Synthesis and Anticancer Evaluation of Sulfur Containing 9-anilinoacridines

拓扑异构酶 阿姆萨克林 细胞毒性 细胞周期 生物化学 DNA 对接(动物) MTT法 化学 DNA复制 生物 分子生物学 细胞生长 体外 细胞 医学 护理部
作者
Chul‐Hoon Kwon,Zhe‐Sheng Chen,Pranav Gupta,R. Kumar
出处
期刊:Recent Patents on Anti-cancer Drug Discovery [Bentham Science]
卷期号:17 (1): 102-119 被引量:1
标识
DOI:10.2174/1574892816666210728122910
摘要

DNA topoisomerases are a class of enzymes that play a critical role in fundamental biological processes of replication, transcription, recombination, repair and chromatin remodeling. Amsacrine (m-AMSA), the best-known compound of 9-anilinoacridines series, was one of the first DNA-intercalating agents to be considered a Topoisomerase II inhibitor.A series of sulfur-containing 9-anilinoacridines related to amsacrine were synthesized and evaluated for their anticancer activity.Cell viability was assessed by the MTT assay. The topoisomerase II inhibitory assay was performed using the Human topoisomerase II Assay kit, and flow cytometry was used to evaluate the effects on the cell cycle of K562 cells. Molecular docking was performed using the Schrödinger Maestro program.Compound 36 was found to be the most cytotoxic of the sulfide series against SW620, K562, and MCF-7. The limited SAR suggested the importance of the methansulfonamidoacetamide side chain functionality, the lipophilicity, and the relative metabolic stability of 36 in contributing to the cytotoxicity. Topoisomerase II α inhibitory activity appeared to be involved in the cytotoxicity of 36 through the inhibition of decatenation of kinetoplast DNA (kDNA) in a concentration- dependent manner. Cell cycle analysis further showed Topo II inhibition through the accumulation of K562 cells in the G2/M phase of the cell cycle. The docking of 36 into the Topo II α-DNA complex suggested that it may be an allosteric inhibitor of Topo II α.Compound 36 exhibits anticancer activity by inhibiting topoisomerase II, and it could further be evaluated in in vivo models.
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