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.
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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)
