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) |
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Pages (from-to) | 269-284 |
Number of pages | 16 |
Journal | Future Medicinal Chemistry |
Volume | 11 |
Issue number | 4 |
DOIs | |
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