Non-aromatic polyketide natural products of marine origin are often characterized by both significant structural complexity and extraordinary biological activities. Because these exciting compounds are not typically available in any meaningful quantities from natural sources, total chemical synthesis is the only means by which sufficient amounts of material may be accessed for the full biological/preclinical evaluation of these compounds. No natural product better exemplifies this class of compound than spongistatin 1. This extraordinarily complex and precious marine natural product has an average IC50 value against the NCI panel of 60 human cancer cell lines of 0.12 pM. The ultimate goal of this proposal is to adapt spongistatin 1 for use in an antibody-drug conjugate (ADC) construct, by way of the design, synthesis and evaluation of a series of analogs of spongistatin 1 to identify appropriate linker sites for bioconjugation and to identify a significanly structurally simplified analog that retains the sub-nanomolar potency of the natural product. Our focus on an ADC approach derives mainly from two considerations: 1) this approach requires far less drug material than conventional approaches, rendering the synthesis of the kinds of amounts required for full clinical evaluation a significantly more realistic proposition, and 2) th low pM potency of spongistatin 1 renders it an ideal candidate for use in an ADC, as so little drug material makes it to the target that extraordinary potency is required for any meaningful clinical efficacy. In order to achieve these goals, we will continue to develop synthetic methods for the synthesis of polyketide natural products that are characterized by unprecedented levels of step-economy, efficiency, and scalability to continue to push the frontiers of efficiency in the chemical synthesis. We will then apply these methods to the development of a synthesis of spongistatin 1 that may easily be adapted for use in the preparation of the designed analogs. Finally, we will identify and synthesize significant quantities of the most significantly structuraly simplified compound equipped with a linker that retains the low pM potency of spongistatin 1.
Spongistatin 1 is a structurally complex macrolide natural product of marine origin that has been shown to be an extraordinarily potent cytotoxic agent with a -tubulin- binding/microtubule-destabilizing mechanism of action. The synthesis and evaluation of analogs of the natural product, with the ultimate aim of advancing a compound into the clinic, will require new synthetic chemistry that is characterized by unprecedented levels of step-economy, efficiency, and scalability. This proposal describes our plans to develop such synthetic chemistry and apply it to the synthesis of a series of analogs of spongistatin 1 to identify and prepare multi-gram quantities of a suitable candidate for use in an antibody-drug conjugate (ADC) approach.
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