Department of Chemistry
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Item Synthesis and evaluation of bile acid amides of α -cyanostilbenes as anticancer agents(Springer, 2018-05) Sakhuja, Rajeev; Jha, Prabhat Nath; Chowdhury, RajdeepA series of amino-substituted [Formula: see text]-cyanostilbene derivatives and their bile acid (cholic and deoxycholic acid) amides were designed and synthesized. A comparative study on the anticancer and antibacterial activity evaluation on the synthesized analogs was carried against the human osteosarcoma (HOS) cancer cell line, and two gram -ve (E. coli and S. typhi) and two gram [Formula: see text]ve (B. subtilis and S. aureus) bacterial strains. All the cholic acid [Formula: see text]-cyanostilbene amides showed an [Formula: see text] in the range 2-13 [Formula: see text] against human osteosarcoma cells (HOS) with the most active analog (6g) possessing an [Formula: see text] of [Formula: see text]. One of the amino-substituted [Formula: see text]-cyanostilbene, 4e, was found to possess an [Formula: see text] of [Formula: see text]. An increase in the number of cells at the sub-[Formula: see text] phase of the cell was observed in the in vitro cell cycle analysis of two most active compounds in the series (4e, 6g) suggesting a clear indication toward induction of apoptotic cascade. With respect to antibacterial screening, amino-substituted [Formula: see text]-cyanostilbenes were found to be more active than their corresponding bile acid amides. The synthesized compounds were also subjected to in silico study to predict their physiochemical properties and drug-likeness score.Item Bile-Acid-Appended Triazolyl Aryl Ketones: Design, Synthesis, In Vitro Anticancer Activity and Pharmacokinetics in Rats(MDPI, 2021-09-17) Sakhuja, Rajeev; Mazumdar, Samrat; Chitkara, DeepakA library of bile-acid-appended triazolyl aryl ketones was synthesized and characterized by detailed spectroscopic techniques such as 1H and 13C NMR, HRMS and HPLC. All the synthesized conjugates were evaluated for their cytotoxicity at 10 µM against MCF-7 (human breast adenocarcinoma) and 4T1 (mouse mammary carcinoma) cells. In vitro cytotoxicity studies on the synthesized conjugates against MCF-7 and 4T1 cells indicated one of the conjugate 6cf to be most active against both cancer cell lines, with IC50 values of 5.71 µM and 8.71 µM, respectively, as compared to the reference drug docetaxel, possessing IC50 values of 9.46 µM and 13.85 µM, respectively. Interestingly, another compound 6af (IC50 = 2.61 µM) was found to possess pronounced anticancer activity as compared to the reference drug docetaxel (IC50 = 9.46 µM) against MCF-7. In addition, the potent compounds (6cf and 6af) were found to be non-toxic to normal human embryonic kidney cell line (HEK 293), as evident from their cell viability of greater than 86%. Compound 6cf induces higher apoptosis in comparison to 6af (46.09% vs. 33.89%) in MCF-7 cells, while similar apoptotic potential was observed for 6cf and 6af in 4T1 cells. The pharmacokinetics of 6cf in Wistar rats showed an MRT of 8.47 h with a half-life of 5.63 h. Clearly, these results suggest 6cf to be a potential candidate for the development of anticancer agentsItem Novel Spiro/non-Spiro Pyranopyrazoles: Eco-Friendly Synthesis, In-vitro Anticancer Activity, DNA Binding, and In-silico Docking Studies(Thieme, 2019) Shukla, Paritosh; Chowdhury, RajdeepCancer being a deadly disease, many reports of new chemical entities are available. Pyranopyrazole (PPZ) compounds have also been disclosed as bioactive molecules but mainly as antimicrobial agents. Based on one previous report and our interest in anticancer drug design, we decided to explore PPZs as anticancer agents. To the best of our knowledge, we found that a comprehensive study, involving synthesis, in-vitro biological activity determination, exploration of the mechanism