BITS Faculty Publications
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Item Novel Pyrido[2′,1′:2,3]imidazo[4,5-c]quinoline Derivative Selectively Poisons Leishmania donovani Bisubunit Topoisomerase 1 to Inhibit the Antimony-Resistant Leishmania Infection in Vivo(ACS, 2023-02) Kumar, AnilThe unique bisubunit structure of Leishmania donovani topoisomerase 1B (LdTop1) is a potential drug target in the parasites unlike the monomeric Top1 from its human host counterpart. Here, we report the design, synthesis, and validation of a chimeric pyrido[2′,1′:2,3]imidazo[4,5-c]quinoline derivative (C17) as a novel antileishmanial agent that poisons topoisomerase 1-DNA covalent complexes (LdTop1cc) inside the parasites and inhibits Top1 religation activity both in the drug sensitive and antimony-resistant L. donovani clinical isolates. Importantly, the human Top1 is not sensitive to C17. Further, C17 overcomes the chemical instability of camptothecin (CPT) by generating persistent LdTop1cc-induced DNA breaks inside the parasites even after 12 h of drug removal. Intraperitoneal administration of C17 results in marked reduction of the Leishmania amastigotes from the infected spleen and liver of BALB/c mice. C17 confers a host protective immune-response up-regulating the Th1 cytokines facilitating parasite clearance which can be exploited for treating drug-resistant leishmaniasisItem Design and Evaluation of Hydroxamate Derivatives as Metal-Mediated Inhibitors of a Protein Tyrosine Kinase(ACS, 2006) Kumar, AnilProtein tyrosine kinases use two Mg2+ ions as cofactors in catalysis, one as the ATP−Mg complex (M1) and the other as an essential activator (M2). The M2-binding site has high affinity for transition metal cations such as cobalt and zinc. Taking advantage of this high affinity, we examined hydroxamates as metal-mediated inhibitors against C-terminal Src kinase (Csk), a protein tyrosine kinase. Of a small group of amino acid hydroxamates, tyrosine and phenylalanine hydroxamates inhibited Csk activity only in the presence of Co2+. Four classes of phenylalanine and tyrosine hydroxamate derivatives were synthesized and evaluated as metal-mediated inhibitors of Csk, leading to improved inhibition and a better understanding of the structure−activity relationships. This study suggests that hydroxamates may serve as a general scaffold for developing metal-mediated inhibitors against protein tyrosine kinases. To the best of our knowledge, this is the first report of designing metal-mediated inhibitors against a protein tyrosine kinase by targeting a metal binding site.Item Synthesis and evaluation of tripodal peptide analogues for cellular delivery of phosphopeptides(ACS, 2007-06-20) Kumar, AnilTripodal peptide analogues were designed on the basis of the phosphotyrosine binding pocket of the Src SH2 domain and assayed for their ability to bind to fluorescein-labeled phosphopeptides. Fluorescence polarization assays showed that a number of amphipathic linear peptide analogues (LPAs), such as LPA4, bind to fluorescein-labeled GpYEEI (F-GpYEEI). LPA4 was evaluated for potential application in cellular delivery of phosphopeptides. Fluorescence microimaging cellular uptake studies with fluorescein-attached LPA4 (F-LPA4) alone or with the mixture of LPA4 and F-GpYEEI in BT-20 cells showed dramatic increase of the fluorescence intensity in cytosol of cells, indicating that LPA4 can function as a delivery tool of F-GpYEEI across the cell membrane. Fluorescent flow cytometry studies showed the cellular uptake of F-LPA4 in an energy-independent pathway and confirmed the cellular uptake of F-GpYEEI in the presence of LPA4. These studies suggest that amphipathic tripodal peptide analogues, such as LPA4, can be used for cellular delivery of phosphopeptidesItem Synthesis and structure-activity relationships of linear and conformationally constrained peptide analogues of CIYKYY as Src tyrosine kinase inhibitors(ACS, 2006) Kumar, AnilA series of peptide analogues of Ac-CIYKYY (1) were synthesized by functional group modifications in peptide side chains or by introducing conformational constraints, to improve the inhibitory potency against active Src kinase. Ac-CIYKF(4-NO2)Y (2, IC50 = 0.53 μM) and conformationally constrained peptide 31 (IC50 = 0.28 μM) exhibited 750- and 1400-fold higher inhibitory activities, respectively, versus that of 1 (IC50 = 400 μM). Compound 2 exhibited a partial competitive inhibition pattern against ATP.Item Cyclic Peptide–Selenium Nanoparticles as Drug Transporters(RSC, 2014) Kumar, AnilA cyclic peptide composed of five tryptophan, four arginine, and one cysteine [W5R4C] was synthesized. The peptide was evaluated for generating cyclic peptide-capped selenium nanoparticles (CP–SeNPs) in situ. A physical mixing of the cyclic peptide with SeO3–2 solution in water generated [W5R4C]–SeNPs via the combination of reducing and capping properties of amino acids in the peptide structure. Transmission electron microscopy (TEM) images showed that [W5R4C]–SeNPs were in the size range of 110–150 nm. Flow cytometry data revealed that a fluorescence-labeled phosphopeptide (F′-PEpYLGLD, where F′ = fluorescein) and an anticancer drug (F′-dasatinib) exhibited approximately 25- and 9-times higher cellular uptake in the presence of [W5R4C]–SeNPs than those of F′-PEpYLGLD and dasatinib alone in human leukemia (CCRF-CEM) cells after 2 h of incubation, respectively. Confocal microscopy also exhibited higher cellular delivery of F′-PEpYLGLD and F′-dasatinib in the presence of [W5R4C]–SeNPs compared to the parent fluorescence-labeled drug alone in human ovarian adenocarcinoma (SK-OV-3) cells after 2 h of incubation at 37 °C. The antiproliferative activities of several anticancer drugs doxorubicin, gemcitabine, clofarabine, etoposide, camptothecin, irinotecan, epirubicin, fludarabine, dasatinib, and paclitaxel were improved in the presence of [W5R4C]–SeNPs (50 μM) by 38%, 49%, 36%, 36%, 31%, 30%, 30%, 28%, 24%, and 17%, respectively, after 48 h incubation in SK-OV-3 cells. The results indicate that CP–SeNPs can be potentially used as nanosized delivery tools for negatively charged biomolecules and anticancer drugs.