(−)-Zampanolide and its structurally related dactylolide are unique microtubule stabilizing agents (MSA) due to the covalent-binding mechanism and effectiveness in suppressing multi-drug resistant cancer cell proliferation. In addition to the limited supply, we envision that the lactone moiety in these two natural products is not drug-like enough due to the metabolically instability. This study aims to seek a stabilized and simplified mimic by replacing the lactone moiety in dactylolide with a macrocyclic ketone and by removing the tetrahydropyran ring. The association between MSAs and prostate cancer through inhibiting androgen receptor nuclear translocation spurred us to focus on the anti-prostate cancer potency. Our previous study indicates that (17R) desTHPdactylolide is more potent than the (17S) configuration in suppressing prostate cancer cell proliferation. The current study aims to synthesize a macrocyclic ketone mimic of (17R) desTHPdactylolide that was anticipated to be metabolically more stable than (17R) desTHPdactylolide. To this end, a macrocyclic ketone mimic has been successfully synthesized through a 16-step linear synthesis from commercially available 2-butyn-1-ol. The critical C17-CH2-C1=C2 bond for the macrocyclic ketone mimic of desTHPdactylolide has been constructed by a cross-coupling alkylation mediated by CuI/TMEDA/LiOMe. A Horner-Wadsworth-Emmons reaction was used to construct the C2-C3 double bond and to close the ring. Our WST-1 cell proliferation assay in human prostate cancer cell models implies that the macrocyclic ketone moiety can serve as a good bioisostere for the lactone in desTHPdactylolide.

Macrocyclic ketone mimic of desTHPdactylolide: Synthesis and antiproliferative evaluation

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