Design and synthesis of novel prodrugs of 2'-deoxy-2'-methylidenecytidine activated by membrane dipeptidase overexpressed in tumor tissues.

Abstract

DNA microarray analysis comparing human tumor tissues with normal tissues including hematopoietic progenitor cells resulted in identification of membrane dipeptidase as a prodrug activation enzyme. Novel prodrugs of 2'-deoxy-2'-methylidenecytidine (DMDC) including compound 23 that are activated by membrane dipeptidase (MDP) preferentially in tumor tissue were designed and synthesized to generate the active drug, DMDC, after hydrolysis of the dipeptide bond followed by spontaneous cyclization of the promoiety.

• Authors: Yasunori Kohchi, Kazuo Hattori, Nobuhiro Oikawa, Eisaku Mizuguchi, Yoshiaki Isshiki, Kohsuke Aso, Kiyoshi Yoshinari, Haruyoshi Shirai, Masanori Miwa, Yukiko Inagaki, Masako Ura, Kotaroh Ogawa, Hisafumi Okabe, Hideo Ishitsuka, Nobuo Shimma
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 17 Issue 8 Pg. 2241-5 (Apr 15 2007) ISSN: 0960-894X [Print] England
• PMID: 17306533 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Membrane Proteins
• Neoplasm Proteins
• Prodrugs
• Deoxycytidine
• Dipeptidases
• dipeptidase
• 2'-deoxy-2'-methylenecytidine

Topics

• Antineoplastic Agents (chemical synthesis, pharmacokinetics)
• Deoxycytidine (analogs & derivatives, chemistry, metabolism, pharmacokinetics)
• Dipeptidases (genetics, metabolism)
• Drug Design
• Gene Expression Regulation, Neoplastic
• Humans
• Hydrolysis
• Membrane Proteins
• Neoplasm Proteins (metabolism)
• Oligonucleotide Array Sequence Analysis
• Prodrugs (chemical synthesis, metabolism)
• Structure-Activity Relationship
• Tumor Cells, Cultured