Biophysical insight into anti-amyloidogenic nature of novel ionic Co(II)(phen)(H2O)4]+[glycinate]- chemotherapeutic drug candidate against human lysozyme aggregation.

In the recent past, there has been an ever-increasing interest in the search for metal-based therapeutic drug candidates for protein misfolding disorders (PMDs) particularly neurodegenerative disorders such as Alzheimer's, Parkinson's, Prion's diseases, and amyotrophic lateral sclerosis. Also, different amyloidogenic variants of human lysozyme (HL) are involved in hereditary systemic amyloidosis. Metallo-therapeutic agents are extensively studied as antitumor agents, however, they are relatively unexplored for the treatment of non-neuropathic amyloidoses. In this work, inhibition potential of a novel ionic cobalt(II) therapeutic agent (CoTA) of the formulation [Co(phen)(H2O)4]+[glycinate]- is evaluated against HL fibrillation. Various biophysical techniques viz., dye-binding assays, dynamic light scattering (DLS), differential scanning calorimetry (DSC), electron microscopy, and molecular docking experiments validate the proposed mechanism of inhibition of HL fibrillation by CoTA. The experimental corroborative results of these studies reveal that CoTA can suppress and slow down HL fibrillation at physiological temperature and pH. DLS and 1-anilino-8-naphthalenesulfonate (ANS) assay show that reduced fibrillation in the presence of CoTA is marked by a significant decrease in the size and hydrophobicity of the aggregates. Fluorescence quenching and molecular docking results demonstrate that CoTA binds moderately to the aggregation-prone region of HL (Kb = 6.6 × 104 M-1), thereby, inhibiting HL fibrillation. In addition, far-UV CD and DSC show that binding of CoTA to HL does not cause any change in the stability of HL. More importantly, CoTA attenuates membrane damaging effects of HL aggregates against RBCs. This study identifies inorganic metal complexes as a therapeutic intervention for systemic amyloidosis.

Quercetin-phenylalanine 3d-transition metal-based {Co(II), Ni(II) & Cu(II)} intercalative therapeutic agents: DNA & BSA interaction studies in vitro and cleavage activity.

New Quercetin-phenylalanine metal-based therapeutic agents of the formulation [Qu(Phe)M(II).(H2O)2].NO3 where M(II) = Co(II) and Ni(II) and [Qu(Phe)Cu(II).(H2O)2] were synthesized and their structure was predicted by IR, UV-vis, EPR and ESI-MS spectroscopic techniques. The bio-molecular interaction studies of the Quercetin-phenylalanine complexes, 1-3 with ct-DNA and BSA were performed using a battery of complimentary biophysical techniques. The corroborative results of these experiments revealed strong binding propensity via electrostatic interactions probably through minor grove binding towards ct-DNA, therapeutic target. The binding affinity of Quercetin-phenylalanine complexes 1-3 was quantified by determining binding constants values, Kb, Ksv, and the magnitude of binding propensity followed the order 3 > 1 > 2, implicating the preferential binding of Cu(II) complex 3 with ct-DNA. The cleavage studies were performed with complexes using gel electrophoretic mobility assay. The complexes 1-3 demonstrated efficient cleaving ability by the hydrolytic cleavage pathway involving hydroxyl (OH) radicals. BSA binding profile of Quercetin-phenylalanine metal therapeutics 1-3 was studied in order to understand the drug carrier potential of these compounds and found that complex 3 was capable of binding preferentially with BSA as compared to other complexes.

Synthesis and structural elucidation of a unique turn-off fluorescent sensor based on oxo-bridged tin (IV) cluster for selective detection of dopamine in biological fluids.

