Mehvash Zaki

Synthesis and structure elucidation of a copper(II) Schiff-base complex: In vitro DNA binding, pBR322 plasmid cleavage and HSA binding studies

New copper(II) complex with Schiff base ligand 4-[(2-Hydroxy-3-methoxy-benzylidene)-amino]-benzoic acid (H₂L) was synthesized and characterized by spectroscopic and analytical and single crystal X-ray diffraction studies which revealed that the complex 1 exist in a distorted octahedral environment. In vitro CT-DNA binding studies were performed by employing different biophysical technique which indicated that the 1 strongly binds to DNA in comparison to ligand via electrostatic binding mode. Complex 1 cleaves pBR322 DNA via hydrolytic pathway and recognizes minor groove of DNA double helix. The HSA binding results showed that ligand and complex 1 has ability to quench the fluorescence emission intensity of Trp 214 residue available in the subdomain IIA of HSA.

Nuclear blebbing of biologically active organoselenium compound towards human cervical cancer cell (HeLa): in vitro DNA/HSA binding, cleavage and cell imaging studies.

New pharmacophore organoselenium compound (1) was designed, synthesized and characterized by various spectroscopic methods (IR, ESI-MS, (1)H, (13)C and (77)Se NMR) and further confirmed by X-ray crystallography. Compound 1 consists of two 3,5-bis(trifluoromethyl)phenyl units which are connected to the selenium atom via the organometallic C-Se bond. In vitro DNA binding studies of 1 was investigated by absorption and emission titration methods which revealed that 1 recognizes the minor groove of DNA in accordance with molecular docking studies with the DNA duplex. Gel electrophoretic assay demonstrates the ability of 1 to cleave pBR322 DNA through hydrolytic process which was further validated by T4 religation assay. To understand the drug-protein interaction of which ultimate molecular target was DNA, the affinity of 1 towards HSA was also investigated by the spectroscopic and molecular modeling techniques which showed hydrophobic interaction in the subdomain IIA of HSA. Furthermore, the intracellular localization of 1 was evidenced by cell imaging studies using HeLa cells.

Synthesis and characterization of Cu(II)-based anticancer chemotherapeutic agent targeting topoisomerase Iα: in vitro DNA binding, pBR322 cleavage, molecular docking studies and cytotoxicity against human cancer cell lines.

New metal-based anticancer chemotherapeutic drug candidates [Cu(phen)L](NO₃)₂ (1) and [Zn(phen)L](NO₃)₂ (2) were synthesized from ligand L (derived from pharmacophore scaffold barbituric acid and pyrazole). In vitro DNA binding studies of the L, 1 and 2 were carried out by various biophysical techniques revealing electrostatic mode. Complex 1 cleaves pBR322 DNA via oxidative pathway and recognizes major groove of DNA double helix. The molecular docking study was carried out to ascertain the mode of action towards the molecular target DNA and enzymes. The complex 1 exhibited remarkably good anticancer activity on a panel of human cancer cell lines (GI₅₀ values < 10 μg/ml), and to elucidate the mechanism of cancer inhibition, Topo-I enzymatic activity was carried out.

Coumarin centered copper(II) complex with appended-imidazole as cancer chemotherapeutic agents against lung cancer: molecular insight via DFT-based vibrational analysis

Coumarins are well known for the design of target-specific therapeutics for cancer oncology. In lieu of their potential applications as antitumor chemotherapeutics, a new coumarin-based copper(II) complex 1 was synthesized employing 6-methyl-3-((quinolin-8-ylimino)methyl)-3H-chromene-2,4-dione (L). The structure elucidation of 1 was done by various spectroscopic techniques (viz., IR, Raman, UV-vis, and EPR), elemental analysis and single crystal X-ray diffraction. Raman and IR combined with B3LYP/DFT frequency calculations were used to characterize the lattice dynamics with an emphasis on the doming mode vibrations of the copper site. Prominent features in the Raman and far-IR spectrum, indicative of doming modes, appeared in the 35–150 cm−1, other out-of-plane and in-plane mode of vibrations in the range of 160–250 cm−1 and 260–700 cm−1, respectively. Furthermore, preliminary in vitro binding studies of L and complex 1 with CT-DNA were carried out by various biophysical techniques. The results demonstrated that 1 avidly binds to CT DNA as compared to L and cisplatin (marketed drug in use for treating solid cancers) via a partial intercalative mode. Furthermore, pBR322 cleavage studies of 1 revealed the hydrolytically double-stranded cleavage pattern verified by T4 ligase religation. The cytotoxicity activity of L and complex 1 was carried out to evaluate cell growth inhibition in a human alveolar epithelial A549 cancer cells (human lung carcinoma) by the MTT assay. Interestingly, the IC50 value of complex 1 was found to be 4.6 ± 0.3 μM which is significantly lower as compared to the IC50 values of previously reported Cu(II) complexes. Furthermore, in the presence of 1, the level of reactive oxygen species (ROS) and thiobarbituric acid reactive substance (TBARS) displayed significant increase, coupled with reduced glutathione (GSH) levels on the A549 cancer cell. Thus, the results confirm the important role of ROS generation and discover Cu(II) complex 1 induced cell apoptosis and validate its potential to act as a robust anticancer drug entity.

