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

Abstract

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.

• Authors: Neha Upadhyay, Kalpana Tilekar, Fulvio Loiodice, Natalia Yu Anisimova, Tatiana S Spirina, Darina V Sokolova, Galina B Smirnova, Jun-Yong Choe, Franz-Josef Meyer-Almes, Vadim S Pokrovsky, Antonio Lavecchia, C S Ramaa
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 107 Pg. 104527 (02 2021) ISSN: 1090-2120 [Electronic] United States
• PMID: 33317839 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• BCL2 protein, human
• Hydantoins
• Proto-Oncogene Proteins c-bcl-2
• Pyrazoles

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, metabolism, pharmacokinetics, therapeutic use)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• DNA Breaks, Double-Stranded (drug effects)
• Drug Design
• Drug Screening Assays, Antitumor
• G1 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• Hydantoins (chemical synthesis, metabolism, pharmacokinetics, therapeutic use)
• Male
• Mice, Inbred BALB C
• Mice, Nude
• Molecular Docking Simulation
• Neoplasms (drug therapy)
• Protein Binding
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Pyrazoles (chemical synthesis, metabolism, pharmacokinetics, therapeutic use)
• Xenograft Model Antitumor Assays