicity of novel Pd(II) and Pt(II) complexes

Four complexes [Pd(L)(bipy)Cl]·4H₂O (1), [Pd(L)(phen)Cl]·4H₂O (2), [Pt(L)(bipy)Cl]·4H₂O (3), and [Pt(L)(phen)Cl]·4H₂O (4), where L = quinolinic acid, bipy = 2,2’-bipyridyl, and phen = 1,10-phenanthroline, have been synthesized and characterized using IR, ¹H NMR, elemental analysis, and single-crystal X-ray diffractometry. The binding of the complexes to FS-DNA was investigated by electronic absorption titration and fluorescence spectroscopy. The results indicate that the complexes bind to FS-DNA in an intercalative mode and the intrinsic binding constants K of the title complexes with FS-DNA are about 3.5?×?10⁴ M^?1, 3.9?×?10⁴ M^?1, 6.1?×?10⁴ M^?1, and 1.4?×?10⁵ M^?1, respectively. Also, the four complexes bind to DNA with different binding affinities, in descending order: complex 4, complex 3, complex 2, complex 1. Gel electrophoresis assay demonstrated the ability of the Pt(II) complexes to cleave pBR322 plasmid DNA.     

Glucose-conjugated platinum(IV) complexes as tumor-targeting agents: design,synthesis and biological evaluation

A new series of glucose-conjugated Pt(IV) complexes that target tumor-specific glucose transporters (GLUTs) was designed, synthesized, and evaluated for their anticancer activities. All six compounds, namely, A1-A6, exhibited increased cytotoxicity that were almost six fold higher than that of oxaliplatin to MCF-7 cells. These Pt(IV) complexes can be reduced to release Pt(II) complexes and cause the death of tumor cells. Simultaneously, the glycosylated Pt(IV) complexes (30.21–91.33?μM) showed lower cytotoxicity that normal LO2 cells compared with cisplatin (5.25?μM) and oxaliplatin (8.34?μM). The intervention of phlorizin as a GLUTs inhibitor increased the IC₅₀ value of the glycosylated Pt(IV) complexes, thereby indicating the potential GLUT transportability. The introduction of glucose moiety to Pt(IV) complexes can effectively enhance the Pt cellular uptake and DNA platination. Results suggested glucose-conjugated Pt(IV) complexes had potential for further study as new anticancer agents.     

Complexes of DNA bases and Watson–Crick base pairs interaction with neutral silver Agn (n = 8, 10, 12) clusters: a DFT and TDDFT study

We study the binding of the neutral Ag_n (n = 8, 10, 12) to the DNA base-adenine (A), guanine (G) and Watson–Crick –adenine-thymine, guanine-cytosine pairs. Geometries of complexes were optimized at the DFT level using the hybrid B3LYP functional. LANL2DZ effective core potential was used for silver and 6–31 + G^** was used for all other atoms. NBO charges were analyzed using the Natural population analysis. The absorption properties of Ag_n–A,G/WC complexes were also studied using time-dependent density functional theory. The absorption spectra for these complexes show wavelength in the visible region. It was revealed that silver clusters interact more strongly with WC pairs than with isolated DNA complexes. Furthermore, it was found that the electronic charge transferred from silver to isolated DNA clusters are less than the electronic charge transferred from silver to the Ag_n–WC complexes. The vertical ionization potential, vertical electron affinity, hardness, and electrophilicity index of Ag_n–DNA/WC complexes have also been discussed.     

Ruthenium(II) carbonyl complexes containing S-methylisothiosemicarbazone based tetradentate ligand: synthesis, characterization and biological applications

A series of hexa-coordinated ruthenium(II) complexes of the type [Ru(CO)(B)L ⁿ ] (n = 1–4; B = PPh₃, AsPh₃ or Py) have been synthesized by reacting dibasic quadridentate Schiff base ligands H₂L ⁿ (n = 1–4) with starting complexes [RuHCl(CO)(EPh₃)₂(B)] (E = P or As; B = PPh₃, AsPh₃ or Py). The synthesized complexes were characterized using elemental and various spectral studies including UV–Vis, FT-IR, NMR (¹H, ¹³C and ³¹P) and mass spectroscopy. An octahedral geometry was tentatively proposed for all the complexes based on the spectral data obtained. The experiments on antioxidant activity showed that the ruthenium(II) S-methylisothiosemicarbazone Schiff base complexes exhibited good scavenging activity against various free radicals (DPPH, OH and NO). The in vitro cytotoxicity of these complexes has been evaluated by MTT assay. The results demonstrate that the complexes have good anticancer activities against selected cancer cell line, human breast cancer cell line (MCF-7) and human skin carcinoma cell line (A431). The DNA cleavage studies showed that the complexes have better cleavage of pBR 322 DNA.     

