title: 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.affiliation: Department of Chemistry Research 2, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Kohchi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Hattori
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Oikawa
authors.forename: Eisaku
authors.initials: E
authors.lastname: Mizuguchi
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Isshiki
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Aso
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yoshinari
authors.forename: Haruyoshi
authors.initials: H
authors.lastname: Shirai
authors.forename: Masanori
authors.initials: M
authors.lastname: Miwa
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Inagaki
authors.forename: Masako
authors.initials: M
authors.lastname: Ura
authors.forename: Kotaroh
authors.initials: K
authors.lastname: Ogawa
authors.forename: Hisafumi
authors.initials: H
authors.lastname: Okabe
authors.forename: Hideo
authors.initials: H
authors.lastname: Ishitsuka
authors.forename: Nobuo
authors.initials: N
authors.lastname: Shimma
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D004150:Dipeptidases / Q000235:genetics / Q000378:metabolism*; D015195:Drug Design; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006868:Hydrolysis; D008565:Membrane Proteins; D009363:Neoplasm Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011355:Prodrugs; D003841:Deoxycytidine; D004150:Dipeptidases; C038937:dipeptidase; C056034:2'-deoxy-2'-methylenecytidine