Synthesis and cytotoxic activity of novel 11-methyl-6H-pyrido[4,3-b]carbazole derivatives linked to amine, N-methylurea, and N-methyl-N-nitrosourea moieties with various types of carbamoyl tethers at the C-5 atom

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• 作者：Asako Kato ; Yusuke Nagatsuka ; Tomokazu Hiratsuka ; Satoko Kiuchi ; Yoko Iwase ; Yuri Okuno ; Tetsuya Tsukamoto ; Y.B. Kiran ; Norio Sakai ; Takeo Konakahara ; ¹ ; ^{konaka@rs.noda.tus.ac.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Ellipticine ; 6H-Pyrido[4 ; 3-b]carbazole ; Synthesis ; Cytotoxic activity ; Cell selectivity ; Odd&ndash ; even effect ; Sarcoma-180 ; HeLa S-3 ; NIH3T3 ; L1210
• 刊名：Tetrahedron
• 出版年：2016
• 出版时间：21 July 2016
• 年：2016
• 卷：72
• 期：29
• 页码：4258-4272
• 全文大小：2602 K

文摘

Thirty-five types of novel pyridocarbazoles (5-(N-alkyl)carbamoyl-11-methyl-6H-pyrido[4,3-b]carbazoles and 5-(N-alkyl)carbamoyl-2,11-dimethyl-6H-pyrido[4,3-b]carbazol-2-ium chloride derivatives), that were conjugated with amine, N-methylurea, and N-methyl-N-nitrosourea moieties through alkyl-, oxyalkyl-, and iminoalkylcarbamoyl linkers, were synthesized by a series of reactions of methyl 11-methyl-6H-pyrido[4,3-b]carbazole-5-carboxylates with polymethylenediamine (n=2–5), p-nitrophenyl N-methylcarbamate, and N-methyl-N-nitrosocarbamate in high yields, and their cytotoxic activities were evaluated against Sarcoma-180, NIH3T3, HeLa S-3, and L1210 cell lines. These compounds exhibited potent cytotoxic activity (IC₅₀=1.6–50 μM) and odd-even alternation effect. 9-Methoxy-2,11-dimethyl-5-((2-(3-methyl-3-nitrosoureido)ethyl)carbamoyl)-6H-pyrido[4,3-b]carbazol-2-ium chloride exhibited the most potent cytotoxic activity (IC₅₀=0.15 μM) and cell selectivity against HeLa S-3. Some of the un-charged 5-(N-alkyl)carbamoyl-6H-pyrido[4,3-b]carbazole derivatives, which were conjugated with the amine and N-methyl-N-nitrosourea moieties through a dimethylene spacer, also exhibited potent cytotoxic activity (IC₅₀=0.43–2.4 μM) and remarkable cell selectivity as well as ellipticine, 9-hydroxyellipticine, and the starting methyl ester of the pyridocarbazole-5-carboxylate (IC₅₀=0.30–2.2 μM).