An oxo-bridged Sn (IV) Cluster, (TOC) was synthesized and fully characterized by FT-IR, UV-vis, 1H NMR, 119Sn NMR, Mass spectrometry and single crystal X-ray diffraction studies. The single-crystal X-ray analysis revealed that the crystal crystallizes in the monoclinic crystal system possessing the P 21/c space group and exhibited a distorted trigonal bipyramidal geometry. The TOC exhibited a unique turn-off fluorescence response for the selective detection of dopamine (DA) over other analytes. The stoichiometry between the TOC and DA was calculated using Job's plot. The value of the detection limit was found to be 1.33 µM. The Hirshfeld surface analysis was carried out on the crystal structure to investigate the H-H, Cl-H, Cl-Cl, Sn-Cl and Cl-C interaction studies in the molecule. Density Functional Theory (DFT) studies further supported the sensing mechanism, which closely agreed with the experimental results. Furthermore, the TOC chemosensor was used to detect DA in human blood plasma, and molecular docking studies validated the interaction between the chemosensor and protein. Confocal fluorescence imaging studies were carried out and validated TOC sensing ability for DA in human blood plasma.

Structural insights into interactions of new polymeric (µ-oxo) bridged Cu(II) complexes of taurine with yeast tRNA by spectroscopic and computational approaches and its application towards chemoresistant cancer lines.

RNA-targeted drugs are considered as safe treatment option for the cure of many chronic diseases preventing off-targeted delivery and acute toxic manifestations. FDA has approved many such RNA therapies in different phases of clinical trials, validating their use for the treatment of various chronic diseases. We report herein, new water-soluble (µ-oxo) bridged polymeric Cu(II) complexes of taurine (2-aminoethane sulfonic acid) complexes 1 and 2. The therapeutic potency of 1 and 2 was ascertained by studying biophysical interactions with tRNA/ct-DNA. The experimental results demonstrated that the complexes interacted avidly to nucleic acids through intercalation mode depicting a specific preference for tRNA in comparison to ct-DNA and, moreover 2 showed higher binding propensity than 1. The electrophoretic behaviour of the complexes with plasmid pBR322 DNA and tRNA were examined by gel mobility assay that revealed a concentration-dependent activity with complex 2 performing more efficient cleavage as compared to complex 1. Cytotoxicity results on cancer cell strains displayed higher cytotoxicity than complex 1 against treated cancer cells. The synthesized copper(II) taurine complexes have met the basic criteria of anticancer drug design as they are structurally well-characterized, exhibiting good solubility in water, lipophilic in nature with superior intercalating propensity towards tRNA and cytotoxic in nature.

Revelation of potential bioactive water-soluble Boc-L-valine and imidazole appended metal complexes {M = Co(II), Cu(II) & Zn(II)}: synthesis, characterization, ct-DNA binding, pBR322 cleavage, SOD mimetic, and cytotoxicity studies.

Bio-compatible water-soluble conjugates of Co(II), Cu(II) and Zn(II) (1-3), [Co(Boc-L-valine)2(imidazole)2], [Cu(Boc-L-valine)2(imidazole)2], and [Zn(Boc-L-valine)2(imidazole)2], were synthesized and comprehensively characterized by various spectroscopic techniques (UV-visible, FT-IR, ESI-MS, EPR, 1H NMR, 13C NMR) and single crystal X-ray diffraction which showed that the complexes 1-3 crystallized in an orthorhombic crystal system, in a slightly distorted octahedral geometry having the space group P21212. Density functional theory calculations were performed to correlate the energy of frontier molecular orbitals with the stability and reactivity of the complexes. In vitro DNA binding interaction studies of complexes were performed by employing various biophysical techniques and their corroborative results revealed (i) the electrostatic mode of binding in the groove region of DNA, (ii) pBR322 plasmid cleavage at a low concentration of 5-12.5 µM via an oxidative pathway in complexes 1 and 2 and the hydrolytic mechanism in the case of 3, (iii) changes in the 1H NMR chemical shift values of the NH2 group of GMP after interaction with complex 3, (iv) alteration in the EPR parameters of complex 2 after complexation with DNA, (v) SOD mimetic activity of complex 2 with the IC50 value of 2.08 µM and (vi) a good and selective cytotoxicity profile against chemo-resistant MCF-7 and MDA-MB-231 cancer cell lines by complex 1. Molecular docking studies complemented the spectroscopic results and confirmed the electrostatic interaction of complexes in the groove region of DNA.

Progress of Metal-Based Anticancer Chemotherapeutic Agents in Last two Decades and their Comprehensive Biological (DNA/RNA Binding, Cleavage and Cytotoxicity Activity) Studies.

