Institute of Organic Chemistry, Polish Academy of Sciences, Ul. Marcina Kasprzaka 44/52, 01-224, Warsaw, Poland.
Laboratory of Growth Regulators, Institute of Experimental Botany of the Czech Academy of Sciences, and Faculty of Science, Palacký University, Šlechtitelů 27, CZ-783 71, Olomouc, Czech Republic; Department of Neurology, University Hospital in Olomouc, I. P. Pavlova 6, CZ-775 20, Olomouc, Czech Republic.
Eur J Med Chem. 2020 Sep 15;202:112520. doi: 10.1016/j.ejmech.2020.112520. Epub 2020 Jun 22.
Natural cardiac-active principles built upon the 14,16β-dihydroxy-5β,14β-androstane core and bearing a heterocyclic substituent at 17β, in particular, a cardenolide - oleandrin and a bufadienolide - bufotalin, are receiving a great deal of attention as potential anticancer drugs. The densely substituted and sterically shielded ring D is the particular structural feature of these compounds. The first synthesis of oleandrigenin from easily available steroid starting material is reported here. Furthermore, selected 17β-(4-butenolidyl)- and 17β-(3-furyl)-14,16β-dihydroxy-androstane derivatives were en route synthesized and examined for their Na/K-ATP-ase inhibitory properties as well as cytotoxic activities in normal and cancer cell lines. It was found that the furyl-analogue of oleandrigenin/bufatalin (7) and some related 17-(3-furyl)- derivatives (19, 21) show remarkably high Na/K-ATP-ase inhibitory activity as well as significant cytotoxicity in vitro. In addition, oleandrigenin 2 compared to derivatives 21 and 25 induced strong apoptosis in human cervical carcinoma HeLa cells after 24 h of treatment.
以 14,16β-二羟基-5β,14β-雄甾烷为核心，在 17β 位带有杂环取代基的天然心脏活性化合物，特别是甾体糖苷类化合物——欧夹竹桃苷和蟾蜍二烯内酯类化合物——蟾毒它灵，作为潜在的抗癌药物受到了广泛关注。D 环的取代基多且空间位阻大是这些化合物的特殊结构特征。本文首次报道了从易得甾体起始原料合成欧夹竹桃苷元。此外，还合成了部分 17β-（4-丁烯内酯基）-和 17β-（3-呋喃基）-14,16β-二羟基雄甾烷衍生物，并对其作为 Na/K-ATP 酶抑制剂的特性以及在正常和癌细胞系中的细胞毒性进行了研究。结果发现，欧夹竹桃苷元/蟾毒它灵（7）的呋喃类似物和一些相关的 17-（3-呋喃基）-衍生物（19、21）具有显著的 Na/K-ATP 酶抑制活性和体外细胞毒性。此外，与衍生物 21 和 25 相比，24 小时处理后，欧夹竹桃苷元 2 能诱导人宫颈癌 HeLa 细胞强烈凋亡。
