Molecular Analysis of the In Vivo Metabolism and Biodistribution of Metabolically and Non-Metabolically Activated Combi-Molecules of the Triazene Class

Title: Molecular Analysis of the In Vivo Metabolism and Biodistribution of Metabolically and Non-Metabolically Activated Combi-Molecules of the Triazene Class

Volume: 3 Issue: 1

Author(s): Qiyu Qiu, Anne-Laure Larroque, Bernard Gibbs, Youqiang Fang, Younes Lakhrissi, Jean-Paul Soucy, Shadreck Mzengeza, Zakaria Rachid and Bertrand J. Jean-Claude

Affiliation:

Keywords: Combi-molecule, EGFR inhibition, DNA damage, In vivo

Abstract: Combi-molecules are novel agents designed to be hydrolyzed into two bioactive species: an epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitor + a DNA alkylating agent. With the purpose of enhancing the tumour concentration of the bioactive species, we synthesized and compared the activities of RB107, a quinazolinotriazene designed to generate the bioactive BJ2000 upon hydrolysis, ZRDM and RB107ZR that require metabolic activation to generate BJ2000. The results showed that RB107 released the highest level of BJ2000 and its degradation product FD105 in vivo and high levels of the DNA alkylating methyl diazonium ion in the brain, kidney, liver and the DU145 tumours as confirmed by 14C-labeling. The results in toto suggest that RB107 was stable enough to deliver the bioactive species to the tumour site and for optimal tumour distribution of the bioactive species, combi-molecules of the triazene class must be designed to be primarily degraded by hydrolytic cleavage and not by metabolic activation.

Cite this article as:

Qiu Qiyu, Larroque Anne-Laure, Gibbs Bernard, Fang Youqiang, Lakhrissi Younes, Soucy Jean-Paul, Mzengeza Shadreck, Rachid Zakaria and Jean-Claude J. Bertrand, Molecular Analysis of the In Vivo Metabolism and Biodistribution of Metabolically and Non-Metabolically Activated Combi-Molecules of the Triazene Class, Drug Metabolism Letters 2009; 3 (1) . https://dx.doi.org/10.2174/187231209787176344