During last two decades, there has been an enormous growth in the discovery of innovative active inorganic anticancer complexes (exerting remarkable cytotoxicity at sub micro-molar levels) derived from myriad ligand scaffolds, mainly acting on cancerous vs healthy cells by either halting or inhibiting their uncontrolled growth. The phenomenal success of cisplatin to treat numerous forms of solid malignancies has placed metal-based drugs to the forefront of treatment strategies against cancers. More than 10,000 platinum anticancer complexes have been developed during the past 40 years, but only five drugs have been approved for usage in humans while ten more complexes are currently undergoing clinical trials. Most of the compounds have failed either at R&D stages or in preclinical trails. This has led to extensive investigations by researchers of medicinal chemistry, including our group to design and prepare tailored 3d-metallo-drugs and organotin(IV) compounds from some naturally occurring bioactive compounds, such as amino-acids, peptides, chromone derivatives and NSAID's etc. that were used either alone or in cocktail combination, capable of specifically targeting DNA, lnc RNAs and proteins. Furthermore, 3d-metal ions such as copper, cobalt and zinc etc. incorporated in these ligand framework are biocompatible and induce a unique multi-modal mechanism of cytotoxic action involving angiogenesis, ROS-induced DNA damage, apoptosis by p53 mitochondrial genes and caspases etc. The results observed a positive correlation between the binding affinity of complexes with DNA (as quantified by intrinsic binding constant values) and their cytotoxic behavior. Complexes with high DNA binding propensity were typically lethal against a diverse panel of malignant cell types compared to normal cells.

A novel Cu(II)-based DNA-intercalating agent: Structural and biological insights using biophysical and in silico techniques.

A new mixed-ligand Cu(II) complex formulated as [Cu(dipic)(amp)(H2O)].H2O (dipic: pyridine-2,6-dicarboxylic acid, amp: 2-amino-4-methylpyridine), was synthesized and structurally characterized by FTIR spectroscopy, CHN analysis, and the single-crystal X-ray crystallographic method. The complex crystallizes in an orthorhombic space group Pna21, and the coordination environment around the metal center was found to be a pentacoordinate CuN2O2OW distorted square-pyramidal geometry. In order to systematically explore a detailed in vitro and in silico study of the DNA binding of the title complex, various biophysical (UV-Vis absorption spectroscopy, fluorescence, competitive binding with ethidium bromide) and theoretical (DFT, molecular docking simulation, and QM/MM) methods were applied which revealed that the complex could intercalate with the insertion of the amp ligand between the DNA base pairs. The experimental thermodynamic parameters of the interaction revealed the spontaneity of the process and the domination of the hydrophobic interactions in the association and stabilization of the DNA-Cu(II) complex adduct, which was in line with the docking and QM/MM data. In vitro cytotoxic potential of the complex against the human breast adenocarcinoma (MCF-7) cells was examined using MTT assay, which indicated that cancerous cells showed inhibition in presence of the complex.

Advances in anticancer alkaloid-derived metallo-chemotherapeutic agents in the last decade: Mechanism of action and future prospects.

Metal-based complexes have occupied a pioneering niche in the treatment of many chronic diseases, including various types of cancers. Despite the phenomenal success of cisplatin for the treatment of many solid malignancies, a limited number of metallo-drugs are in clinical use against cancer chemotherapy till date. While many other prominent platinum and non­platinum- based metallo-drugs (e.g. NAMI-A, KP1019, carboplatin, oxaliplatin, titanocene dichloride, casiopeinas® etc) have entered clinical trials, many have failed at later stages of R&D due to deleterious toxic effects, intrinsic resistance and poor pharmacokinetic response and low therapeutic efficacy. Nonetheless, research in the area of medicinal inorganic chemistry has been increasing exponentially over the years, employing novel target based drug design strategies aimed at improving pharmacological outcomes and at the same time mitigating the side-effects of these drug entities. Over the last few decades, natural products became one of the key structural motifs in the anticancer drug development. Many eminent researchers in the area of medicinal chemistry are devoted to develop new 3d-transition metal-based anticancer drugs/repurpose the existing bioactive compounds derived from myriad pharmacophores such as coumarins, flavonoids, chromones, alkaloids etc. Metal complexes of natural alkaloids and their analogs such as luotonin A, jatrorrhizine, berberine, oxoaporphine, 8-oxychinoline etc. have gained prominence in the anticancer drug development process as the naturally occurring alkaloids can be anti-proliferative, induce apoptosis and exhibit inhibition of angiogenesis with better healing effect. While some of them are inhibitors of ERK signal-regulated kinases, others show activity based on cyclooxygenases-2 (COX-2) and telomerase inhibition. However, the targets of these alkaloid complexes are still unclear, though it is well-established that they demonstrate anticancer potency by interfering with multiple pathways of tumorigenesis and tumor progression both in vitro and in vivo. Over the last decade, many significant advances have been made towards the development of natural alkaloid-based metallo-drug therapeutics for intervention in cancer chemotherapy that have been summarized below and reviewed in this article.

