Next-Generation Hypoxic Cell Radiosensitizers: Nitroimidazole Alkylsulfonamides

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.