Synthesis of new camptothecin analogs with improved antitumor activities.
Novel hexacyclic camptothecin analogs containing cyclic amidine, urea, or thiourea moiety were designed and synthesized based on the proposed 3D-structure of the topoisomerase I (Topo I)/DNA/camptothecin ternary complex. The analogs were prepared from 9-nitrocamptothecin via 7,9-diaminocamptothecin derivatives as a key intermediate. Among them, 7c exhibited in vivo antitumor activities superior to CPT-11 in human cancer xenograft models in mice at their maximum tolerated doses though its in vitro antiproliferative activity was comparable to SN-38 against corresponding cell lines.
Niizuma
Satoshi
S
Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
Tsukazaki
Masao
M
Suda
Hitomi
H
Murata
Takeshi
T
Ohwada
Jun
J
Ozawa
Sawako
S
Fukuda
Hiroshi
H
Murasaki
Chikako
C
Kohchi
Masami
M
Morikami
Kenji
K
Yoshinari
Kiyoshi
K
Endo
Mika
M
Ura
Masako
M
Tanimura
Hiromi
H
Miyazaki
Yoko
Y
Takasuka
Tsuyoshi
T
Kawashima
Akira
A
Nanba
Eitaro
E
Nakano
Kounosuke
K
Ogawa
Kotaro
K
Kobayashi
Kazuko
K
Okabe
Hisafumi
H
Umeda
Isao
I
Shimma
Nobuo
N
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D006801:Humans; D051379:Mice; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; C541284:CH 0793076; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin