Design, synthesis, and biological evaluation of pyrrolobenzodiazepine-containing hypoxia-activated prodrugs
- Bioorg Med Chem Lett. 2017 Dec 1;27(23):5300-5304. doi: 10.1016/j.bmcl.2017.10.023.
- 1. Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: [email protected].
- 2. Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
- 3. Wuxi Apptec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
The ability of various pyrrolobenzodiazepine(PBD)-containing cytotoxic compounds to function as hypoxia-activated prodrugs was assessed. These molecules incorporated a 1-methyl-2-nitro-1H-imidazole hypoxia-activated trigger (present in the clinically evaluated compound TH-302) in a manner that masked a reactive imine moiety required for cytotoxic activity. Incubation of the prodrugs with cytochrome P450-reductase under normoxic and hypoxic conditions revealed that some, but not all, were efficient substrates for the enzyme. In these experiments, prodrugs derived from PBD-monomers underwent rapid conversion to the parent cytotoxic compounds under low-oxygen conditions while related PBD-dimers did not. The ability of a given prodrug to function as an efficient cytochrome P450-reductase substrate correlated with the ratio of cytotoxic potencies measured for the compound against NCI460 cells under normoxic and hypoxic conditions.