Short description
(English)
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The project involves the total synthesis of a series of new analogs of the natural product L-783277 and their biological assessment as potential angiogenesis inhibitors. L-783277 is a potent protein kinase inhibitor, which may serve as a lead structure for the development of new drug candidates for angiogenesis-directed anticancer therapy. This project will ad-dress some specific key questions on the structure-activity relationships for L-783277, which are largely unexplored so far. The results of these studies will allow a more informed assessment of the potential of L-783277 as a lead structure for angiogenesis-directed drug discovery and they could provide an extended basis for future lead optimization.
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Partners and International Organizations
(English)
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BE, CH, CY, CZ, DE, DK, ES, FR, GR, HR, IE, IL, IT, NO, PL, RS, SE, SI, SK, TR, UK
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Abstract
(English)
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This project was directed at the total synthesis of a series of new analogs of the fungal natural product L-783277 and the assessment of their kinase inhibitory and anti-angiogenic activity. L-783277 is a potent protein kinase inhibitor and a potential lead structure for the development of new drug candidates for angiogenesis-directed anticancer therapy. One of the major objectives of this project has been the synthesis of the lactam analog of L-783277 as a potentially metabolically more stable alternative to the natural product. The synthesis of this analog proved to be substantially more demanding than originally anticipated; the compound could not be prepared by a simple adaptation of the route that had been followed previously in the synthesis of L-783277 and its synthesis has been successfully completed. Instead, only the corresponding C7'-C8' trans analog has been obtained. The biochemical and biological characterization of this compound is ongoing. Inspired by structural data for protein-ligand complexes with other resorcylic lactones, we have also prepared three deoxy variants of L-783277 and studied their kinase inhibitory activity. Remarkably, 5’-deoxy L-783277 retains almost the full in vitro potency and selectivity of natural L-783277, with low nM IC50 values against the most sensitive kinases. In contrast, both the 4’-deoxy and the 4’,5’-bis-deoxy analogs of L-783277 exhibit significantly reduced kinase inhibitory activity. Lastly, we have also prepared two new analogs of L-783277 which incorporate a pyrrolidine amide moiety as a (non-reactive) isostere of the enone system in the natural product. Both of these compounds were devoid of any kinase inhibitory activity.
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