Next-Generation Hypoxic Cell Radiosensitizers: Nitroimidazole Alkylsulfonamides

  • J Med Chem. 2018 Feb 8;61(3):1241-1254. doi: 10.1021/acs.jmedchem.7b01678.
Muriel Bonnet  1 ,  Cho Rong Hong  1 ,  Way Wua Wong  1 ,  Lydia P Liew  1  2 ,  Avik Shome  1 ,  Jingli Wang  1 ,  Yongchuan Gu  1  2 ,  Ralph J Stevenson  1 ,  Wen Qi  3 ,  Robert F Anderson  1  3  2 ,  Frederik B Pruijn  1  2 ,  William R Wilson  1  2 ,  Stephen M F Jamieson  1  4  2 ,  Kevin O Hicks  1  2 ,  Michael P Hay  1  2
Affiliations
  • 1. Auckland Cancer Society Research Centre, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland , Private Bag 92019, Auckland, New Zealand.
  • 2. Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland , 3 Symonds St, Auckland, New Zealand.
  • 3. School of Chemical Sciences, Faculty of Science, University of Auckland , Private Bag 92019, Auckland, New Zealand.
  • 4. Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland , Private Bag 92019, Auckland, New Zealand.
PMID: 29253343 DOI: 10.1021/acs.jmedchem.7b01678
Abstract

Innovations in the field of radiotherapy such as stereotactic body radiotherapy, along with the advent of radio-immuno-oncology, herald new opportunities for classical oxygen-mimetic radiosensitizers. The role of hypoxic tumor cells in resistance to radiotherapy and in suppression of immune response continues to endorse tumor hypoxia as a bona fide, yet largely untapped, drug target. Only nimorazole is used clinically as a radiosensitizer, and there is a dearth of new radiosensitizers in development. Here we present a survey of novel nitroimidazole alkylsulfonamides and document their cytotoxicity and ability to radiosensitize anoxic tumor cells in vitro. We use a phosphate prodrug approach to increase aqueous solubility and to improve tumor drug delivery. A 2-nitroimidazole and a 5-nitroimidazole analogue demonstrated marked tumor radiosensitization in either ex vivo assays of surviving clonogens or tumor regrowth delay.