Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, Novi Sad, Serbia.
Oncology Institute of Vojvodina, Faculty of Medicine, University of Novi Sad, Put Dr Goldmana 4, 21204, Sremska Kamenica, Serbia.
Eur J Med Chem. 2020 Sep 15;202:112597. doi: 10.1016/j.ejmech.2020.112597. Epub 2020 Jul 6.
A new, modified total synthesis of (-)-cleistenolide (1) and sixteen new analogues or derivatives was achieved starting from commercially available 1,2-O-isopropylidene-α-d-glucofuranose. The synthesis of 1 proceeds in six steps and 67% overall yield, using single-carbon atom degradation of a protected chiral precursor, (Z)-selective Wittig olefination, and acid catalyzed δ-lactonization. A new Lewis acid promoted procedure for one-pot O-debenzylation/O-acylation has been developed to complete the synthesis of natural product 1 and selected analogues. The synthesized compounds were tested in vitro to evaluate their cytotoxicity against K562, HL-60, Jurkat, Raji, MCF-7, MDA-MB 231, HeLa, A549, and MRC-5 cell lines. All (-)-cleistenolide analogues exhibited significantly higher cytotoxicity than lead 1 against the majority of cell lines tested. Most of the synthesized compounds are more active than doxorubicin on at least one malignant cell line, but were almost completely inactive against normal MRC-5 cells. The structural features of the tested compounds responsible for their antiproliferative activity have been identified by preliminary SAR analysis.
从商业上可获得的 1,2-O-异亚丙基-α-d-葡萄糖呋喃糖出发，实现了 (-)-cleistenolide (1) 的新型改良全合成以及十六种新的类似物或衍生物。1 的合成经过六步反应，总收率为 67%，使用了保护手性前体的单碳原子降解、(Z)-选择性 Wittig 烯烃化和酸催化的 δ-内脂化。已经开发了一种新的路易斯酸促进一锅法 O-去苄基/O-酰化程序，以完成天然产物 1 和选定类似物的合成。合成的化合物在体外进行测试，以评估它们对 K562、HL-60、Jurkat、Raji、MCF-7、MDA-MB 231、HeLa、A549 和 MRC-5 细胞系的细胞毒性。所有 (-)-cleistenolide 类似物对大多数测试的细胞系的细胞毒性均明显高于先导化合物 1。大多数合成化合物在至少一种恶性细胞系上比阿霉素更具活性，但对正常的 MRC-5 细胞几乎完全没有活性。通过初步 SAR 分析确定了测试化合物对其增殖活性负责的结构特征。
