New water-soluble duocarmycin derivatives: synthesis and antitumor activity of A-ring pyrrole compounds bearing beta-heteroarylacryloyl groups.
A series of A-ring pyrrole compounds of duocarmycin bearing 4'-methoxy-beta-heteroarylacryloyl 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 4'-methoxy-beta-heteroarylacrylates displayed in vitro anticellular activity equivalent to that of 4'-methoxycinnamates. Among the 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxy-beta-heteroarylacrylates, compound 15b having a (4-methoxy-3,5-pyrimidinyl)acryloyl as segment-B (Seg-B) showed remarkably potent in vivo antitumor activity and low peripheral blood toxicity compared with the A-ring pyrrole derivatives having the trimethoxyindole skeleton in Seg-B, which were equal to 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxycinnamates. Moreover, these 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxy-beta-heteroarylacrylates had high aqueous solubility.
Amishiro
N
N
Pharmaceutical Research Institute, Kyowa Hakko Kogyo Company, Ltd., 1188, Shimotogari, Nagaizumi, Sunto, Shizuoka 411-0943, Japan.
Nagamura
S
S
Kobayashi
E
E
Gomi
K
K
Saito
H
H
D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012510:Sarcoma 180 / Q000188:drug therapy / Q000473:pathology; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000473:pathology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
D007211:Indoles; D011758:Pyrroles; C117660:methyl 1-(bromomethyl)-7-methyl-5-((4-methylpiperazinyl)carbonyloxy)-3-(2-(4-methoxy-3,5-pyrimidinyl)ethen-1-ylcarbonyl)-1,2-dihydro-3H-pyrrolo(3,2-e)indole-8-carboxylate