Ru(II)(ƞ6-p-cymene) Conjugates Loaded onto Graphene Oxide: An Effective pH-Responsive Anticancer Drug Delivery System.

Graphene oxide-based nanodrug delivery systems are considered one of the most promising platforms to deliver therapeutic drugs at the target site. In this study, Ru(II)(ƞ6-p-cymene) complexes containing the benzothiazole ligand were covalently anchored on graphene oxide using the ultrasonication method. The nanoconjugates GO-NCD-1 and GO-NCD-2 were characterized by FT-IR, UV-visible, 1H NMR, TGA, SEM, and TEM techniques, which confirmed the successful loading of both the complexes (NCD 1 and NCD 2) on the carrier with average particle diameter sizes of 17 ± 6.9 nm and 25 ± 6.5 nm. In vitro DNA binding studies of the nanoconjugates were carried out by employing various biophysical methods to investigate the binding interaction with the therapeutic target biomolecule and to quantify the intrinsic binding constant values useful to understand their binding affinity. Our results suggest (i) high Kb and Ksv values of the graphene-loaded conjugates (ii) effective cleavage of plasmid DNA at a lower concentration of 7.5 µM and 10 µM via an oxidative pathway, and (iii) fast release of NCD 2 at an acidic pH that could have a good impact on the controlled delivery of drug. It was found that 90% of the drug was released in an acidic pH (5.8 pH) environment in 48 h, therefore suggesting pH-responsive behavior of the drug delivery system. Molecular docking, DFT studies, and cytotoxicity activity against three cancer cell lines by SRB assay were also performed.

Water soluble transition metal [Ni(II), Cu(II) and Zn(II)] complexes of N-phthaloylglycinate bis(1,2-diaminocyclohexane). DNA binding, pBR322 cleavage and cytotoxicity.

To validate the effect of metal ions in analogous ligand scaffolds on DNA binding and cytotoxic response, we have synthesized a series of water-soluble ionic N-phthaloylglycinate conjugated bis(diaminocyclohexane)M2+ complexes where M = Ni(II), Cu(II) and Zn(II) (1-3). The structural characterization of the complexes (1-3) was achieved by spectroscopic {FT-IR, EPR, UV-vis absorption data, 1H NMR, ESI-MS and elemental analysis} and single crystal X-ray diffraction studies, which revealed different topologies for the late 3d-transition metals. The Ni(II) and Zn(II) complexes exhibited an octahedral geometry with coordinated labile water molecules in the P1̄ space group while the Cu(II) complex revealed a square planar geometry with the P21/c space lattice. In vitro DNA-complexation studies were performed employing various complementary biophysical methods to quantify the intrinsic binding constant Kb and Ksv values and to envisage the binding modes and binding affinity of (1-3) at the therapeutic targets. The corroborative results of these experiments revealed a substantial geometric and electronic effect of (1-3) on DNA binding and the following inferences were observed, (i) high Kb and Ksv values, (ii) remarkable cleavage efficiency via an oxidative pathway, (iii) condensation behavior and (iv) good cytotoxic response to HepG2 and PTEN-caP8 cancer cell lines, with copper(II) complex 2 outperforming the other two complexes as a most promising anticancer drug candidate. Copper(II) complexes have been proven in the literature to be good anticancer drug entities, displaying inhibition of uncontrolled-cell growth by multiple pathways viz., anti-angiogenesis, inducing apoptosis and reactive oxygen species mediated cell death phenomena. Nickel(II) and zinc(II) ionic complexes 1 and 3 have also demonstrated good chemotherapeutic potential in vitro and the bioactive 1,2-diaminocyclohexane fragment in these complexes plays an instrumental role in anticancer activity.

