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

doi:10.4155/fmc-2018-0511

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

Carcinogenesis and Chemoprevention

Research output: Contribution to journal › Article › peer-review

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 language	English (US)
Pages (from-to)	269-284
Number of pages	16
Journal	Future Medicinal Chemistry
Volume	11
Issue number	4
DOIs	https://doi.org/10.4155/fmc-2018-0511
State	Published - 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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NBGNU : A hypoxia-activated tripartite combi-nitrosourea prodrug overcoming AGT-mediated chemoresistance. / Ge, Yao; Lai, Xinxin; Li, Jintao; Yu, Ran; Zhuang, Zhuochen; Sun, Guohui; Cui, Xin; Zhang, Na; Zhao, Lijiao; Upadhyaya, Pramod; Zhong, Rugang.

In: Future Medicinal Chemistry, Vol. 11, No. 4, 02.2019, p. 269-284.

Research output: Contribution to journal › Article › peer-review

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title = "NBGNU: A hypoxia-activated tripartite combi-nitrosourea prodrug overcoming AGT-mediated chemoresistance",

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.",

keywords = "O-Alkylguanine DNA alkyltransferase inhibition, anticancer efficacy, chloroethylnitrosoureas, hypoxia-activated prodrug, tumor targeting",

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

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AU - Yu, Ran

AU - Zhuang, Zhuochen

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KW - chloroethylnitrosoureas

KW - hypoxia-activated prodrug

KW - tumor targeting

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