Novel Seco Cyclopropa[c]pyrrolo[3,2-e]indole Bisalkylators Bearing a 3,3‘-Arylenebisacryloyl Group as a Linker

• Published in: Journal of medicinal chemistry Vol. 44; no. 9; pp. 1396 - 1406
• Main Authors: Fukuda, Yasumichi, Seto, Shigeki, Furuta, Hirosuke, Ebisu, Hiroyuki, Oomori, Yasuo, Terashima, Shiro
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.04.2001; Amer Chemical Soc
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents, Alkylating - chemical synthesis; Antineoplastic Agents, Alkylating - chemistry; Antineoplastic Agents, Alkylating - pharmacology; Benzylidene Compounds - chemical synthesis; Benzylidene Compounds - chemistry; Benzylidene Compounds - pharmacology; Biological and medical sciences; Chemistry, Medicinal; Drug Screening Assays, Antitumor; General aspects; Humans; Indoles - pharmacology; Inhibitory Concentration 50; Life Sciences & Biomedicine; Medical sciences; Mice; Mice, Nude; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Science & Technology; Structure-Activity Relationship; Transplantation, Heterologous; Tumor Cells, Cultured; Urea - analogs & derivatives; Urea - pharmacology; DNA CROSS-LINKING; ANTITUMOR ANTIBIOTICS; STREPTOMYCES SP; TRIFLUOROMETHYL GROUPS; SEQUENCE SPECIFICITY; ANALOGS; ALKYLATION; METHOXYCARBONYL; CC-1065; DUOCARMYCIN-A; Antineoplastic agent; Intravenous administration; Nitrogen heterocycle; Cytotoxicity; Uterine cervix; Ester; Structure activity relation; Chlorine Organic compounds; Vinylic compound; Intestinal disease; Aromatic compound; Colon; Chemical synthesis; Tumor cell; Human; Rodentia; Malignant tumor; Tricyclic compound; In vitro; In vivo; Vertebrata; Alkylating agent; Chemotherapy; Experimental disease; Mammalia; Cell line; Mouse; Animal; Phenols; Digestive diseases; Carboxamide; Fluorine Organic compounds
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm000107x

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.