of inhibition and finally in-silico docking studies, was missing in earlier reports. This is what the present study intends to accomplish. Methods: Ten spiro and eleven non-spiro PPZ molecules were synthesized by environment-friendly multicomponent reaction (MCR) strategy. After subjecting each of the newly synthesized molecules to Hep3b hepatocellular carcinoma cell lines assay, we selectively measured the Optical Density (OD) of the most active ones. Then, the compound exhibiting the best activity was docked against human CHK- 1 protein to get an insight into the binding affinities and a quick structure activity relationship (SAR) of the PPZs. Results: The two series of spiro and non-spiro PPZs were easily synthesized in high yields using microwave assisted synthesis and other methods. Among the synthesized compounds, most compounds showed moderate to good anticancer activity against the MTT assay. After performing the absorbance studies we found that the non-spiro molecules showed better apoptosis results and appeared to bind to DNA causing disruption in their structures. Finally, the docking results of compound 5h (having N,Ndimethylamino substituted moiety) clearly showed good binding affinities as predicted by our experimental findingItem Synthesis and anticancer activities of novel 3,5-disubstituted-1,2,4-oxadiazoles(Elsiever, 2009-05) Kumar, DalipA series of 3,5-disubstituted-1,2,4-oxadiazoles were synthesized and evaluated for their in vitro anti-proliferative activities against various cancer cell lines. Formation of 1,2,4-oxadiazole ring was accomplished by the reaction of amidoxime with carboxylic acids. The in vitro cytotoxic effects of 3,5-disubstituted-1,2,4-oxadiazoles have been demonstrated across a wide array of tumor cell types and a few compounds exhibited specificity towards pancreatic (3f, 3h, 3j, and 3k) and prostate (3n) cancer cells. Among the prepared 3,5-disubstituted-1,2,4-oxadiazoles, compound 3n is the most selective (>450-fold) and compound 3p is the most cytotoxic (10 nM) against prostate cancer cell lines.Item Novel porphyrin–psoralen conjugates: synthesis, DNA interaction and cytotoxicity studies(CBI, 2013) Kumar, DalipThe indole ring system is the most privileged heterocycle in nature and embedded in many biological systems. The demonstration of many indole containing alkaloids as leads for the new pharmaceutical agents, the recognition of the importance of essential amino acid tryptophan in human nutrition and the discovery of plant hormones served to bring about a massive search on indole chemistry. This led to report vast number of structurally diversified bio-active natural and synthetic indoles. The present review focuses on the structure-based drug design of variety of classes of synthetic indoles as potent anticancer agents. Particularly, the recent developments on natural-product inspired rational synthesis of functionalized indoles, indolylazoles and bis(indoles) and their anticancer activities are presented. This review also drawn the attention towards combretastatin-based structural class of indoles and well discussed their potentials as tubulin polymerization inhibitorsItem Synthesis and anticancer activity study of indolyl hydrazide–hydrazones(Springer, 2016-03-03) Kumar, DalipA series of N′-((1-(substituted)-1H-indol-3-yl)methylene)hydrazides were synthesized and evaluated for their in vitro antiproliferative activities against various cancer cell lines. Formation of indole hydrazide–hydrazones was accomplished by the reaction of indole 3-carboxaldehyde with aryl/alkyl hydrazides in the presence of acetic acid. Out of synthesized twenty-two compounds, some of the analogs exhibited specificity toward breast (18b, 18d, 18f and 18j) and prostate (18t and 18v) cancer cells. Among the prepared derivatives, compounds 18b, 18d and 18j were most cytotoxic (IC50 = 0.9, 0.4 and 0.8 µM, respectively) against