Synthesis and biological activities of a pH-dependently activated water-soluble prodrug of a novel hexacyclic camptothecin analog.
CH0793076 (1) is a novel hexacyclic camptothecin analog showing potent antitumor activity in various human caner xenograft models. To improve the water solubility of 1, water-soluble prodrugs were designed to generate an active drug 1 nonenzymatically, thus expected to show less interpatient PK variability than CPT-11. Among the prodrugs synthesized, 4c (TP300, hydrochloride) having a glycylsarcosyl ester at the C-20 position of 1 is highly water-soluble (>10mg/ml), stable below pH 4 and rapidly generates 1 at physiological pH in vitro. The rapid (ca. <1min) generation of 1 after incubation of TP300 with plasma (mouse, rat, dog and monkey) was also demonstrated. TP300 showed a broader antitumor spectrum and more potent antitumor activity than CPT-11 in various human cancer xenograft models.
Research Division, Chugai Pharmaceutical Co., Ltd, Kajiwara, Kamakura, Kanagawa, Japan.
Jun
J
Ohwada
Sawako
S
Ozawa
Masami
M
Kohchi
Hiroshi
H
Fukuda
Chikako
C
Murasaki
Hitomi
H
Suda
Takeshi
T
Murata
Satoshi
S
Niizuma
Masao
M
Tsukazaki
Kazutomo
K
Ori
Kiyoshi
K
Yoshinari
Yoshiko
Y
Itezono
Mika
M
Endo
Masako
M
Ura
Hiromi
H
Tanimura
Yoko
Y
Miyazaki
Akira
A
Kawashima
Shunsuke
S
Nagao
Eitarou
E
Namba
Koutarou
K
Ogawa
Kazuko
K
Kobayashi
Hisafumi
H
Okabe
Isao
I
Umeda
Nobuo
N
Shimma
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004285:Dogs; D000882:Haplorhini; D006801:Humans; D006863:Hydrogen-Ion Concentration; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D059004:Topoisomerase I Inhibitors; D014183:Transplantation, Heterologous; D014867:Water / Q000737:chemistry
D000970:Antineoplastic Agents; C541284:CH 0793076; D011355:Prodrugs; D059004:Topoisomerase I Inhibitors; D014867:Water; D000077146:Irinotecan; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin