Antiproliferative 4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamides, a new tubulin inhibitor chemotype

Bioorg Med Chem Lett. 2014 Sep 15;24(18):4477-4481. doi: 10.1016/j.bmcl.2014.07.089. Epub 2014 Aug 8.

Abstract

We discovered a new chemical class of antiproliferative agents, 4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamides. SAR-guided optimization of the two distinct terminal fragments yielded a compound with 120 nM potency in an antiproliferative assay. Biological activity profile studies (COMPARE analysis) demonstrated that 4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamides act as tubulin inhibitors, and this conclusion was confirmed via biochemical assays with pure tubulin and demonstration of increased numbers of mitotic cells following treatment of a leukemia cell line.

Keywords: Chemotherapeutic agents; DU-145; Prostate cancer; Rational single-molecule polypharmacy; Screening; Tubulin inhibitor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Discovery
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Structure
  • Oxadiazoles / chemical synthesis
  • Oxadiazoles / chemistry
  • Oxadiazoles / pharmacology*
  • Piperidines / chemical synthesis
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Structure-Activity Relationship
  • Tubulin / metabolism*
  • Tubulin Modulators / chemical synthesis
  • Tubulin Modulators / chemistry
  • Tubulin Modulators / pharmacology*

Substances

  • 4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamide
  • Antineoplastic Agents
  • Oxadiazoles
  • Piperidines
  • Tubulin
  • Tubulin Modulators