title: Synthesis and antitumor activity evaluation of a novel combi-nitrosourea prodrug: Designed to release a DNA cross-linking agent and an inhibitor of O(6)-alkylguanine-DNA alkyltransferase.
abstract: The drug resistance of CENUs induced by O(6)-alkylguanine-DNA alkyltransferase (AGT), which repairs the O(6)-alkylated guanine and subsequently inhibits the formation of dG-dC cross-links, hinders the application of CENU chemotherapies. Therefore, the discovery of CENU analogs with AGT inhibiting activity is a promising approach leading to novel CENU chemotherapies with high therapeutic index. In this study, a new combi-nitrosourea prodrug 3-(3-(((2-amino-9H-purin-6-yl)oxy)methyl)benzyl)-1-(2-chloroethyl)-1-nitrosourea (6), designed to release a DNA cross-linking agent and an inhibitor of AGT, was synthesized and evaluated for its antitumor activity and ability to induce DNA interstrand cross-links (ICLs). The results indicated that 6 exhibited higher cytotoxicity against mer(+) glioma cells compared with ACNU, BCNU, and their respective combinations with O(6)-benzylguanine (O(6)-BG). Quantifications of dG-dC cross-links induced by 6 were performed using HPLC-ESI-MS/MS. Higher levels of dG-dC cross-link were observed in 6-treated human glioma SF763 cells (mer(+)), whereas lower levels of dG-dC cross-link were observed in 6-treated calf thymus DNA, when compared with the groups treated with BCNU and ACNU. The results suggested that the superiority of 6 might result from the AGT inhibitory moiety, which specifically functions in cells with AGT activity. Molecular docking studies indicated that five hydrogen bonds were formed between the O(6)-BG analogs released from 6 and the five residues in the active pocket of AGT, which provided a reasonable explanation for the higher AGT-inhibitory activity of 6 than O(6)-BG.
authors.affiliation: Beijing Key Laboratory of Environmental & Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, PR China.
authors.forename: Guohui
authors.initials: G
authors.lastname: Sun
authors.affiliation: Beijing Key Laboratory of Environmental & Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, PR China.
authors.forename: Na
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Beijing Key Laboratory of Environmental & Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, PR China. Electronic address: zhaolijiao@bjut.edu.cn.
authors.forename: Lijiao
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Beijing Key Laboratory of Environmental & Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, PR China.
authors.forename: Tengjiao
authors.initials: T
authors.lastname: Fan
authors.affiliation: Beijing Key Laboratory of Environmental & Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, PR China.
authors.forename: Shufen
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Beijing Key Laboratory of Environmental & Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, PR China.
authors.forename: Rugang
authors.initials: R
authors.lastname: Zhong
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D009607:Nitrosourea Compounds / Q000494:pharmacology*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors*; D011355:Prodrugs / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors; D009607:Nitrosourea Compounds; D011355:Prodrugs; D019853:O(6)-Methylguanine-DNA Methyltransferase
keywords: Combi-nitrosourea; Cytotoxicity; Drug resistance; O(6)-alkylguanine-DNA alkyltransferase; dG–dC cross-links