1,2,3-Triazole-totarol conjugates as potent PIP5K1α lipid kinase inhibitors

Bioorg Med Chem. 2024 May 1:105:117727. doi: 10.1016/j.bmc.2024.117727. Epub 2024 Apr 23.

Abstract

The human phosphatidylinositol 4-phosphate 5-kinase type I α (hPIP5K1α) plays a key role in the development of prostate cancer. In this work, seventeen derivatives of the natural diterpene totarol were prepared by copper(I)-catalysed Huisgen 1,3-dipolar cycloaddition reaction of the correspondingO-propargylated totarol with aryl or alkyl azides and screened for their inhibitory activities toward hPIP5K1α. Five compounds, 3a, 3e, 3f, 3i, and 3r, strongly inhibited the enzyme activity with IC50 values of 1.44, 0.46, 1.02, 0.79, and 3.65 µM, respectively, with the most potent inhibitor 3e 13-[(1-(3-nitrophenyl)triazol-4yl)methoxy]-totara-8,11,13-triene). These compounds were evaluated on their antiproliferative effects in a panel of prostate cancer cell lines. Compound 3r inhibited the proliferation of LNCaP, PC3 and DU145 cells at 20 µM, strongly, but also has strong cytotoxic effects on all tested cells.

Keywords: Cancer; Inhibitors; PIP5K1α lipid kinase; Totarol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation* / drug effects
  • Diterpenes / chemical synthesis
  • Diterpenes / chemistry
  • Diterpenes / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor*
  • Humans
  • Male
  • Molecular Docking Simulation
  • Molecular Structure
  • Phosphotransferases (Alcohol Group Acceptor)*
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / pathology
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Structure-Activity Relationship
  • Triazoles* / chemical synthesis
  • Triazoles* / chemistry
  • Triazoles* / pharmacology

Substances

  • Triazoles
  • Antineoplastic Agents
  • 1-phosphatidylinositol-4-phosphate 5-kinase
  • Diterpenes
  • Protein Kinase Inhibitors
  • Phosphotransferases (Alcohol Group Acceptor)