Design, synthesis, in-vitro, in-silico, DFT and POM studies of a novel family of sulfonamides as potent anti-triple-negative breast cancer agents

Comput Biol Chem. 2024 Dec:113:108214. doi: 10.1016/j.compbiolchem.2024.108214. Epub 2024 Sep 19.

Abstract

In this study, a new family of ethacrynic acid-sulfonamides and indazole-sulfonamides was synthesized and tested in vitro against MDA-MB-468 triple-negative breast cancer cells and PBMCs human peripheral blood mononuclear cells, using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. The aim of this research is to discover novel compounds with potential therapeutic effects on breast cancer. The antiproliferative activity of these compounds showed a significant dose-dependent activity, with IC50 values ranging between 2.83 and 7.52 µM. The lead compounds 8 and 9 displayed similar IC50 values to paclitaxel with 2.83, 3.84 and 2.72 µM, respectively. This highlights the novelty and potential of these compounds as alternatives to current treatments. The binding properties of 8, 9, and paclitaxel with the active sites of the PARP1(Poly(ADP-ribose) polymérase 1) and EGFR (Epidermal growth factor receptor) proteins were analyzed by molecular docking methods showing, for PARP1 protein, binding affinities of -9.8 Kcal /mol, -10 Kcal /mol, and -9.4 Kcal /mol, respectively. While their binding affinities for EGFR protein are -7.5 Kcal/mol, -7.2 Kcal/mol and -6.9 Kcal/mol, respectively. Moreover, drug-likeness and ADMET (Absorption-distribution-metabolism-excretion-toxicity) analyses demonstrated that both molecules are orally bioavailable and have good pharmacokinetic and non-toxic profiles. DFT (Density functional theory) was also carried out on both compounds 8 and 9 additionally to POM (Petra/Osiris/Molinspiration) studies on all compounds. The outcomes of this study suggest that compounds 8 and 9 are promising candidates for further development as therapeutic agents against triple-negative breast cancer.

Keywords: ADMET; Anti-breast cancer agents; Breast cancer; Ethacrynic acid; Indazole-sulfonamides; Molecular docking; POM.

MeSH terms

  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation* / drug effects
  • Density Functional Theory*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor*
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism
  • Female
  • Humans
  • Molecular Docking Simulation*
  • Molecular Structure
  • Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors
  • Poly (ADP-Ribose) Polymerase-1 / metabolism
  • Structure-Activity Relationship
  • Sulfonamides* / chemical synthesis
  • Sulfonamides* / chemistry
  • Sulfonamides* / pharmacology
  • Triple Negative Breast Neoplasms* / drug therapy
  • Triple Negative Breast Neoplasms* / metabolism
  • Triple Negative Breast Neoplasms* / pathology

Substances

  • Antineoplastic Agents
  • Sulfonamides
  • Poly (ADP-Ribose) Polymerase-1
  • ErbB Receptors
  • PARP1 protein, human
  • EGFR protein, human