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

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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

Bibliographical note

Funding Information:
This work was supported by National Natural Science Foundation of China (grant number 21778011), Beijing Natural Science Foundation (grant numbers 7162015 and 7184192), China Postdoctoral Science Foundation funded project (grant number 2017M620567), Beijing Postdoctoral Research Foundation (grant number 2018-ZZ-022), Education Commission Science and Technology Project of Beijing Municipality (grant number PXM2015 014204 500175) and the Great Wall scholars program of Beijing Municipal Education Commission (grant number CIT&TCD20180308). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Publisher Copyright:
© 2019 2018 Lijiao Zhao.

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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",

note = "Funding Information: This work was supported by National Natural Science Foundation of China (grant number 21778011), Beijing Natural Science Foundation (grant numbers 7162015 and 7184192), China Postdoctoral Science Foundation funded project (grant number 2017M620567), Beijing Postdoctoral Research Foundation (grant number 2018-ZZ-022), Education Commission Science and Technology Project of Beijing Municipality (grant number PXM2015 014204 500175) and the Great Wall scholars program of Beijing Municipal Education Commission (grant number CIT&TCD20180308). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Publisher Copyright: {\textcopyright} 2019 2018 Lijiao Zhao.",

year = "2019",

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doi = "10.4155/fmc-2018-0511",

language = "English (US)",

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T2 - A hypoxia-activated tripartite combi-nitrosourea prodrug overcoming AGT-mediated chemoresistance

AU - Ge, Yao

AU - Lai, Xinxin

AU - Li, Jintao

AU - Yu, Ran

AU - Zhuang, Zhuochen

AU - Sun, Guohui

AU - Cui, Xin

AU - Zhang, Na

AU - Zhao, Lijiao

AU - Upadhyaya, Pramod

AU - Zhong, Rugang

N1 - Funding Information: This work was supported by National Natural Science Foundation of China (grant number 21778011), Beijing Natural Science Foundation (grant numbers 7162015 and 7184192), China Postdoctoral Science Foundation funded project (grant number 2017M620567), Beijing Postdoctoral Research Foundation (grant number 2018-ZZ-022), Education Commission Science and Technology Project of Beijing Municipality (grant number PXM2015 014204 500175) and the Great Wall scholars program of Beijing Municipal Education Commission (grant number CIT&TCD20180308). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Publisher Copyright: © 2019 2018 Lijiao Zhao.

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N2 - 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.

AB - 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.

KW - O-Alkylguanine DNA alkyltransferase inhibition

KW - anticancer efficacy

KW - chloroethylnitrosoureas

KW - hypoxia-activated prodrug

KW - tumor targeting

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

Abstract

Bibliographical note

Keywords

UN SDGs

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