Synthesis and crystal structure elucidation of new copper(II)-based chemotherapeutic agent coupled with 1,2-DACH and orthovanillin: Validated by in vitro DNA/HSA binding profile and pBR322 cleavage pathway.

New copper(II)-based complex (1) was synthesized and characterized by analytical, spectroscopic and single crystal X-ray diffraction. The in vitro binding studies of complex 1 with CT DNA and HSA have been investigated by employing biophysical techniques to examine the binding propensity of 1 towards DNA and HSA. The results showed that 1 avidly binds to CT DNA via electrostatic mode along with the hydrogen bonding interaction of NH2 and CN groups of Schiff base ligand with the base pairs of DNA helix, leads to partial unwinding and destabilization of the DNA double helix. Moreover, the CD spectral studies revealed that complex 1 binds through groove binding interaction that stabilizes the right-handed B-form of DNA. Complex 1 showed an impressive photoinduced nuclease activity generating single-strand breaks in comparison with the DNA cleavage activity in presence of visible light. The mechanistic investigation revealed the efficiency of 1 to cleave DNA strands by involving the generation of reactive oxygen species. Furthermore, the time dependent DNA cleavage activity showed that there was gradual increase in the amount of NC DNA on increasing the photoexposure time. However, the interaction of 1 and HSA showed that the change of intrinsic fluorescence intensity of HSA was induced by the microenvironment of Trp residue.

Synthesis, structure elucidation and DFT studies of a new coumarin-derived Zn(II) complex: in vitro DNA/HSA binding profile and pBR322 cleavage pathway

A new mononuclear zinc complex 1 bearing the bioactive coumarin scaffold 5,10-dioxo-5,10-dihydro-chromeno[5,4,3-cde]chromene-2,7-dicarboxylic acid was synthesized, characterized by elemental analysis and spectroscopic techniques, and further analyzed by single-crystal X-ray diffraction. Density functional theory studies were performed using an ab initio Gaussian 09 software package with a B3LYP/6-31+g(d,p) basis function. The in vitro DNA binding studies of complex 1 with calf-thymus DNA in Tris–HCl buffer was studied by various biophysical techniques, which revealed that 1 binds to calf-thymus DNA non-covalently via electrostatic interactions. Competitive binding experiments showed that 1 has the ability to displace DNA-bound ethidium bromide. Compound 1 exhibits efficient photoinduced DNA cleavage with supercoiled pBR322 involving the hydrolytic cleavage pathway due to the presence of coordinated water molecules. Such synthetic hydrolytic nucleases, in particular those that cleave DNA with sequence selectivity different from that of the natural enzymes, are gaining considerable attention owing to their importance in biotechnology and drug design.

Synthesis and crystal structure determination of a mononuclear cobalt(II) complex derived from 4-(pyridin-4-ylmethoxy)-benzoic acid: evaluation of the DNA/protein interaction and photo-induced pBR322 DNA cleavage

New metal-based chemotherapeutic drug candidate [Co(L)2·(H2O)4] (1) was synthesized from ligand 4-(pyridin-4-ylmethoxy)-benzoic acid (HL) and thoroughly characterized by spectroscopic, analytical and single crystal X-ray diffraction techniques. The crystal structure analysis reveal that the asymmetric unit of the complex consists of one Co(II) ion, one L− ligand and two coordinated aqua molecules. The Co(II) ion is coordinated to four oxygen atoms from four aqua molecules. Hence, the geometry around the Co(II) ion can be described as a MN2O4 octahedral geometry. In vitro DNA binding studies of complex 1 with CT DNA were carried out by employing various biophysical techniques viz. electronic absorption, fluorescence and circular dichroism techniques to examine the binding propensity of 1 towards CT DNA. The experimental results revealed that complex 1 avidly binds to CT DNA via an electrostatic mode and the intrinsic binding constant Kb value was found to be 4.25 × 104 M−1. Complex 1 shows significant DNA photo cleavage activity through the formation of hydroxyl radicals via a photo-redox pathway. Futhermore, interaction studies of complex 1 with human serum albumin (HSA) revealed the quenching of intrinsic fluorescence of the HSA Trp 214 residue through a static quenching mechanism.