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Item Indolyl-α-keto-1,3,4-oxadiazoles: Synthesis, anti-cell proliferation activity, and inhibition of tubulin polymerization(Elsevier, 2021-04) Kumar, Anil; Kumar, DalipA series of novel indolyl-α-keto-1,3,4-oxadiazole derivatives have been synthesized by employing molecular iodine-mediated oxidative cyclization of acylhydrazones. In vitro anti cell proliferation activity of these derivatives against various cancer cells lines such as human lymphoblast (U937), leukemia (Jurkat & SB) and human breast (BT474) was investigated. Among the synthesized indolyl-α-keto-1,3,4-oxadiazoles 19a-p, only one compound (19e) exhibited significant antiproliferative activity against a panel of cell lines. The compound 19e with 3,4,5-trimethoxyphenyl motif, endowed strong cytotoxicity against U937, Jurkat, BT474 and SB cancer cells with IC50 values of 7.1, 3.1, 4.1, and 0.8 µM, respectively. Molecular docking studies suggested a potential binding mode for 19e in the colchicine binding site of tubulin. When tested for in vitro tubulin polymerizaton, 19e inhibited tubulin polymezations (IC50 = 10.66 µM) and induced apoptosis through caspase 3/7 activation. Further, the derivative 19e did not cause necrosis when measured using lactate dehydrogenase assay.Item Synthesis and Biological Evaluation of 5′-O-Fatty Acyl Ester Derivatives of 3′-Fluoro-2′,3′-dideoxythymidine as Potential Anti-HIV Microbicides(MDPI, 2022-05) Kumar, AnilA number of 5′-O-fatty acyl derivatives of 3′-fluoro-2′,3′-dideoxythymidine (FLT, 1) were synthesized. These conjugates were evaluated for their potential as topical microbicides with anti-HIV activity against cell-free (X4 and R5), cell-associated, and multidrug-resistant viruses. Compared to FLT and 3′-azido-2′,3′-dideoxythymidine (AZT), 5′-O-(12-azidododecanoyl) (5), 5′-O-myristoyl (6), and 5′-O-(12-thioethyldodecanoyl) (8) derivatives of FLT were found to be more active against both cell-free viruses (lymphocytotropic and monocytotropic strains) with EC50 values of 0.4 μM, 1.1 μM, and <0.2 μM, respectively, as well as cell-associated virus with EC50 values of 12.6, 6.4, and 2.3 μM, respectively. Conjugates 5, 6, and 8 exhibited >4 and >30 times better antiviral index than FLT and AZT, respectively. Conjugates 5 and 8 were significantly more potent than FLT against many multidrug-resistant strains. A comparison of the anti-HIV activity with the corresponding non-hydrolyzable ether conjugates suggested that ester hydrolysis to FLT and fatty acids is critical to enable anti-HIV activity. Cellular uptake studies were conducted using fluorescent derivatives of FLT attached with 5(6)-carboxyfluorescein through either β-alanine (23) or 12-aminododecanoic acid (24) spacers. The lipophilic fluorescent analog with a long chain (24) showed more than 12 times higher cellular uptake profile than the fluorescent analog with a short chain (23). These studies further confirmed that the attachment of fatty acids improved the cellular uptake of nucleoside conjugates. In addition, 5, 6, and 8 were the least cytotoxic and did not alter vaginal cell and sperm viability compared to the positive control, a commercial topical spermicide (N-9), which significantly decreased sperm and vaginal cell viability inducing the generation of proinflammatory cytokines.Item A Facile and Microwave-assisted Rapid Synthesis of 2-Arylamino-4-(3'-indolyl)- thiazoles as Apoptosis Inducing Cytotoxic Agents(Bentham Science, 2017) Kumar, Anil; Kumar, DalipThe clinical success of the chemotherapeutic drugs is restricted by the nonspecific toxicity-related adverse side effects. The diverse implication of indoles and thiazoles in medicinal chemistry prompted us to develop a new series of novel 2-aryl-amino-4-(3′-indolyl)thiazoles as more effective and less toxic anti-cancer compounds. Method and Results: One-pot microwave-assisted rapid and high yielding synthesis of 2-arylamino-4-(3′- indolyl)thiazoles involved the reaction of easily available α-tosyloxy-ketones with N-arylthioureas in polyethylene glycol-400 (PEG-400). In vitro cytotoxicity study of 2-arylamino-4-(3′-indolyl)thiazoles against a panel of human cancer cell lines by MTT assay revealed IC50 values in the low micromolar range. Of the fifteen synthesized arylaminothiazoles, compounds 17b, 17d, 17g and 17il showed significant anti-proliferative activity against the selected cancer cell lines with IC50 < 10 μM. The compound 17b was identified as the most potent ligand of the series, which exhibited good cytotoxic activity against MCF-7 breast cancer cells with an IC50 value of 1.86 μM but minimal toxicity on normal human cells. Investigation of the underlying mechanism by flow cytometry indicated that 17b induced ROS-mediated apoptosis in MCF-7 cells in a dose-dependent manner as supported by upregulation of Bax and caspase-3 and down-regulation of Bcl-2 (by Western blot).Item Design and synthesis of bis(indolyl)ketohydrazide-hydrazones: Identification of potent and selective novel tubulin inhibitors(Elsiever, 2017-08-18) Kumar, Anil; Kumar, DalipA novel series of ketohydrazide-hydrazones as analogues of naturally occurring coscinamides has been synthesized and evaluated for their anticancer activity against five cancer cell lines. Of the twenty-synthesized ketohydrazide-hydrazones, compounds, 21c, 21f, 21g, 21k and 21o showed cytotoxic effects (less than 50% cell survival) against multiple cancer cell lines when tested at a final concentration of 10 μM. IC50 of three compounds 21f, 21k and 21o was determined to be less than 5 μM for all tested cancer cell lines. Compound 21k exhibited significant anticancer activity against MCF-7, MDA-MB-231, HCT-116 and JURKAT cancer cell lines with IC50 values of 0.8 μM, 0.50 μM, 0.15 μM, and 0.22 μM, respectively. Also, 21k was found to be more selectively cytotoxic against tumor cells when compared to normal cells. Preliminary mechanism of action studies indicated that the most active compound 21k induced caspase-dependent apoptosis in cells. 21k arrests cell cycle in G2/M phase by inhibiting of tubulin polymerization (IC50 = 0.6 μM).