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.

Post-COVID-19 performance evaluation of urban metro transit system in Delhi and influence on access mode.

The impact of the COVID-19 pandemic has been observed to affect the travel patterns, routes and traffic in public transportation systems across the world. It is important to evaluate the performance of the Delhi Metro (DM) post-COVID-19 pandemic for its successful operation. In this study, the BLUE line of DM with the longest route and highest number of metro stations has been examined for performance evaluation. The performance is evaluated based on travel time components (access, egress, transfer, waiting and main haul time) to calculate various performance indicators i.e., Level of Service (LOS), Service Time Ratio (STR), Passengers Waiting Index (PWI), Total Travel Ratio (TTR) and Interconnectivity Ratio (IR). The post-COVID-19 LOS evaluation indicates that the users are spending 72.6 % to 84.4 % of their main haul time on their access-egress trips. The STR shows that the users are spending 10.9 % to 12.6 % of their total travel time in waiting and transferring only during the main haul trip. The mean PWI, RI and TTR are noted as 1.008, 0.794 and 2.069 respectively. The IR is observed as 0.312 for the given route. The median and average main haul distances across all access modes are observed to be (12-21) Km. and (19.69 ± 11.19) Km. respectively. It is revealed that the observed mean value of LOS is (0.775 ± 0.575). It is further revealed that the metro fare per trip and the access-egress trip cost per day are significant factors for access mode choice in the case of walking and auto-rickshaw whereas LOS, RI and PWI are other significant operator's performance indicators influencing the access mode choice. The study reveals that post-COVID-19 the performance indicators exhibit the unsatisfactory performance of DM and there is further scope to improve the UMTS performance.

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.

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.