Quinazolinone-based Anticancer Agents: Synthesis, Anti-proliferative SAR, Anti-tubulin Activity and Tubulin Co-crystal Structure

Research output: Contribution to journalArticlepeer-review

Authors

  • Wolfgang Dohle
  • Fabrice L. Jourdan
  • Grégory Menchon
  • Andrea E. Prota
  • Pascoe Mannion
  • Ernest Hamel
  • Mark P. Thomas
  • Philip G. Kasprzyk
  • Eric Ferrandis
  • Michel O. Steinmetz
  • Mathew P. Leese
  • Barry V. L. Potter

Colleges, School and Institutes

External organisations

  • Medicinal Chemistry & Drug Discovery, Department of Pharmacology, University of Oxford
  • University of Bath
  • Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institute
  • Centre for Endocrinology; Diabetes and Metabolism; Birmingham Health Partners; Birmingham B15 2TH UK
  • Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute
  • IPSEN
  • Institut de Recherche Henri Beaufour, IPSEN

Abstract

Quinazolinone-based anti-cancer agents were designed, decorated with functional groups from a 2-methoxyestradiol-based microtubule disruptor series, incorporating the aryl sulfamate motif of steroid sulfatase (STS) inhibitors. The steroidal AB-ring system was mimicked, favoring conformations with an N-2 substituent occupying D-ring space. Evaluation against breast and prostate tumor cell lines identified 7b with DU-145 anti-proliferative activity (GI50 300 nM). A preliminary structure-activity relationship afforded compounds (e.g. 7j GI50 50 nM) with activity exceeding that of the parent. Both 7b and 7j inhibit tubulin assembly in vitro and colchicine binding and 7j was successfully co-crystallized with the αβ-tubulin heterodimer as the first of its class, its sulfamate group interacting positively at the colchicine binding site. Microtubule destabilization by 7j likely prevents the curved-to-straight conformational transition. Quinazolinone sulfamates surprisingly showed weak STS inhibition. Preliminary in vivo studies in a multiple myeloma xenograft model for 7b showed oral activity, confirming the promise of this template.

Details

Original languageEnglish
JournalJournal of Medicinal Chemistry
Early online date11 Dec 2017
Publication statusE-pub ahead of print - 11 Dec 2017

Keywords

  • Journal Article