An amide mimic of desTHPdactylolide: Total synthesis and antiproliferative evaluation.
An amide mimic of desTHPdactylolide: Total synthesis and antiproliferative evaluation.
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DOI：
10.1016/j.bmcl.2021.127970
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发表时间：
2021-05-15
影响因子：
2.7
通讯作者：
Chen QH
中科院分区：
文献类型：
--
作者：
Chen G;Gonzalez M;Jiang Z;Zhang Q;Wang G;Chen QH
(−)-赞帕内酯是一种独特的微管稳定剂，具有共价结合机制和对多药耐药癌细胞的低纳米分子抗增殖活性。MSA通过抑制雄激素受体核转位与前列腺癌有特殊的联系。Zampanolide和结构上相关的Dactylolide因此被我们作为开发抗前列腺癌药物的先导化合物而受到追捧。DesTHPdactylolide是一种简化的Dactylolide模拟物，以前我们已经在两种构型下合成过，其中(17R)构型更有效地抑制前列腺癌细胞的增殖。本研究旨在合成一种比(17R)desTHPdactylolide更稳定的(17R)desTHPdactylolide的酰胺类化合物。为此，以2-丁烯-1-醇为原料，经过26步反应，成功地合成了酰胺类化合物。我们的WST-1细胞在五个人前列腺癌细胞模型中的增殖实验表明，内酰胺部分可以作为去THPdactylolide中内酯的生物等价酶。
(−)-Zampanolide is a unique microtubule stabilizing agent (MSA) with covalent-binding mechanism and low nanomolar anitproliferative potency towards multi-drug resistant cancer cells. MSAs have a special connection with prostate cancer by inhibiting androgen receptor nuclear translocation. Zampanolide and the structurally related dactylolide have thus been sought after by us as lead compounds for development of anti-prostate cancer agents. DesTHPdactylolide is a simplified mimic of dactylolide and has previously been synthesized by us in both configurations, with the (17R) configuration being more potent in suppressing prostate cancer cell proliferation. The current study aims to synthesize an amide mimic of (17R) desTHPdactylolide that was anticipated to be metabolically more stable than (17R) desTHPdactylolide. To this end, the amide mimic has been successfully synthesized through a 26-step transformation from 2-butyn-1-ol. Our WST-1 cell proliferation assay in five human prostate cancer cell models indicated that the lactam moiety can serve as a bioisostere for the lactone in desTHPdactylolide.
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