NBGNU: a hypoxia-activated tripartite combi-nitrosourea prodrug overcoming AGT-mediated chemoresistance | Zendy

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

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

Author(s) -

Ge Yao,

Xinxin Lai,

Jintao Li,

Ran Yu,

Zhuochen Zhuang,

Guohui Sun,

Xin Cui,

Na Zhang,

Lijiao Zhao,

Pramod Upadhyaya,

Rugang Zhong

Publication year - 2018

Publication title -

future medicinal chemistry

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 0.708

H-Index - 69

eISSN - 1756-8927

pISSN - 1756-8919

DOI - 10.4155/fmc-2018-0511

Subject(s) - prodrug , nitrosourea , cytotoxicity , chemistry , dna , guanine , in vitro , hypoxia (environmental) , dna damage , tumor hypoxia , moiety , biochemistry , cancer research , pharmacology , microbiology and biotechnology , stereochemistry , biology , oxygen , gene , chemotherapy , nucleotide , medicine , genetics , organic chemistry , radiation therapy

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.

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