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
| Autor: | Tetsuya Tsukamoto, Asako Kato, Takeo Konakahara, Yuri Okuno, Yusuke Nagatsuka, Y. B. Kiran, Satoko Kiuchi, Norio Sakai, Yoko Iwase, Tomokazu Hiratsuka |
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| Rok vydání: | 2016 |
| Předmět: |
chemistry.chemical_classification
biology 010405 organic chemistry Carbazole Stereochemistry Organic Chemistry Conjugated system 010402 general chemistry biology.organism_classification 01 natural sciences Biochemistry Chloride 0104 chemical sciences HeLa chemistry.chemical_compound chemistry Drug Discovery medicine Cytotoxic T cell Amine gas treating IC50 Alkyl medicine.drug |
| Zdroj: | Tetrahedron. 72:4258-4272 |
| ISSN: | 0040-4020 |
| DOI: | 10.1016/j.tet.2016.05.068 |
| Popis: | 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). |
| Databáze: | OpenAIRE |
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