Apigenin alleviates cancer drug Sorafenib induced multiple toxic effects in Swiss albino mice via anti-oxidative stress.

Sorafenib is an FDA-approved chemotherapeutic drug used as standard therapy for advanced-stage cancers. However, Sorafenib-induced multiple adverse effects are a major limitation that directly impacts patients' physical and physiological well-being. Therefore, it is vital to identify agents that can lessen the associated adverse effects and enhance efficacy. Apigenin, a dietary plant flavone, is a bioactive-compound present in fruits and vegetables having anti-oxidant, anti-inflammatory, and anti-cancer properties. Our study aimed to investigate Sorafenib-induced toxic effects at genomic, cellular, and tissue level and the potential protective effects of Apigenin. To achieve our goal, we treated Swiss albino mice with Apigenin (50 mg/kg bw) alone or in combination with Sorafenib (40 mg/kg bw). Next, we performed DNA interaction, genotoxicity, oxidative damages, anti-oxidant activities, liver enzyme levels, and histopathological studies. We demonstrated that Apigenin and Sorafenib bind DNA via electrostatic interaction. Further, Sorafenib induces genetic, oxidative, and tissue damages characterized by an increase in chromosomal aberrations and micronucleus, reactive oxygen species (ROS) and reactive nitrogen species (RNS), oxidative and DNA damage, lipid peroxidation, and hepato-renal damages, and a decrease in antioxidant-enzymes. Interestingly, the Sorafenib-induced adverse effects were ameliorated by Apigenin. Our findings indicate that Apigenin has protective effects against Sorafenib-induced toxicity and could be combined with Sorafenib to lessen its adverse effects and enhance its efficacy. However, further pre-clinical and clinical studies are required to evaluate Apigenin's effectiveness with Sorafenib.

Biophysical binding profile with ct-DNA and cytotoxic studies of a modulated nanoconjugate of umbelliferone cobalt oxide loaded on graphene oxide (GO) as drug carrier.

In an attempt to identify suitable nano-carriers for drug delivery, natural drug umbelliferone was chosen to synthesize new modulated nanoconjugate of umbelliferone cobalt oxide with cobalt (II) nitrate in one pot assembly in the presence of tannic acid. The synthesized nanoconjugate drug (NCD) was then loaded on graphene oxide (GO) as drug carrier by simple ultrasonication method and thoroughly characterized by various spectroscopic techniques (FT-IR, SEM, TEM, XRD, EPR and thermogravimetric analysis) which revealed the successful loading of the nanoconjugate drug on GO. The UV-visible, fluorescence and electrochemical studies suggested that strong π-π stacking interactions exist between nanoconjugate drug and GO. The binding studies of NCD-GO with ct-DNA were performed by various optical and biophysical methods viz., UV-visible, fluorescence, circular dichroism (CD) and cyclic voltammetry (CV) which indicated electrostatic mode of binding towards the ct-DNA. Furthermore, condensate of nanoconjugate drug-loaded GO (NCD-GO) with ct-DNA was prepared and analyzed by scanning electron microscopy (SEM) which revealed that the interaction of NCD-GO with ct-DNA had occurred. Cleavage activity of NCD-GO with pBR322 was evaluated by gel electrophoresis and it was found that NCD-GO cleave DNA through hydrolytic pathway involving hydroxyl radical (OH). The cytotoxicity of NCD-GO was evaluated against human liver carcinoma (Huh-7), prostate cancer (Du-145) cell lines along with normal cell line (PNT 2). The results obtained showed selective cytotoxic activity of NCD-GO against Du-145 cell lines. The intracellular uptake was visualized by confocal microscopy which revealed the significant cellular uptake and internalization of nanoparticles by cells. Moreover, the adsorption of cobalt oxide umbelliferone on GO was studied by density functional theory. The process of adsorption was found exothermic in nature and the optimized geometry structure is quite stable. Communicated by Ramaswamy H. Sarma.

