Chemico-Biological Interactions ( IF 5.1 ) Pub Date : 2018-02-16 Kranthi Vanchanagiri, Daniel Emmerich, Monique Bruschke, Matthias Bache, Franziska Seifert, René Csuk, Dirk Vordermark, Reinhard Paschke
In this report, we describe the synthesis, characterization, in vitro anticancer activity and Carbonic anhydrase IX (CAIX) inhibition of new sulfamate conjugates of Betulin and Betulinic acid (BA). The betulinyl sulfamates were subjected to inhibit carbonic anhydrases (CA), e.g. CAIX, an attractive target for tumor-selective therapy strategies in cancer cells. Data on combined in vitro antitumor activity with CAIX inhibition are very rare. The betulinyl sulfamates were tested against five tumor cell lines and normal human skin fibroblasts. The mode of cell death on MCF7 breast cancer cells induced by the most active compounds CAI1, CAI3 and CAI6 was investigated by Fluorescence Activated Cell Sorting (FACS) experiments. The compounds showed inhibitory activity towards CAIX, which was determined via in vitro enz-yme assay. Our preliminary investigations revealed that all compounds showed potent anticancer properties with IC50 values below 20 μM against all tumor cells. Interestingly, among the panel of sulfamate conjugates, CAI3 found to be highly cytotoxic (average IC50 = 5–10 μM) and possess high inhibitory activity (Ki = 1.25 nM) towards CAIX. Our results suggest that betulinyl sulfamates seem to be attractive substances, due to their possibility of targeted drug delivery they deserve to be proceeded for further pre-clinical (kinetic studies) and in vivo investigations.
中文翻译:
新型碳酸酐酶IX(CAIX)抑制剂的合成和生物学研究
在本报告中,我们描述了新的桦木蛋白和桦木酸(BA)的氨基磺酸盐共轭物的合成,表征,体外抗癌活性和碳酸酐酶IX(CAIX)抑制作用。对苯丁氨酰氨基磺酸盐进行抑制,以抑制碳酸酐酶(CA),例如CAIX,这是癌细胞中肿瘤选择性治疗策略的引人注目的靶标。具有CAIX抑制作用的体外抗肿瘤活性的数据非常罕见。测试了甜菜酸苄丁酯对五种肿瘤细胞系和正常人皮肤成纤维细胞的作用。活性最高的化合物CAI1,CAI3和CAI6诱导MCF7乳腺癌细胞死亡的方式通过荧光激活细胞分选(FACS)实验进行了研究。化合物显示出对CAIX的抑制活性,这是通过体外酶法测定的。我们的初步研究表明,所有化合物均对所有肿瘤细胞显示出有效的抗癌特性,IC 50值低于20μM。有趣的是,在氨基磺酸盐偶联物组中,CAI3被发现具有高度的细胞毒性(平均IC 50 = 5–10μM)并具有很高的抑制活性(K i = 1.25 nM)。我们的结果表明,甜菜碱磺酰间苯二酸酯似乎是有吸引力的物质,由于其靶向药物递送的可能性,值得进一步进行临床前(动力学研究)和体内研究。