Novel seco cyclopropa[c]pyrrolo[3,2-e]indole bisalkylators bearing a 3,3'-arylenebisacryloyl group as a linker.
We synthesized the novel seco cyclopropa[c]pyrrolo[3,2-e]indole (CPI) bisalkylators and evaluated their antitumor activity. Among these derivatives, 11a (AT-760), in which the two seco 3-methoxycarbonyl-2-trifluoromethyl CPI (MCTFCPI) moieties are connected with a 3,3'-(1,4-phenylene)bisacryloyl group, was found to exhibit more potent cytotoxicity and antitumor activity against HeLaS3 human uterine cervix carcinoma cells and Colon 26 adenocarcinoma cells, respectively, than 8 (bizelesin, U-77,779). It also appeared that compound 11a exhibits improved in vivo efficacy in the human colon CX-1 model when compared to either compound 8 or mitomycin C (MMC). Efficacious doses for 11a were found to be 2-fold lower than those for 8.
Fukuda
Y
Y
Central Research Laboratories, Kyorin Pharmaceutical Company Ltd., Mitarai, Nogi, Tochigi 329-0114, Japan. yasumichi-fukuda@mb2.kyorin-pharm.co.jp
Seto
S
S
Furuta
H
H
Ebisu
H
H
Oomori
Y
Y
Terashima
S
S
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001597:Benzylidene Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D000080890:Duocarmycins; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
C116802:AT 760; D018906:Antineoplastic Agents, Alkylating; D001597:Benzylidene Compounds; D000080890:Duocarmycins; D007211:Indoles; D011758:Pyrroles; D014508:Urea; C072257:bizelesin