Pharmacophore hybridization approach to discover novel pyrazoline-based hydantoin analogs with anti-tumor efficacy

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. © 2020 Elsevier Inc.

Upadhyay N.1 , Tilekar K.1 , Loiodice F.2 , Anisimova N.Y.3 , Spirina T.S.3 , Sokolova D.V. 3 , Smirnova G.B.3 , Choe J.-Y.4 , Meyer-Almes F.-J.5 , Pokrovsky V.S. 3, 6 , Lavecchia A.7 , Ramaa C.S.1
Academic Press Inc.
  • 1 Department of Pharmaceutical Chemistry, Bharati Vidyapeeth's College of Pharmacy, Navi Mumbai, India
  • 2 Department of Pharmacy-Drug Science, University of Bari “Aldo Moro”, Via E. Orabona, 4, Bari, 70126, Italy
  • 3 Laboratory of Combined Therapy, N.N. Blokhin Cancer Research Center, Moscow, Russian Federation
  • 4 East Carolina Diabetes and Obesity Institute, Department of Chemistry, East Carolina University, Greenville, NC, United States
  • 5 Department of Chemical Engineering and Biotechnology, University of Applied Science, Darmstadt, Germany
  • 6 Department of Biochemistry, People's Friendship University, Moscow, Russian Federation
  • 7 Department of Pharmacy, “Drug Discovery” Laboratory, University of Napoli “Federico II”, Via D. Montesano, 49, Napoli, 80131, Italy
Ключевые слова
Bcl-2; Caspase activation; Cell cycle; DNA damage; Hybrid; Hydantoin; Pyrazoline
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