Identification and characterization of mercaptopyrimidine-based small molecules as inhibitors of nonhomologous DNA end joining

Ray, U and Gopinatha, VK and Sharma, S and Goyary, L and Choudhary, B and Mantelingu, K and Rangappa, KS and Raghavan, SC (2022) Identification and characterization of mercaptopyrimidine-based small molecules as inhibitors of nonhomologous DNA end joining. In: FEBS Journal .

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Abstract

Mercaptopyrimidine derivatives are heterocyclic compounds with potent biological activities including antiproliferative, antibacterial, and anti-inflammatory properties. The present study describes the synthesis and characterization of several mercaptopyrimidine derivatives through condensation of 5,6-diamino-2-mercaptopyrimidin-4-ol with various heterocyclic and aromatic aldehydes. Previous studies have shown that SCR7, synthesized from 5,6-diamino-2-mercaptopyrimidin-4-ol, induced cytotoxicity by targeting cancer cells by primarily inhibiting DNA Ligase IV involved in nonhomologous end joining, one of the major DNA double-strand break repair pathways. Inhibition of DNA repair pathways is considered as an important strategy for cancer therapy. Due to limitations of SCR7 in terms of IC50 in cancer cells, here we have designed, synthesized, and characterized potent derivatives of SCR7 using 5,6-diamino-2-mercaptopyrimidin-4-ol as the starting material. Several synthesized imine compounds exhibited significant improvement in inhibition of end joining and cytotoxicity up to 27-fold lower concentrations than SCR7. Among these, two compounds, SCR116 and SCR132, showed increased cancer cell death in a Ligase IV-dependent manner. Treatment with the compounds also led to reduction in V(D)J recombination efficiency, cell cycle arrest at G2/M phase, accumulation of double-strand breaks inside cells, and improved anti-cancer potential when combined with γ-radiation and radiomimetic drugs. Thus, we describe novel inhibitors of NHEJ with higher efficacy and potential, which can be developed as cancer therapeutics. © 2022 Federation of European Biochemical Societies.

Item Type:	Journal Article
Publication:	FEBS Journal
Publisher:	John Wiley and Sons Inc
Additional Information:	The copyright for this article belongs to the John Wiley and Sons Inc.
Keywords:	cancer therapeutics; DNA Ligase IV; double-strand break repair; genomic instability; NHEJ inhibitor; V(D)J recombination
Department/Centre:	Division of Biological Sciences > Biochemistry
Date Deposited:	06 Oct 2022 11:05
Last Modified:	06 Oct 2022 11:05
URI:	https://eprints.iisc.ac.in/id/eprint/77253

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