NBGNU: A hypoxia-activated tripartite combi-nitrosourea prodrug overcoming AGT-mediated chemoresistance

Yao Ge, Xinxin Lai, Jintao Li, Ran Yu, Zhuochen Zhuang, Guohui Sun, Xin Cui, Na Zhang, Lijiao Zhao, Pramod Upadhyaya, Rugang Zhong

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Aim: A hypoxia-activated combi-nitrosourea prodrug, N-(2-chloroethyl)-N′-2-(2-(4-nitrobenzylcarbamate)-O 6-benzyl-9-guanine)ethyl-N-nitrosourea (NBGNU), was synthesized and evaluated for its hypoxic selectivity and anticancer activity in vitro. Results: The prodrug was designed as a tripartite molecule consisting of a chloroethylnitrosourea pharmacophore to induce DNA interstrand crosslinks (ICLs) and an O 6-benzylguanine analog moiety masked by a 4-nitrobenzylcarbamate group to induce hypoxia-activated inhibition of O 6-alkylguanine-DNA alkyltransferase. NBGNU was tested for hypoxic selectivity, cytotoxicity and DNA ICLs ability. The reduction product amounts, cell death rates and DNA ICL levels induced by NBGNU under hypoxic conditions were all significantly higher than those induced by NBGNU under normoxic conditions. Conclusion: The tripartite combi-nitrosourea prodrug exhibits desirable tumor-hypoxia targeting ability and abolished chemoresistance compared with the conventional chloroethylnitrosoureas.

Original languageEnglish (US)
Pages (from-to)269-284
Number of pages16
JournalFuture Medicinal Chemistry
Volume11
Issue number4
DOIs
StatePublished - Feb 2019

Keywords

  • O-Alkylguanine DNA alkyltransferase inhibition
  • anticancer efficacy
  • chloroethylnitrosoureas
  • hypoxia-activated prodrug
  • tumor targeting

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

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  • Cite this

    Ge, Y., Lai, X., Li, J., Yu, R., Zhuang, Z., Sun, G., Cui, X., Zhang, N., Zhao, L., Upadhyaya, P., & Zhong, R. (2019). NBGNU: A hypoxia-activated tripartite combi-nitrosourea prodrug overcoming AGT-mediated chemoresistance. Future Medicinal Chemistry, 11(4), 269-284. https://doi.org/10.4155/fmc-2018-0511