2. Academic Validation
  3. Synthesis and biological evaluation of hypoxia-activated prodrugs of SN-38

Synthesis and biological evaluation of hypoxia-activated prodrugs of SN-38

  • Eur J Med Chem. 2017 May 26:132:135-141. doi: 10.1016/j.ejmech.2017.03.040.
Chen Jin 1,  Qiumeng Zhang 1,  Wei Lu 2
Affiliations

Affiliations

  • 1 School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, PR China.
  • 2 School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, PR China. Electronic address: wlu@chem.ecnu.edu.cn.
PMID: 28350997 DOI: 10.1016/j.ejmech.2017.03.040
Abstract

We designed new hypoxia-activated prodrugs by conjugating (1-methyl-2-nitro-1H-imidazol-5-yl)methanol with 7-ethyl-10-hydroxy camptothecin (SN-38). Initially, we improved the method of multi-gram scale synthesis of (1-methyl-2-nitro-1H-imidazol-5-yl)methanol, which increased the yield to 42% compared to 8% by the original synthesis method. The improved method was used to synthesize evofosfamide (TH-302) and hypoxia-activated prodrugs of SN-38. Two different linkages between (1-methyl-2-nitro-1H-imidazol-5-yl)methanol and SN-38 were evaluated that afforded different hypoxia-selectivity and toxicity. Compound 16 (IOS), containing an ether linkage, was considered to be a promising hypoxia-selective antitumor agent.

Keywords

2-Nitroimidazole; Hypoxia-activated prodrug; SN-38.

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