Synthesis and biological evaluation of DIDS analogues as efficient inhibitors of RAD51 involved in homologous

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Real-time Observation of the DNA Strand Exchange Reaction Mediated by Rad51
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Real-time Observation of the DNA Strand Exchange Reaction Mediated by Rad51

Published on: February 13, 2019

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Alexandre Demeyer1, Lucie Fonteneau1, Marion Liennard2

  • 1Nantes Université, CNRS, US2B, UMR 6286, DNA-repair Group, F-44000 Nantes, France.

Bioorganic & Medicinal Chemistry Letters
|March 29, 2023
PubMed

Insights

Researchers developed novel RAD51 inhibitors based on the DIDS molecule. These compounds show potential for enhancing cancer treatment efficacy by targeting homologous recombination DNA repair in cancer cells.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • RAD51 protein is crucial for homologous recombination DNA repair.
  • Overexpression of RAD51 in cancer cells can reduce sensitivity to chemotherapy and radiotherapy.
  • Targeting RAD51 offers a strategy to re-sensitize cancer cells to existing treatments.

Purpose of the Study:

  • To develop novel RAD51 inhibitors.
  • To investigate structure-activity relationships of DIDS analogues as RAD51 inhibitors.
  • To identify potent RAD51 inhibitors for potential cancer therapy.

Main Methods:

  • Synthesis of two series of 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) analogues with varying substituents.
  • Structure-activity relationship (SAR) studies.
  • Assay of RAD51 inhibitory activity and homologous recombination (HR) inhibition.

Main Results:

  • Several DIDS analogues were synthesized and evaluated for RAD51 inhibitory potential.
  • Three compounds, including cyano (12), benzamide (23), and phenylcarbamate (29) analogues, demonstrated potent RAD51 inhibition.
  • These novel inhibitors exhibited homologous recombination inhibition in the micromolar range.

Conclusions:

  • The synthesized DIDS analogues represent a new class of potent RAD51 inhibitors.
  • These compounds hold promise for restoring cancer cell sensitivity to radio- and chemotherapy.
  • Further development of these inhibitors could lead to improved cancer treatment strategies.
Keywords:
DNA repairHomologous recombinationInhibitorRAD51Stilbene 2,2′-disulfonic compounds

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