Discovery of a cobalt complex with high MEK1 binding affinity

A series of Schiff base ligands (L¹–L⁵) and their cobalt(II) complexes (1–5) were designed and synthesized for MEK1 binding experiment. The biological evaluation results showed that Bis(N,N′-disalicylidene)-3,4-phenylenediamine-cobalt(II) 1 and Bis(N,N′-disalicylidene)-1,2-cyclohexanediamine-cobalt(II) 2 are much more effective than the parent Schiff bases (L¹ and L²). Importantly, 2 exhibited MEK1 binding affinity with IC₅₀71 nM, which is so far the best result for metal complexes and more potent than U0126 (7.02 μM) and AZD6244 (2.20 μM). Docking study was used to elucidate the binding modes of complex 2 with MEK1. Thus cobalt(II) complex 2 may be further developed as a novel MEK1 inhibitor.     

Endophytic fungi from Combretum leprosum with potential anticancer and antifungal activity

The recent increase in human diseases and cancers requires new drugs to combat them. Sources have been found in rare microorganisms, those from extreme habitats, and from endophytes. In this study, the biological activity of endophytic fungi associated with the Brazilian medicinal plant Combretum leprosum was assessed. Cytotoxic and antiproliferative effects were evaluated using seven human cancer cells lines (HeLa, ECV304, B16F10, J744, P388, Jurkat and k562). In addition the minimum inhibitory concentration (MIC) against pathogenic human fungal was determined using four Candida species and the filamentous fungi Cryptococcus neoformans and Trichophyton rubrum. A compound from extracts of phylotype Aspergillus oryzae CFE108 exhibited the most significant cytotoxicity effect against histiocytic sarcoma J774 (IC₅₀ of 0.80 μg?mL^?1), leukemia Jurkat (IC₅₀ of 0.89 μg?mL^?1), bladder carcinoma ECV304 (IC₅₀ of 3.08 μg?mL^?1) and cervical cancer HeLa (IC₅₀ of 2.97 μg?mL^?1). The extract from phylotypes Fusarium oxysporum CFE177 displayed antifungal activity and inhibited the growth of Candida glabrata (4 μg?mL^?1) as well as that of C. neoformans and T. rubrum with the lowest MIC being 62.5 μg?mL^?1. In addition, the fractions from A. oryzae CFE108 showed marked morphological activity (rounding up) on endothelial cells (tEnd.1 cells), which is indicative of potential antivascular activity. Our results indicate that the endophytes associated with this medicinal plant may be a source of novel drugs.     

Titanium dioxide nanoparticles preferentially bind in subdomains IB,IIA of HSA and minor groove of DNA

Titanium dioxide nanoparticles (TiO₂-NPs) interaction with human serum albumin (HSA) and DNA was studied by UV–visible spectroscopy, spectrofluorescence, circular dichroism (CD), and transmission electron microscopy (TEM) to analyze the binding parameters and protein corona formation. TEM revealed protein corona formation on TiO₂-NPs surface due to adsorption of HSA. Intrinsic fluorescence quenching data suggested significant binding of TiO₂-NPs (avg. size 14.0 nm) with HSA. The Stern–Volmer constant (K_sv) was determined to be 7.6 × 10² M^?1 (r² = 0.98), whereas the binding constant (K_a) and number of binding sites (n) were assessed to be 5.82 × 10² M^?1 and 0.97, respectively. Synchronous fluorescence revealed an apparent decrease in fluorescence intensity with a red shift of 2 nm at Δλ = 15 nm and Δλ = 60 nm. UV–visible analysis also provided the binding constant values for TiO₂-NPs–HSA and TiO₂-NPs-DNA complexes as 2.8 × 10² M^?1 and 5.4 × 10³ M^?1. The CD data demonstrated loss in α-helicity of HSA and transformation into β-sheet, suggesting structural alterations by TiO₂-NPs. The docking analysis of TiO₂-NPs with HSA revealed its preferential binding with aromatic and non-aromatic amino acids in subdomain IIA and IB hydrophobic cavity of HSA. Also, the TiO₂-NPs docking revealed the selective binding with A-T bases in minor groove of DNA.     

