Design and synthesis of novel prodrugs of 2'-deoxy-2'-methylidenecytidine activated by membrane dipeptidase overexpressed in tumor tissues.
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.
Kohchi
Yasunori
Y
Department of Chemistry Research 2, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
Hattori
Kazuo
K
Oikawa
Nobuhiro
N
Mizuguchi
Eisaku
E
Isshiki
Yoshiaki
Y
Aso
Kohsuke
K
Yoshinari
Kiyoshi
K
Shirai
Haruyoshi
H
Miwa
Masanori
M
Inagaki
Yukiko
Y
Ura
Masako
M
Ogawa
Kotaroh
K
Okabe
Hisafumi
H
Ishitsuka
Hideo
H
Shimma
Nobuo
N
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
D000970:Antineoplastic Agents; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011355:Prodrugs; D003841:Deoxycytidine; D004150:Dipeptidases; C038937:dipeptidase; C056034:2'-deoxy-2'-methylenecytidine