Tripodi Farida, Dapiaggi Federico, Orsini Fulvia, Pagliarin Roberto, Sello Guido, Coccetti Paola
Department of Biotechnology and Biosciences , University of Milano-Bicocca , Milan , Italy . Email:
Department of Chemistry , University of Milano , Milano , Italy . Email:
Medchemcomm. 2018 Apr 4;9(5):843-852. doi: 10.1039/c8md00147b. eCollection 2018 May 1.
Several synthetic combretastatin A4 () derivatives were recently prepared to increase the drug efficacy and stability of the natural product isolated from the South African tree . A group of ten 3-amino-2-azetidinone derivatives, as combretastatin A4 analogues, was selected through docking experiments, synthesized and tested for their anti-proliferative activity against the colon cancer SW48 cell line. These molecules, through the formation of amide bonds in position 3, allow the synthesis of various derivatives that can modulate the activity with great resistance to hydrolytic conditions. The cyclization to obtain the 3-aminoazetidinone ring is highly diastereoselective and provides a biologically active isomer under mild reaction conditions with better yields than the 3-hydroxy-2-azetidinone synthesis. All compounds showed IC values ranging between 14.0 and 564.2 nM, and the most active compound showed inhibitory activity against tubulin polymerization , being a potential therapeutic agent against colon cancer.
最近制备了几种合成的康普瑞他汀A4（）衍生物，以提高从南非树木中分离出的天然产物的药物疗效和稳定性。通过对接实验选择了一组十个3-氨基-2-氮杂环丁酮衍生物作为康普瑞他汀A4类似物，进行合成并测试其对结肠癌SW48细胞系的抗增殖活性。这些分子通过在3位形成酰胺键，能够合成各种衍生物，这些衍生物在耐水解条件下能很好地调节活性。环化以获得3-氨基氮杂环丁酮环具有高度非对映选择性，并且在温和的反应条件下能提供具有生物活性的异构体，产率比3-羟基-2-氮杂环丁酮合成法更高。所有化合物的IC值在14.0至564.2 nM之间，最具活性的化合物对微管蛋白聚合具有抑制活性，是一种潜在的抗结肠癌治疗剂。
