title: Synthesis and Antitumor Activity Evaluation of a Novel Combi-nitrosourea Prodrug: BGCNU.
abstract: Chloroethylnitrosoureas (CENUs) are an important type of alkylating agent employed in the clinical treatment of cancer. However, the anticancer efficacy of CENUs is greatly decreased by a DNA repairing enzyme, O6-alkylguanine-DNA alkyltransferase (AGT), by preventing the formation of interstrand cross-links (ICLs). In this study, a combi-nitrosourea prodrug, namely,N-(2-chloroethyl)-N'-2-(O6-benzyl-9-guanine)ethyl-N-nitrosourea (BGCNU), which possesses an O6-benzylguanine (O6-BG) derivative and CENU pharmacophores simultaneously, was synthesized and evaluated for its ability to induce ICLs. The target compound is markedly more cytotoxic in human glioma cells than the clinically used CENU chemotherapies ACNU, BCNU, and their respective combinations with O6-BG. In the AGT-proficient cells, significantly higher levels of DNA ICLs were observed in the groups treated by BGCNU than those by ACNU and BCNU, which indicated that the activity of AGT was effectively inhibited by the O6-BG derivatives released from BGCNU.
authors.affiliation: Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology , Beijing 100124, P. R. China.
authors.forename: Yameng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology , Beijing 100124, P. R. China.
authors.forename: Ting
authors.initials: T
authors.lastname: Ren
authors.affiliation: Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology , Beijing 100124, P. R. China.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Lai
authors.affiliation: Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology , Beijing 100124, P. R. China.
authors.forename: Guohui
authors.initials: G
authors.lastname: Sun
authors.affiliation: Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology , Beijing 100124, P. R. China.
authors.forename: Lijiao
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology , Beijing 100124, P. R. China.
authors.forename: Na
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology , Beijing 100124, P. R. China.
authors.forename: Rugang
authors.initials: R
authors.lastname: Zhong
keywords: AGT inhibition; Combi-nitrosourea; DNA interstrand cross-links; anticancer activity; chloroethylnitrosourea