Optimized synthesis and antiproliferative activity of desTHPdactylolides. Issue 12 (23rd July 2018)

• Record Type: Journal Article
• Authors: Chen, Guanglin; Wang, Rubing; Vue, Bao; Patanapongpibul, Manee; Zhang, Qiang; Zheng, Shilong; Wang, Guangdi; White, James D.; Chen, Qiao-Hong
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 12(2018)
• Page Start: 3514
• Page End: 3520
• Publication Date: 2018-07-23
• Subjects: Dactylolide -- Zampanolide -- Prostate cancer cell line -- Antiproliferative activity; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.05.026
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: Synthesis of (17 S ) desTHPdactylolide was optimized. (17 R ) DesTHPdactylolide was first synthesized. Antiproliferative activity on prostate cancer cell models was evaluated. (17 R ) DesTHPdactylolide was identified as eutomer. Four analogues are equipotent towards docetaxel sensitive/resistance cancer cells. Abstract: Dactylolide and certain analogues are attractive targets for study due to their structural resemblance to zampanolide, a very promising anticancer lead compound and a unique covalent-binding microtubule stabilizing agent. The primary goal of this project is identification and synthesis of simplified analogues of dactylolide that would be easier to prepare and could be investigated for antiproliferative activity in comparison with zampanolide. Extension of Almann's concept of a simplified zampanolide analogue to dactylolide in the form of desTHPdactylolide was attractive not only for reasons of synthetic simplification but also for the prospect that analogues of dactylolide could be prepared in both (17 S ) and (17 R ) configurations. Since Altmann's overall yield for the six-step procedure leading to the C9–C18 fragment of desTHPdactylolide was only 8.7%, a study focused on optimized synthesis and antiproliferative evaluation of each enantiomer of desTHPdactylolide was initiated using Altmann's route as a framework. To this end, two optimized approaches to this fragment C9–C18 were successfully developed by us using allyl iodide or allyl tosylate as the starting material for a critical Williamson ether synthesis. Both (17 S ) and (17 R ) desTHPdactylolides were readily synthesized in our laboratory using optimized methods in yields of 37–43%. Antiproliferative activity of the pair of enantiomeric desTHPdactylolides, together with their analogues, was evaluated in three docetaxel-sensitive and two docetaxel-resistant prostate cancer cell models using a WST-1 cell proliferation assay. Surprisingly, (17 R ) desTHPdactylolide was identified as the eutomer in the prostate cancer cell models. It was found that (17 S ) and (17 R ) desTHPdactylolide exhibit equivalent antiproliferative potency towards both docetaxel-sensitive (PC-3 and DU145) and docetaxel-resistant prostate cancer cell lines (PC-3/DTX and DU145/DTX).