Kovačević Ivana, Popsavin Mirjana, Benedeković Goran, Kojić Vesna, Jakimov Dimitar, Rodić Marko V, Srdić-Rajić Tatjana, Bogdanović Gordana, Divjaković Vladimir, Popsavin Velimir
Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia.
Oncology Institute of Vojvodina, Put Doktora Goldmana 4, 21204, Sremska Kamenica, Serbia.
Eur J Med Chem. 2016 Jan 27;108:594-604. doi: 10.1016/j.ejmech.2015.12.011. Epub 2015 Dec 12.
A new synthesis of goniobutenolides A (1) and B (2) and the corresponding 7-epimers has been achieved starting from diacetone d-glucose. The key step of the synthesis is a new one-pot sequence that commenced with Z-selective Wittig (or Horner-Wadsworth-Emmons) olefination, followed by successive γ-lactonisation and β-elimination. The above-mentioned unsaturated lactones were then converted to the corresponding 5-halogenated crassalactone D derivatives by using the appropriate haloetherification protocol. The most of synthesized compounds exhibited potent cytotoxic activities against a panel of tumour cell lines. The main structural features responsible for their antitumour potency have been revealed by means of SAR analysis. Flow cytometry data suggested that cytotoxic effects of these compounds in the culture of K562 cells might be mediated by apoptosis, additionally revealing that these molecules induced changes in cell cycle distribution of these cells. Results of semi-quantitative Western blot analysis indicate that the most of synthesized compounds induce apoptosis in a caspase-dependent manner.
以双丙酮 -D-葡萄糖为起始原料，实现了对戈尼布内酯A（1）和B（2）以及相应7-差向异构体的新合成。该合成的关键步骤是一个新的一锅法序列，该序列始于Z-选择性维蒂希（或霍纳 - 沃兹沃思 - 埃蒙斯）烯烃化反应，随后依次进行γ-内酯化和β-消除反应。然后，通过适当的卤醚化方案将上述不饱和内酯转化为相应的5-卤代厚壳内酯D衍生物。大多数合成化合物对一组肿瘤细胞系表现出强大的细胞毒活性。通过构效关系分析揭示了其抗肿瘤效力的主要结构特征。流式细胞术数据表明，这些化合物在K562细胞培养中的细胞毒作用可能由凋亡介导，此外还表明这些分子诱导了这些细胞的细胞周期分布变化。半定量蛋白质免疫印迹分析结果表明，大多数合成化合物以半胱天冬酶依赖性方式诱导凋亡。
