Design, synthesis and ex vivo evaluation of colon-specific azo based prodrugs of anticancer agents

• Published in: Bioorganic & medicinal chemistry letters 2013-10, Vol.23 (19), p.5332-5338
• Main Authors: Sharma, Rajiv, Rawal, Ravindra K., Gaba, Tripti, Singla, Nishu, Malhotra, Manav, Matharoo, Sahil, Bhardwaj, T.R.
• Format: Article
• Language: English
• Subjects: adverse effects; analytical methods; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor agents; Azo Compounds - chemical synthesis; Azo Compounds - chemistry; Azo Compounds - pharmacology; Azoreductase; buffers; cecum; Cell Line, Tumor; colon; Colon - drug effects; Colon-specific; Colonic Neoplasms - drug therapy; colorectal neoplasms; cytotoxicity; Drug Design; Drug-Related Side Effects and Adverse Reactions; feces; Feces - chemistry; Gemcitabine; Humans; Inhibitory Concentration 50; Mesalamine - chemistry; Methotrexate; Oxaliplatin; Prodrug; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacology; Rats
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.07.059

The ex vivo release capability of synthesized prodrugs with fresh rat fecal material was 60–70% after 24h incubation at 37°C. In the presence of rat cecum content more than 80% of drug was released. Colon-specific azo based prodrugs of anticancer agents like methotrexate (6), gemcitabine (7) and analogue of oxaliplatin (RTB-4) (8) were synthesized and characterized by modern analytical techniques. The prepared prodrugs were stable in acidic (pH 1.2) and basic (pH 7.4) buffers which showed their stability in upper GIT environment. Further, an assay was performed which demonstrated the presence of azoreductase enzyme in the rat fecal material, rat cecum content and other parts of intestinal content which reduce specifically the azo bond and release the drug. The in vitro cytotoxicity assay was also performed which clearly indicated that these azo based prodrugs are active against human colorectal cancer cell lines (COLO 205, COLO 320 DM and HT-29). The release behavior of prodrugs (10, 11 and 15) was 60–70% after 24h incubation at 37°C. Therefore, the synthesized azo linked prodrugs of methotrexate, gemcitabine and RTB-4 are the potential candidates for colon targeted drug delivery system with minimal undesirable side effects.