Department of Chemistry, California State University, Fresno, 2555 E. San Ramon Avenue, M/S SB70, Fresno, CA 93740, United States.
Department of Chemistry and RCMI Cancer Research Center, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, United States.
Bioorg Med Chem Lett. 2021 May 15;40:127970. doi: 10.1016/j.bmcl.2021.127970. Epub 2021 Mar 19.
(-)-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.
（-）-Zampanolide 是一种具有独特的微管稳定作用（MSA）的化合物，具有共价结合机制和针对多药耐药癌细胞的低纳摩尔抗增殖活性。MSA 与前列腺癌有特殊的联系，通过抑制雄激素受体核易位。因此，Zampanolide 和结构相关的 Dactylolide 一直是我们作为开发抗前列腺癌药物的先导化合物的目标。DesTHPdactylolide 是 Dactylolide 的简化模拟物，此前我们已通过两种构型合成了它，其中（17R）构型在抑制前列腺癌细胞增殖方面更有效。本研究旨在合成（17R）DesTHPdactylolide 的酰胺类似物，预计其代谢稳定性优于（17R）DesTHPdactylolide。为此，通过从 2-丁炔-1-醇进行 26 步转化，成功合成了酰胺类似物。我们在五种人前列腺癌细胞模型中的 WST-1 细胞增殖测定表明，内酰胺部分可以作为 DesTHPdactylolide 中内酯的生物等排体。
