Monoterpene substituted thiazolidin-4-ones as novel TDP1 inhibitors: Synthesis, biological evaluation and docking.

Reynisson

Abstract

Tyrosyl-DNA phosphodiesterase 1(TDP1) is a promising target for a new therapy in oncological disease as an adjunct to topoisomerase 1 (TOP1) drugs. In this paper, novel thiazolidin-4-one derivatives with a benzyl and monoterpene substituents were synthesized. Compounds with a monoterpene fragment attached via a phenyloxy linker were active against TDP1 with IC50 values in the 1 ÷ 3 µM range, while direct attachment of monoterpene moiety to the thiazolidin-4-one fragment had no activity. Molecular modelling predicted two plausible binding modes of the active compounds both effectively blocking access to the catalytic site of TDP. At non-toxic concentrations the active ligands potentiated the efficacy of the TOP1 poison topotecan in human cervical cancer HeLa cells, but not in non-cancerous HEK293A cells.

Citation

Reynisson. (2022). Monoterpene substituted thiazolidin-4-ones as novel TDP1 inhibitors: Synthesis, biological evaluation and docking. Bioorganic and Medicinal Chemistry Letters, https://doi.org/10.1016/j.bmcl.2022.128909

• Acceptance Date: Jul 23, 2022
• Publication Date: Oct 1, 2022
• Publicly Available Date: Jun 20, 2023
• Journal: Bioorganic & Medicinal Chemistry Letters
• Print ISSN: 0960-894X
• Publisher: Elsevier
• DOI: https://doi.org/10.1016/j.bmcl.2022.128909
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0960894X22003857?via%3Dihub