Synthesis and Biological Evaluation of Pyrazoline and Pyrrolidine-2,5-dione Hybrids as Potential Antitumor Agents
| Autor: | Franz-Josef Meyer-Almes, Neha Upadhyay, Natalia Yu. Anisimova, T. S. Spirina, Antonio Lavecchia, Fulvio Loiodice, Darina V. Sokolova, Vadim S. Pokrovsky, Jun-yong Choe, Galina B. Smirnova, Kalpana Tilekar, C.S. Ramaa |
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| Přispěvatelé: | Tilekar, K., Upadhyay, N., Meyer-Almes, F. -J., Loiodice, F., Anisimova, N. Y., Spirina, T. S., Sokolova, D. V., Smirnova, G. B., Choe, J. -Y., Pokrovsky, V. S., Lavecchia, A., S Ramaa, C. |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
Pyrrolidines Cytotoxicity Cell Population Mice Nude Antineoplastic Agents Pyrazoline Pharmacology 01 natural sciences Biochemistry Docking Mice Structure-Activity Relationship chemistry.chemical_compound Synthesis In vivo Cell Line Tumor Drug Discovery medicine Animals Humans Bcl-2 General Pharmacology Toxicology and Pharmaceutics education IC50 Cell Proliferation Pyrrolidine-2 5-dione Mice Inbred BALB C education.field_of_study Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Organic Chemistry Antitumor agent Neoplasms Experimental 0104 chemical sciences Bioavailability Molecular Docking Simulation 010404 medicinal & biomolecular chemistry medicine.anatomical_structure chemistry Cell culture Pyrazoles Molecular Medicine Drug Screening Assays Antitumor |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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