Metal complexes of naphthoquinone based ligand: synthesis,characterization, protein binding,DNA binding/cleavage and cytotoxicity studies

Protein binding, DNA binding/cleavage and in vitro cytotoxicity studies of 2-((3-(dimethylamino)propyl)amino)naphthalene-1,4-dione (L) and its four coordinated M(II) complexes [M(II) = Co(II), Cu(II), Ni(II) and Zn(II)] have been investigated using various spectral techniques. The structure of the ligand was confirmed by spectral and single crystal XRD studies. The geometry of the complexes has been established using analytical and spectral investigations. These complexes show good binding tendency to bovine serum albumin (BSA) exhibiting high binding constant values (10⁵ M^?1) when compared to free ligand. Fluorescence titration studies reveal that these compounds bind strongly with CT-DNA through intercalative mode (K_app 10⁵ M^?1) and follow the order: Cu(II) > Zn(II) > Ni(II) > Co(II) > L. Molecular docking study substantiate the strength and mode of binding of these compounds with DNA. All the complexes efficiently cleaved pUC18-DNA via hydroxyl radical mechanism and the Cu(II) complex degraded the DNA completely by converting supercoiled form to linear form. The complexes demonstrate a comparable in vitro cytotoxic activity against two human cancer cell lines (MCF-7 and A-549), which is comparable with that of cisplatin. AO/EB and DAPI staining studies suggest apoptotic mode of cell death, in these cancer cells, with the compounds under investigation.     

Molecular docking,PASS analysis,bioactivity score prediction,synthesis, characterization and biological activity evaluation of a functionalized 2-butanone thiosemicarbazone ligand and its complexes

2-Butanone thiosemicarbazone ligand was prepared by condensation reaction between thiosemicarbazide and butanone. The ligand was characterized by ¹H NMR, ¹³C NMR, FT-IR, mass spectrometry and UV spectroscopic studies. Docking studies were performed to study inhibitory action against topoisomerase II (Topo II) and ribonucleoside diphosphate reductase (RR) enzymes. Inhibition constants (K _i ) of the ligand were 437.87 and 327.4 μM for the two enzymes, respectively. The ligand was tested for its potential anticancer activity against two cancer cell lines MDA-MB-231 and A549 using MTT assay and was found to exhibit good activity at higher doses with an IC₅₀ = 80 μM against human breast cancer cell line MDA-MB-231. On the other hand, no significant activity was obtained against the lung carcinoma cell line A549. Antibacterial activity of the ligand was tested against Staphylococcus aureus and E. coli using the disc diffusion method. Ligand did not exhibit any significant antibacterial activity. Four complexes of Co(III), Fe(II), Cu(II), and Zn(II) were prepared with the ligand and characterized by various spectroscopic studies. Low molar conductance values were obtained for all complexes displaying non-electrolyte nature except in Co(III) complex. As expected, complexation with metal ions significantly increased the cytotoxicity of the ligand against the tested cell lines viz. IC₅₀ values of <20 μM for Co, Fe, and Zn complexes and approx. 80 μM against MDA cells versus IC₅₀ value of <20 μM for Co and Cu complexes and that of 30 and 50 μM for Fe and Zn complexes, respectively, against A549 cells. The Cu complex was found to be active against E. coli and S. aureus with MIC values in the range of 6–10 mg/mL. Other than Cu, only Co complex was found to possess antibacterial activity with MIC values of 5–10 mg/mL when tested against S. aureus. Bioactivity score and Prediction of Activity Spectra for Substances (PASS) analysis also depicted the drug-like nature of ligand and complexes.     

4-Bromo-4’-chloro pyrazoline analog of curcumin augmented anticancer activity against human cervical cancer,HeLa cells: in silico-guided analysis,synthesis, and in vitro cytotoxicity

Abstract

Inspired by the synergistic effects of hetero-aromatic scaffolds on curcumin, a novel array of pyrazoline substituted curcumin analogs was designed. Multi-scale computational studies were carried out to target the proposed analogs on human kinase β (IKK-β), a potential anti-cancer target. In molecular docking analysis, all the eleven molecules were observed to bind the target site and 4-bromo-4’-chloro analog displayed three hydrogen bond interactions with a docking score of –11.534?kcal/mol higher than parent molecule, curcumin (docking score = –7.12?kcal/mol) as the propellant shaped of analogs aided in proper binding with Kinase Domain binding pocket. The molecular dynamics and simulations studies revealed that the stable complexes of lead molecule were developed as the minimal deviations per residue of protein found within the range of 0.11 to 0.92?Å. The proposed compounds were synthesized, characterized and biologically evaluated against human cervical cancer cell line, HeLa, using standard MTT cell assay. Bio-evaluation studies exhibited superior cytotoxic profile for many analogs as Chloro bromo analog with IC₅₀ value (8.7?µg/mL) exhibited fivefolds improvement in the potency in comparison to curcumin (IC₅₀ = 42.4?µg/mL) but was less potent than the standard drug, paclitaxel (IC₅₀ = 0.008µg/mL). The apoptotic effect was evaluated in the terms of caspase-3 enzyme cleavage and exhibited 70.5% of apoptosis significantly (p?<?0.05) higher than 19.9% induced by curcumin. In short, 4-bromo-4’-chloro analog was the potent cytotoxic agent in this structural class and must be evaluated further under a set of stringent parameters for transforming in to a clinically viable therapeutic molecule.

