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Pharmacophore hybridization approach to discover novel pyrazoline-based hydantoin analogs with anti-tumor efficacyстатья
Статья опубликована в высокорейтинговом журнале
Статья опубликована в журнале из списка Web of Science и/или Scopus- Авторы: Upadhyay N., Tilekar K., Loiodice F., Anisimova N.Y., Spirina T.S., Sokolova D.V., Smirnova G.B., Choe J.Y., Meyer-Almes F.J., Pokrovsky V.S., Laveccia A., Ramaa C.S.
- Журнал: Bioorganic Chemistry
- Том: 107
- Год издания: 2021
- Издательство: Academic Press
- Местоположение издательства: United States
- DOI: 10.1016/j.bioorg.2020.104527
- Аннотация: In search for new and safer anti-cancer agents, a structurally guided pharmacophore hybridization strategy of two privileged scaffolds, namely diaryl pyrazolines and imidazolidine-2,4-dione (hydantoin), was adopted resulting in a newfangled series of compounds (H1-H22). Herein, a bio-isosteric replacement of "pyrrolidine-2,5-dione" moiety of our recently reported antitumor hybrid incorporating diaryl pyrazoline and pyrrolidine-2,5-dione scaffolds with "imidazoline-2,4-dione" moiety has been incorporated. Complete biological studies revealed the most potent analog among all i.e. compound H13, which was at-least 10-fold more potent compared to the corresponding pyrrolidine-2,5-dione, in colon and breast cancer cells. In-vitro studies showed activation of caspases, arrest of G0/G1 phase of cell cycle, decrease in the expression of anti-apoptotic protein (Bcl-2) and increased DNA damage. In-vivo assay on HT-29 (human colorectal adenocarcinoma) animal xenograft model unveiled the significant anti-tumor efficacy along with oral bioavailability with maximum TGI 36% (i.p.) and 44% (per os) at 50 mg/kg dose. These findings confirm the suitability of hybridized pyrazoline and imidazolidine-2,4-dione analog H13 for its anti-cancer potential and starting-point for the development of more efficacious analogs.
- Добавил в систему: Покровский Вадим Сергеевич