Cytotoxic activities of novel hexahydroindolizino[8,7-b]indole derivatives prepared by 1,3-dipolar cycloaddition reactions of 3,4-dihydro-β-carboline ylides

• Published in: Bioorganic & medicinal chemistry Vol. 9; no. 8; pp. 2155 - 2164
• Main Authors: Bertrand, Martial, Poissonnet, Guillaume, Théret-Bettiol, Marie-Hélène, Gaspard, Christiane, Werner, Georges H., Pfeiffer, Bruno, Renard, Pierre, Léonce, Stéphane, Dodd, Robert H.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.08.2001; Elsevier Science
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Carbolines - chemistry; Cell Cycle - drug effects; Cell Survival - drug effects; General aspects; Humans; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; K562 Cells; Medical sciences; Pharmacology. Drug treatments; Antineoplastic agent; Human; Nitrile; Angular nitrogen heterocycle; Leukemia; Cytotoxicity; L1210-Leukemia; Tetracyclic compound; Doxorubicin; In vitro; Resistance; Cell line; Structure activity relation; Aromatic compound; Chemical synthesis; Tumor cell
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(01)00119-5

A series of 1-cyano and 2-cyanohexahydroindolizino[8,7-b]indole derivatives was prepared by 1,3-dipolar cycloaddition of acrylonitrile with ylides derived from 3,4-dihydro-β-carboline and its 6-methoxy, 6-benzyloxy, 9-methyl and 9-benzyl analogues. The products, together with their reduced 1- or 2-aminomethyl derivatives, were evaluated for cytotoxic activity in L1210 cancer cells. Compounds derived from 6-benzyloxy or 9-benzyl-3,4-dihydro-β-carboline were found to be the most active, with IC 50's in the 2–50 μM range. Of these, two compounds, the 1- and 2-cyano 8-benzyloxyindolizino[8,7-b]indole derivatives 20a and 20c, respectively, were found by cytometric flux analysis to stop cancer cell growth at the G 2M and 8N (>G 2M) stage of the cell cycle. These two compounds also showed no loss of cytotoxic activity in K562R cancer cells resistant to doxorubicin. The title compounds were synthesized and their cytotoxic properties toward L1210 cancer cells were evaluated in vitro. Compounds 20a and 20c displayed IC 50's in the 15 μM range and were found to stop cancer cell growth at the G2M and 8N stage of the cell cycle. These compounds were also active in a mutidrug resistance cancer cell line.