Synthesis and Biological Evaluation of Pyrazoline and Pyrrolidine-2,5-dione Hybrids as Potential Antitumor Agents |
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Authors: | Kalpana Tilekar Neha Upadhyay Prof. Franz-Josef Meyer-Almes Dr. Fulvio Loiodice Natalia Y. Anisimova Tatiana S. Spirina Darina V. Sokolova Galina B. Smirnova Dr. Jun-yong Choe Dr. Vadim S. Pokrovsky Prof. Antonio Lavecchia Prof. C S Ramaa |
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Affiliation: | 1. Department of Pharmaceutical Chemistry, Bharati Vidyapeeth's College of Pharmacy, Sector 8, CBD Belapur, 400614 Navi Mumbai, India;2. Department of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Haardtring 100, 64295 Darmstadt, Germany;3. Department of Pharmacy-Drug Science, University of Bari “Aldo Moro”, Via E. Orabona, 4, 70126 Bari, Italy;4. Laboratory of Combined Therapy, N.N. Blokhin Cancer Research Center, 115478 Moscow, Russia;5. East Carolina Diabetes and Obesity Institute Department of Chemistry, East Carolina University, 27834 Greenville, North Carolina, USA;6. Department of Pharmacy, University of Naples “Federico II”, Via D. Montesano 49, 80131 Napoli, Italy |
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Abstract: | In search of novel and effective antitumor agents, pyrazoline-substituted pyrrolidine-2,5-dione hybrids were designed, synthesized and evaluated in silico, in vitro and in vivo for anticancer efficacy. All the compounds exhibited remarkable cytotoxic effects in MCF7 and HT29 cells. The excellent antiproliferative activity toward MCF7 (IC50=0.78±0.01 μM), HT29 (IC50=0.92±0.15 μM) and K562 (IC50=47.25±1.24 μM) cell lines, prompted us to further investigate the antitumor effects of the best compound S2 (1-(2-(3-(4-fluorophenyl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-oxoethyl)pyrrolidine-2,5-dione). In cell-cycle analysis, S2 was found to disrupt the growth phases with increased cell population in G1/G0 phase and decreased cell population in G2/M phase. The excellent in vitro effects were also supported by inhibition of anti-apoptotic protein Bcl-2. In vivo tumor regression studies of S2 in HT29 xenograft nude mice, exhibited equivalent and promising tumor regression with maximum TGI, 66 % (i. p. route) and 60 % (oral route) at 50 mg kg−1 dose by both the routes, indicating oral bioavailability and antitumor efficacy. These findings advocate that hybridization of pyrazoline and pyrrolidine-2,5-dioes holds promise for the development of more potent and less toxic anticancer agents. |
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Keywords: | Pyrrolidine-2,5-diones Synthesis Cytotoxicity Docking Antitumor agents Bcl-2 Pyrazolines |
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