2. Academic Validation
  3. Design, synthesis, and biological evaluation of pyrrolobenzodiazepine-containing hypoxia-activated prodrugs

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.
Peter S Dragovich 1,  Fabio Broccatelli 2,  Jinhua Chen 3,  Peter Fan 2,  Hoa Le 2,  Weiguang Mao 2,  Thomas H Pillow 2,  Andrew G Polson 2,  John Wai 3,  Zijin Xu 3,  Hui Yao 3,  Donglu Zhang 2
Affiliations

Affiliations

  • 1 Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: dragovich.peter@gene.com.
  • 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.
PMID: 29079474 DOI: 10.1016/j.bmcl.2017.10.023
Abstract

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.

Keywords

Hypoxia; P450-reductase; Prodrug; Pyrrolobenzodiazepine.

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