Deciphering the effect of hydrophobicity on protein binding interaction in cobalt(II) complexes by multispectroscopic and computational methods.

In the present work, we report the synthesis, characterization of two cobalt complexes (1 and 2) and their HSA binding studies by multispectroscopic methods. Hirshfeld surfaces analysis and fingerprint plot analysis were carried out to identify intermolecular interactions viz., N-H···O, O-H···O and C-H···O linkages in crystal framework of the complexes. Density functional theory (DFT) studies were carried out to ascertain the electronic structure and molecular geometry of the complexes 1 and 2, and determine the localization of HOMO and LUMO in the complexes. A comparative in vitro interaction study of complex 1 and 2 with human serum albumin protein was carried out by employing UV-vis, fluorescence, circular dichroism, FTIR and molecular docking techniques. Interestingly, the HSA binding affinity of complex 2 was found to be more than complex 1 which was evidenced from the higher binding constant values owing to its strong hydrophobic topology. Further, a significant conformational change in microenvironment of HSA was noticed upon binding with complexes 1 and 2, nevertheless more perturbations were noticed in presence of complex 1. Molecular docking studies were carried out to validate the spectroscopic results and ascertain the preferential binding mode of complexes at the specific target site of HSA.Communicated by Ramaswamy H. Sarma.

Structure elucidation, in vitro binding studies and ROS-dependent anti-cancer activity of Cu(II) and Zn(II) phthaloylglycinate(phen) complexes against MDA-MB-231 cells.

New mononuclear Cu(II) and Zn(II)-based complexes 1 [Cu(L)2(diimine)HOCH3] and 2 [Zn(L)2(diimine)] have been synthesized as anti-cancer chemotherapeutics targeted to tRNA. The structure elucidation of complexes 1 and 2 was carried out by spectroscopic and single X-ray diffraction studies. In vitro interaction studies of complexes 1 and 2 with ct-DNA/tRNA were performed by employing various biophysical techniques to evaluate and predict their interaction behavior and preferential selectivity at biomolecular therapeutic targets. The corroborative results of the interaction studies demonstrated that complexes 1 and 2 exhibited avid binding propensity via intercalative mode of binding toward ct-DNA/tRNA. Electrophoretic assay revealed that the complexes 1 and 2 were able to promote single- and double-strand cleavage of the plasmid DNA at low micromolar concentrations under physiological conditions in the absence of an additional oxidizing or reducing agent. RNA hydrolysis studies revealed that the complexes 1 and 2 could promote tRNA cleavage in a concentration and time-dependent manner. The cytotoxic potential of complexes 1 and 2 was evaluated against the MDA-MB-231 cell line, which showed that the complexes were able to inhibit the cell growth in a dose-dependent manner. The intracellular ROS production and mitochondrial superoxide anion assay revealed that the complexes 1 and 2 induce a dose-dependent activity, suggesting the involvement of ROS-mediated mitochondrial apoptotic pathway leading to cell death.

Biochemical pathways of copper complexes: progress over the past 5 years.

Copper is an essential trace element with vital roles in many metalloenzymes; it is also prominent among nonplatinum anticancer metallodrugs. Copper-based complexes are endogenously biocompatible, tenfold more potent than cisplatin, exhibit fewer adverse effects, and have a wide therapeutic window. In cancer biology, copper acts as an antitumor agent by inhibiting cancer via multiple pathways. Herein, we present an overview of advances in copper complexes as 'lead' antitumor drug candidates, and in understanding their biochemical and pharmacological pathways over the past 5 years. This review will help to develop more efficacious therapeutics to improve clinical outcomes for cancer treatments.

Molecular docking, DFT and antimicrobial studies of Cu(II) complex as topoisomerase I inhibitor.

