Chemical and Pharmaceutical Bulletin p. 1393 - 1403 (1999)
Update date:2022-08-03
Topics:
Amishiro, Nobuyoshi
Nagamura, Satoru
Kobayashi, Eiji
Okamoto, Akihiko
Gomi, Katsushige
Saito, Hiromitsu
A series of A-ring pyrrole compounds of duocarmycin bearing 5-membered heteroarylacryloyl groups (thienylacryloyl and pyrrolylacryloyl) and heteroarylcarbonyl groups were synthesized and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. Most of the thienylacrylates displayed in vitro anticellular activity equivalent to 4'-methoxycinnamates. Among the 8- O-[(N-methylpiperazinyl)carbonyl] derivatives of methoxy-thienylacrylates, compound 11b, having 4'-methoxy-2'-thienylacryloyl as segment-B (Seg-B), showed remarkably potent antitumor activity and low peripheral blood toxicity in vivo, which were equal to those of 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxycinnamates, compared with the A-ring pyrrole derivatives having the trimethoxyindole skeleton in SegB. On the other hand, the 2'-pyrrolylacrylates having a double bond as spacer showed 102- to 103- fold stronger anticellular activity than 2'-pyrrolecarboxylates (IC50<0.3 nM, 72 h-exposure). The 8-O-acetate and 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 2'-pyrrolylacrylates exhibited an antitumor effect at a lower dose compared with the 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'- methoxycinnamate (1j). Moreover, it was expected that the antitumor activity would be increased by the strength of the extra hydrogen bond formed between the nitrogen of the pyrrole amido group and DNA, owing to the increase of the number of N-methyl-2'-pyrrolecarboxamide units. However, 2'-pyrrolylacrylates having three N-methyl-2'-pyrrolecarboxamide units showed nearly equal antitumor activity to 2'-pyrrolylacrylates having only one N-methyl-2'- pyrrolecarboxamide unit.
View MoreJIANGXI ZHANGFENG CHEMICAL CO., LTD.
Contact:+86-0799-3413066
Address:Xiyuan village, Xiabu Town, Xiangdong District
website:http://www.np-chem.com
Contact:0086-25-52346877
Address:199, Jian Ye Road, Nanjing, China
Contact:0550-7041128 0550-7090578
Address:Wangdian Street,Xinjie Town
Beijing Apis Biotechnology Co., Ltd.
Contact:86-010-67856775-8551
Address:NO.4PUHUANGYU ROAD,FENTAI DISTRICT, BEIJING, CHINA
Contact:0086-27-83607103/83642615
Address:No.498, Jianshe Ave, Wuhan, China
Doi:10.1021/om9903691
(1999)Doi:10.1016/S0040-4039(97)00887-3
(1997)Doi:10.1021/acs.joc.5b02226
(2015)Doi:10.1016/S0040-4020(99)00867-4
(1999)Doi:10.1016/S0960-894X(99)00544-2
(1999)Doi:10.1021/om990688s
(1999)
