The marine macrolide (-)-zampanolide has been identified as a promising anti-cancer lead due to its unique covalent-binding with tubulin and superior cytotoxic potency compared to paclitaxel against multi-drug resistant cancers. This fascinating lead compound needs further studies of in vivo anticancer efficacy, pharmacokinetics, and toxicity, to guide its extension towards a clinical chemotherapeutic. However, the isolation efforts and the current published synthesis attempts do not produce zampanolide in quantities sufficient to evaluate it as a viable drug candidate. More importantly, we envision that zampanolide possesses poor pharmacokinetic profiles as a drug candidate due to its instability. The overarch research objective of this project is to identify simplified and stabilized mimics of (-)-zampanolide as well as manageable synthetic methods. With this goal, we have explored the synthetic studies toward a new eighteen-membered core structure of our desired simplified and stabilized zampanolide mimics, varying at different ring closing methods. Our studies have so far culminated in one successful synthesis of the core structure through slightly over twenty steps of reactions with Horner-Wadsworth-Emmons reaction as the ring closing reaction. Intriguingly, our attempted Grubbs Ring-Closing Metathesis exclusively generates a six-membered cyclic ether ring rather than the desired eighteen-membered one. This presentation will report the full details of our synthetic studies toward the core structure synthesis.

Construction of a new eighteen-membered core structure for simplified and stabilized zampanolide mimics

253rd National Meeting (2017)

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