Prodrug Strategies for Targeting Tumour Hypoxia

摘要: Tumour hypoxia is a critically important, but elusive, target in cancer therapy; the importance of eliminating hypoxic cells underscored by their central roles tumour progression and resistance to cytotoxic chemotherapy radiotherapy. While many molecular targets may offer synthetic lethal interactions with hypoxia, development prodrugs that are activated generate cytotoxins one-electron (1e) reduction represents more direct approach. Although conceptually simple, significant challenges need be overcome achieve useful therapeutic activity. These include designing able diffuse efficiently into tissue, avoidance off-target (oxygen-insensitive) two-electron (2e) reduction, maximizing bystander effects from diffusion active metabolites exploit severely regions tumours (critically) predictive biomarkers for what fact multifaceted (comprising activating reductases determinants sensitivity metabolites). Here we provide an overview recent progress towards these goals context four classes hypoxia-activated (HAPs) clinical trial or advanced preclinical development, namely benzotriazine di-oxides (tirapazamine SN30000), dinitrobenzamide mustard (DNBM) PR-104, phosphoramidate TH-302 nitrochloromethylbenzindoline (nitroCBI) potent DNA minor groove alkylators.