Synthesis and antitumor activity of duocarmycin derivatives: A-ring pyrrole compounds bearing beta-(5',6',7'-trimethoxy-2'-indolyl)acryloyl group.
A series of A-ring pyrrole derivatives of duocarmycin bearing beta-(5',6',7'-trimethoxy-2'-indolyl)acryloyl group were synthesized, and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. New Seg-B analogues bearing beta-(5',6',7'-trimethoxy-2'-indolyl)acryloyl group containing double bond as spacer had lower peripheral blood toxicity than the derivatives bearing 5',6',7'-trimethoxyindole-2'-carboxyl group in Seg-B of the natural type. Moreover, most of them exhibited potent antitumor activity against in vivo murine tumor models.
Amishiro
N
N
Pharmaceutical Research Institute, Kyowa Hakko Kogyo Company, Ltd., Sunto, Shizuoka, Japan. cmurakata@kyowa.co.jp
Nagamura
S
S
Kobayashi
E
E
Okamoto
A
A
Gomi
K
K
Okabe
M
M
Saito
H
H
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D000080890:Duocarmycins; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007958:Leukocyte Count; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy; D010976:Platelet Count; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013997:Time Factors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000080890:Duocarmycins; D007211:Indoles; D011758:Pyrroles; D011760:Pyrrolidinones; C057901:pyrindamycin B; C057900:pyrindamycin A; C060648:duocarmycin B1; C060649:duocarmycin B2; C058289:duocarmycin A