Herein, we report the synthesis and single crystal X-ray structure of Cu(II)-picolinic acid complex, 1 as a potent topoisomerase I inhibitor. The complex 1 crystallized in the triclinic crystal system with space group P-1. Comparative in vitro binding studies of complex 1 with CT DNA and tRNA were carried out revealing an electrostatic binding mode with higher binding propensity towards tRNA. The intrinsic bonding constant value, Kb was calculated to be 4.36 × 104 and 8.78 × 104 M-1 with CT DNA and tRNA respectively. DNA cleavage activity was carried out with a pBR322 plasmid DNA substrate to ascertain the cleaving ability. Furthermore, Topo-I inhibition assay of complex 1, performed via gel electrophoresis revealed a significant inhibitory effect on the enzyme catalytic activity at a minimum concentration of 15 µM. The DFT studies were carried out to provide better insight in the electronic transitions observed in the absorption spectrum of the complex 1. Molecular docking studies were carried out with DNA, RNA and Topo-I to determine the specific binding preferences at the target site and complement the spectroscopic studies. The antimicrobial potential of complex 1 was screened against E. coli, S. aureus, P. aeruginosa, B. subtilis and C. albicans; and compared with doxycycline, exhibiting an excellent maximum zone of inhibition of 28 mm against E. coli.Communicated by Ramaswamy H. Sarma.

RNA-targeted Cu(II)-based potential antitumor drug entity: comprehensive structural, biological {DNA/RNA binding, cleavage, cytotoxicity} and computational studies.

Copper-based bis(hydroxy naphthaldehyde) complex with axial mono aqua-coordination was synthesized and thoroughly characterized by various spectroscopic{IR, UV-vis, EPR}, ESI-Mass and single X-ray crystallographic studies. The single X-ray crystallography of the complex revealed the square pyramidal coordination geometry with P21 space group with axial water molecule ligated to copper centre. The geometry of the complex was further validated by DFT calculations, which was in accordance with other spectroscopic studies. The binding profile of the complex with ct-DNA and tRNA was carried out by employing various biophysical (absorption, fluorescence, circular dichroism, morphological studies) and computational studies (DFT, molecular docking). The experimental results revealed efficient binding of the complex with both ct-DNA and tRNA primarily, via non-covalent interactions. The binding studies Kb and K values revealed 10-fold greater binding affinity of the complex for tRNA as compared to ct-DNA. The in silico molecular docking further validated the interaction of complex within the hydrophobic pocket of ct-DNA and tRNA. The concentration and time dependent cleavage studies of DNA and tRNA were performed by employing gel electrophoresis assay. The cytotoxic activity of the complex was performed on a panel of human cell lines viz., leukemia (K-562), pancreatic (MIA-PA-CA-2), hepatoma (Hep-G2), cervical (HeLa), and breast (MDA-MB-231) by SRB assay. The complex exhibited selectively remarkably good cytotoxic potential on leukemia (K-562), cervical (HeLa) and hepatoma (Hep-G2) cancer cell lines.Communicated by Ramaswamy H. Sarma.

"Turn-on" benzophenone based fluorescence and colorimetric sensor for the selective detection of Fe2+ in aqueous media: Validation of sensing mechanism by spectroscopic and computational studies.

A diaminobenzophenone Schiff base derived probe 1, was synthesized and structure elucidation was carried out by spectroscopic studies viz., FT-IR, UV-vis, 1H, and 13C NMR and mass spectrometry. The sensing phenomenon with different metal ions (Cr3+, Mn2+, Fe2+, Fe3+, Co2+, Ni2+, Cu2+, Zn2+, Cd2+) was investigated by employing absorption and fluorescence titrations, which demonstrated that probe 1 exhibited selective fluorescent sensing behavior towards Fe2+ ion among various other metal ions. The porobes selceteclivity towards Fe2+ was also examined by colorimetric assay which revealed a change in the color from light yellow to brown upon addition of Fe2+ ion. A remarkable increase in the fluorescence intensity of probe 1 was observed towards Fe2+ ion, which was found to be associated with the inhibition of photoinduced electron-transfer (PET) and CN isomerization processes, respectively. The chemosensor exhibited an association constant value of 6.173 × 107 M-2 as determined by using non-linear least square fit data. Job's plot calculated the binding stoichiometry, and the sensing phenomenon of Fe2+ towards the probe was further supported by Density Functional Theory (DFT) calculations and 1H NMR studies. The detection limit of probe 1 was found to be 0.0363 µM, which is below the permissible limits according to the WHO guideline (5 µM) for Fe2+ ions in the drinking water. Furthermore, the practical application of probe 1 was studied by analyzing the content of Fe2+ in different water samples.

