Synthesis and antitumor activity of duocarmycin derivatives: a-ring pyrrole compounds bearing 5-membered heteroarylacryloyl groups.
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 Seg-B. On the other hand, the 2'-pyrrolylacrylates having a double bond as spacer showed 10(2)- to 10(3)-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] 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.
Amishiro
N
N
Pharmaceutical Research Institute, Kyowa Hakko Kogyo Company, Ltd., Shizuoka, Japan.
Nagamura
S
S
Kobayashi
E
E
Okamoto
A
A
Gomi
K
K
Saito
H
H
D000179:Acrylates / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001773:Blood Cells / Q000187:drug effects; D020650:Combinatorial Chemistry Techniques; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D000080890:Duocarmycins; D006367:HeLa Cells; D006801:Humans; D007211:Indoles; D051379:Mice; D008956:Models, Chemical; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D011760:Pyrrolidinones / Q000737:chemistry; D012510:Sarcoma 180; D013329:Structure-Activity Relationship
D000179:Acrylates; D000970:Antineoplastic Agents; D000080890:Duocarmycins; D007211:Indoles; D011758:Pyrroles; D011760:Pyrrolidinones; C057901:pyrindamycin B; C057900:pyrindamycin A; C060648:duocarmycin B1; C060649:duocarmycin B2; C066098:duocarmycin SA; D004247:DNA; C058289:duocarmycin A