Communicated by Ramaswamy H. Sarma     

Bisindolylmethane thiosemicarbazides as potential inhibitors of urease: Synthesis and molecular modeling studies

Bisindolylmethane thiosemicarbazides 1-18 were synthesized, characterized by ¹H NMR and ESI MS and evaluated for urease inhibitory potential. All analogs showed outstanding urease inhibitory potentials with IC₅₀ values ranging between 0.14?±?0.01 to 18.50?±?0.90?μM when compared with the standard inhibitor thiourea having IC₅₀ value 21.25?±?0.90?μM. Among the series, analog 9 (0.14?±?0.01?μM) with di-chloro substitution on phenyl ring was identified as the most potent inhibitor of urease. The structure activity relationship has been also established on the basis of binding interactions of the active analogs. These binding interactions were identified by molecular docking studies.     

Novel fluorine‐containing chiral hydrazide‐hydrazones: Design,synthesis, structural elucidation,antioxidant and anticholinesterase activity,and in silico studies

In this study, a series of fluorine‐containing chiral hydrazide‐hydrazone derivatives [III‐XII] from ?‐cysteine ethyl ester hydrochloride was synthesized as new antioxidant and anticholinesterase agents. The antioxidant activity of these derivatives was evaluated by ABTS^+· and DPPH^· scavenging and CUPRAC assays and the anticholinesterase activity by the Ellman method spectrophotometrically. The results of the antioxidant assay showed that compounds V , IX , and X exhibited higher activity than BHT and α‐tocopherol used as positive standards. Among the synthesized derivatives, compound IX (IC₅₀: 2.3 ± 1.6 μM) exhibited higher acetylcholinesterase inhibitory activity than galantamine (IC₅₀: 4.5 ± 0.8 μM). Compounds XI (IC₅₀: 9.6 ± 1.0 μM), IX (IC₅₀: 12.5 ± 1.6 μM), III (IC₅₀: 16.0 ± 1.6 μM), X (IC₅₀: 17.2 ± 1.8 μM), VI (IC₅₀: 20.2 ± 0.8 μM), XII (IC₅₀: 21.5 ± 1.0 μM), and VII (IC₅₀: 24.6 ± 0.6 μM) displayed better butyrylcholinesterase inhibitory activity than galantamine (IC₅₀: 46.03 ± 0.14 μM). ADME‐Tox analysis was used to probe the drug‐like properties of the compounds. Molecular docking studies were also applied to understand the interactions between compounds and targets. The docking calculations were supported by the experimental data. In particular, compound IX , having better activity than galantamine against acetylcholinesterase and butyrylcholinesterase enzymes, was visualized using molecular docking.     

Effect of lipophilicity of amylamine and amylglycine ligands on biological activity of new anticancer cisplatin analog

Investigation of side effects and solubility of anticancer drugs is a major challenge in chemotherapy science. Thus, design and synthesis of cisplatin analogs with higher lipophilicity as novel water-soluble anticancer drugs is valuable. In this work, two new Pt(II) complexes were synthesized with formula cis-[Pt(NH₃)₂(amylgly)]NO₃ and cis-[Pt(amylamine)₂(amylgly)]NO₃, where gly is penthyl glycine as an amino acid. The new compounds were synthesized and extensively characterized using analytical techniques; spectroscopic methods, and conductivity measurement. The anticancer activity of synthesized complexes was investigated against colon cancer cell line HCT116 using MTT assay and results showed excellent anticancer activity with Cc₅₀ values of 36 and 270 M after 24-h incubation time for cis-[Pt(NH₃)₂(amylgly)]NO₃ and cis-[Pt(NH₂-amyl)₂(amylgly)]NO₃, respectively; which is lower than that for cisplatin. These complexes were also interacted with highly polymerized calf thymus DNA and the binding mode of the complexes to CT-DNA was evaluated by fluorescence, circular dichroism, and UV spectroscopy. The calculation of binding and thermodynamic of Pt(II) complexes with CT-DNA can provide deeper insight into mechanism of the action of these types of complexes with nucleic acids. So, thermodynamic parameters were also determined according to isothermal titration. In comparison with cis-[Pt(NH₃)₂(amylgly)]NO₃ in DNA interaction, the result show that cis-[Pt(NH₂-amyl)₂(amylgly)]NO₃ has higher affinity with binding constant K_f = 8.72 mM to CT-DNA. The results indicate that cis-[Pt(amylamine)₂(amylgly)]NO₃ with large and bulky aliphatic group bind to CT-DNA by different modes and covalent and groove bindings were preferred mode of interaction with DNA.