Water soluble ionic Co(II), Cu(II) and Zn(II) diimine-glycinate complexes targeted to tRNA: structural description, in vitro comparative binding, cleavage and cytotoxic studies towards chemoresistant prostate cancer cells.

Four new water soluble Co(ii), Cu(ii) and Zn(ii) ionic metal complexes (1-4) [Cu(diimine)(H2O)2(glycinate)]+[glycinate]-, [Co(diimine)(H2O)4]+[glycinate]- and [Zn(diimine) (H2O)4]+[glycinate]-, where diimine = 2,2'-bipyridine (1-3) and 1,10-phenanthroline (4) were synthesized and thoroughly characterized by spectroscopic and single X-ray crystallographic studies. Complex 1 possesses a triclinic crystal system with a penta-coordinated geometry whereas complexes 2-4 crystallized in an isostructural monoclinic system having distorted octahedral geometry. Density functional theory (DFT) studies for complexes 1-4 were performed to correlate their geometrical parameters and to calculate the energy of frontier molecular orbitals. The corroborative results of spectroscopic and voltammetric studies with ct-DNA and tRNA revealed that the complexes bind noncovalently via an electrostatic mode of binding with specificity for tRNA as compared to ct-DNA. Gel electrophoresis experiments revealed that all the complexes unwind the plasmid pBR322 DNA at low micromolar concentrations (2-9 µM) following an oxidative mechanism for Cu(ii) and Co(ii) complexes (1, 2 and 4) whereas the Zn(ii) complex (3) mediates DNA cleavage by the hydrolytic pathway. The tRNA cleavage showed concentration and time dependent activity of the complexes to promote RNA hydrolysis. Furthermore, the BSA binding ability of complexes 1-4 was monitored, which revealed that the complexes could quench the intrinsic fluorescence in a static manner. Complexes 1-4 were found to be non-toxic towards normal prostate epithelial cells, PNT2, but were potent against chemoresistant metastatic prostate cancer cells, Du145, with GI50 values ranging from 12.75-37 µM. Complexes 1 and 2 also showed cytotoxic activity against cancer stem cells having GI50 values of 14.70 and 14.90 µM, respectively. Molecular docking studies were performed with DNA and tRNA which further validated the spectroscopic analysis demonstrating the higher binding affinity of the complexes towards tRNA.

Copper (II)-based halogen-substituted chromone antitumor drug entities: Studying biomolecular interactions with ct-DNA mediated by sigma hole formation and cytotoxicity activity.

Copper-based antitumor drug entities 1-3 derived from substituted (F-, Br-, -CH3) 3-formylchromone pharmacophore were synthesized and thoroughly characterized by spectroscopic and single X-ray crystallographic studies. These complexes show structural novelty due to presence of the X-bonds in chromone scaffold which could facilitate higher propensity for nucleic acids via sigma σ-hole interactions. Therefore, structure-activity relationship of 1-3 was studied by performing ct-DNA binding, pBR322 cleavage and cytotoxicity activity to validate their potential to act as chemotherapeutic drug entities. The binding studies of 1-3 with ct- DNA were carried out employing many biophysical techniques and the corroborative results of these experiments showed intercalation mode of binding and the order of binding was found to be 2 > 1 > 3. The structure of drug entities could facilitated strong halogen bonding interaction (in case of 1 &2) and stability of X bond was rationalized by sigma hole region of positive electrostatic potential on the surface of C-X covalent bond, as determined by gas phase B3LYP computational DFT studies. Interestingly, 2 exhibited most avid binding affinity due to presence of Br- electron withdrawing and polarizable group. Further, cleavage studies of 1-3 with pBR322 plasmid DNA were performed which demonstrated significant cleavage activity, the supercoiled form (Form I) of plasmid DNA was converted to nicked form (Form II) with the appearance of linearized form (Form III) in between two, implicating lethal double strand breaks of DNA. 2 showed predominantly higher cleavage activity following the similar trend as observed for binding studies. The cytotoxicity of the complexes 1-3 was evaluated by MTT assay against the human liver carcinoma (Huh-7) and prostate cancer (DU-145) cell lines; complex 2 exhibited specific and selective cytotoxicity for the DU-145 cancer cell line with LC50 value of 1.6 µM.