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: Guohui Sun, Na Zhang, Lijiao Zhao, Tengjiao Fan, Shufen Zhang, Rugang Zhong
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 24 Issue 9 Pg. 2097-107 (May 01 2016) ISSN: 1464-3391 [Electronic] England
• PMID: 27041398 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Cross-Linking Reagents
• Enzyme Inhibitors
• Nitrosourea Compounds
• Prodrugs
• O(6)-Methylguanine-DNA Methyltransferase

Topics

• Antineoplastic Agents (pharmacology)
• Cross-Linking Reagents (chemistry)
• Enzyme Inhibitors (pharmacology)
• Humans
• Nitrosourea Compounds (pharmacology)
• O(6)-Methylguanine-DNA Methyltransferase (antagonists & inhibitors)
• Prodrugs (pharmacology)