Article

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

Department of Chemistry Research 2, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
Bioorganic & Medicinal Chemistry Letters (impact factor: 2.55). 05/2007; 17(8):2241-5. DOI:10.1016/j.bmcl.2007.01.066 pp.2241-5
Source: PubMed

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.

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Keywords

activated
 
compound 23
 
dipeptide bond
 
DMDC
 
DNA microarray analysis
 
hematopoietic progenitor cells
 
human tumor tissues
 
membrane dipeptidase
 
Novel prodrugs
 
prodrug activation enzyme
 
promoiety
 
tumor tissue
 

Yasunori Kohchi