Synthesis and Biological Evaluation of Pyrazoline and Pyrrolidine‐2,5‐dione Hybrids as Potential Antitumor Agents
Male
0301 basic medicine
Pyrrolidines
Cytotoxicity
610
Mice, Nude
Antineoplastic Agents
Pyrazoline
Docking
Synthesis
Mice
Structure-Activity Relationship
03 medical and health sciences
Cell Line, Tumor
Animals
Humans
Bcl-2
5-diones
Pyrazolines
Pyrrolidine-2,5-dione
Cell Proliferation
Mice, Inbred BALB C
0303 health sciences
Antitumor agents
Dose-Response Relationship, Drug
Molecular Structure
Antitumor agent
Pyrrolidine-2,5-diones
Neoplasms, Experimental
540
Molecular Docking Simulation
Pyrrolidine-2
Pyrazoles
Antitumor agents; Bcl-2; Cytotoxicity; Docking; Pyrazolines; Pyrrolidine-2,5-diones; Synthesis
Drug Screening Assays, Antitumor
DOI:
10.1002/cmdc.202000458
Publication Date:
2020-07-27T05:53:50Z
AUTHORS (12)
ABSTRACT
AbstractIn 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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