the screened cancer cell lines. Exposure of PC3 cells to either 18d or 18j resulted in increased levels of cleaved PARP1, indicating that indolyl hydrazide–hydrazones induce apoptosis in PC3 cells.Item Synthesis and biological evaluation of novel carbazolyl glyoxamides as anticancer and antibacterial agents(RSC, 2016) Kumar, DalipA new library of 24 carbazolyl glyoxamides 14a–x were designed and synthesized from glyoxalic acids and arylamines in the presence of HATU as a coupling reagent under MW irradiation. The synthesized carbazolyl glyoxamides were evaluated for their in vitro anticancer and antibacterial activities. Of the synthesized carbazolyl glyoxamides, compounds 14l and 14q exhibited the most potent cytotoxicity towards a breast cancer cell line with IC50 values of 9.3 and 9.8 μM, respectively. Further, caspase-3 assay for carbazolyl glyoxamides indicated that these compounds induced apoptotic cell death in Jurkat cells. Furthermore, some of the synthesized carbazolyl glyoxamides 14g, 14k, 14l and 14n exhibited comparable or even better antibacterial activity (MIC = 8–16 μg mL−1) than chloramphenicol against the selected bacterial strainsItem One-pot synthesis and in-vitro anticancer evaluation of 5-(2′-indolyl)thiazoles(Springer Nature, 2016-03-29) Kumar, DalipA series of 5-(2′-indolyl)thiazoles were synthesized and evaluated for their cytotoxicity against selected human cancer cell lines. The reaction of thioamides 3 with 3-tosyloxypentane-2,4-dione 4 led to in situ formation of 5-acetylthiazole 5 which upon treatment with arylhydrazines 6 in polyphosphoric acid resulted in the formation of 5-(2′-indolyl)thiazoles 2. Among the synthesized 5-(2′-indolyl)thiazoles, compounds 2d–f and 2h exhibited encouraging anticancer activity and also selectivity towards particular cell lines (IC50 = 10–30 μM). Further studies on the SAR of compound 2e may result in good anticancer activity.Item 3-substitued indoles: one-pot synthesis and evaluation of anticancer and Src kinase inhibitory activities(Elsiever, 2011-06-15) Kumar, AnilAn efficient and economical method was developed for the synthesis of 3-substituted indoles by one-pot three-component coupling reaction of a substituted or unsubstituted benzaldehyde, N-methylaniline, and indole or N-methylindole using Yb(OTf)3–SiO2 as a catalyst. All the synthesized compounds were evaluated for inhibition of cell proliferation of human colon carcinoma (HT-29), human ovarian adenocarcinoma (SK-OV-3), and c-Src kinase activity. The 4-methylphenyl (4o and 4p) and 4-methoxyphenyl (4q) indole derivatives inhibited the cell proliferation of SK-OV-3 and HT-29 cells by 70–77% at a concentration of 50 μM. The unsubstituted phenyl (4d) and 3-nitrophenyl (4l) derivatives showed the inhibition of c-Src kinase with IC50 values of 50.6 and 58.3 μM, respectively.Item Design, synthesis and bioevaluation of novel 6-(4-Hydroxypiperidino)naphthalen-2-ol-based potential Selective Estrogen Receptor Modulators for breast cancer(Elsiever, 2015-03) Kumar, AnilIn a study directed towards development of novel Selective Estrogen Receptor Modulators (SERMs), 1-(4-(2-(dialkylamino)ethoxy)benzyl)-6-(4-hydroxypiperidin-1-yl)-2-naphthol and corresponding aryl methyl ethers were synthesized and bioevaluated against the estrogen-responsive human MCF-7 breast cancer cell line. The phenolic analogs displayed little or no activity, but aryl methyl ether analogs showed significant cytotoxic potency. Also, representative compounds from the aryl methyl ether series showed significant binding and antagonistic activity against ERα. Two representative compounds were also evaluated for in vitro membrane permeability, plasma stability as well as in-vivo toxicity in mice. The compounds displayed well-acceptable drug-like in vitro membrane permeability as well as plasma stability and were well-tolerated in experimental mice at 300 mg/kg dose.