Journal
CHEMMEDCHEM
Volume 11, Issue 24, Pages 2675-2681Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201600391
Keywords
antitumor agents; apoptosis; carbazole aminoalcohols; cell-cycle arrest; topoisomerase
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Funding
- Fundamental Research Funds for the Central Universities (China)
- National Natural Science Foundation of China [21302054, 21502181]
- Shanghai Committee of Science and Technology [13ZR1453100]
- Opening Fund of Shanghai Key Laboratory of Chemical Biology [SKLCB-2012-05]
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Novel carbazole aminoalcohols were designed and synthesized as anticancer agents. Among them, alkylamine-chain-substituted compounds showed the most promising antiproliferative activity, with IC50 values in the single-digit micromolar range against two human tumor cell lines. Topoisomerase I (topo I) is likely to be one of the targets of these compounds. Results of comet assays and molecular docking indicate that the representative compounds may act as topoI poisons, causing single-strand DNA damage by stabilizing the topo I-DNA cleavage complex. In particular, the most potent compound, 1-(butylamino)- 3-(3,6-dichloro-9H-carbazol-9-yl) propan-2-ol (6), was shown to be able to induce G2-phase cell-cycle arrest and apoptosis in HeLa cells.
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