Synthesis and Evaluation of Lysolipin I and Analogues

Numerous xanthone natural products, including monomeric and dimeric derivatives with different saturation levels of the xanthone core, exhibit pronounced biological activity in a broad range of diseases. Thus, a strong interest in such privileged structures as probe molecules or drug leads for the treatment of a variety of diseases has developed. Lysolipin I, a complex natural product with 24 carbon atoms, is one of the largest aromatic polyketides known to date. Besides its challenging molecular structure, the molecule was found to inhibit cell-wall biosynthesis and thus showed activity against Gram-positive as well as Gram- negative bacteria. For further investigation of the antibiotic mode of action and to study the cytotoxicity of lysolipin I against cancer cells, synthetic access to the natural product and analogues is of utmost importance. In this proposal, a highly flexible and convergent route to lysolipin I and congeners starting from readily available building blocks is presented, which will enable us to pursue our venture of going beyond total synthesis but to access numerous analogues and to evaluate their biological activity. The stereogenic centers of the natural product will be introduced employing Sharpless asymmetric dihydroxylation of an isoquinolone and a phenanthrene moiety, respectively. In previous syntheses of congeners, formation of the phenanthrene moiety was a critical step. Accordingly, we plan to investigate alternative and new strategies to access this substructure of the natural product. Thus, the development of an unprecedented transition metal-mediated biaryl coupling and cycloisomerization of silylene tethered alkynyl-biaryl substrates will be investigated which will be backed up by attractive alternatives including oxidative as well as dehydrogenative biaryl formation. The characteristic xanthone moiety of the natural product will be constructed using an atom economical and highly regioselective photo-Fries rearrangement to create the carbonyl biaryl- linkage followed by closure of the oxygen bridge under basic conditions. Finally, protecting group operations will finish the total synthesis of lysolipin I in 15-20 steps along the longest linear sequence, depending on the strategy applied for phenanthrene formation. Precursors, analogues, and intermediates of the natural product will be readily available along sequence for lysolipin I and will be screened in the National Cancer Institute (NCI) 60 cell cancer lines in collaboration with Dr. John Beutler. Furthermore the Novartis Institute for BioMedical Research will conduct biological investigations to examine the mode of action for cytotoxicity of lysolipin I. Design and synthesis of derivatives will depend on the outcome of initial biological test of lysolipin analogues and will be subject of our research throughout the duration of the proposed project.

Natural products like Lysolipin I bearing interesting biological activity are frequently utilized as starting point by the pharmaceutical industry to find new therapeutics. Frequently, modified scaffolds, so called analogs, are found to have even better pharmacological properties than their parent natural products and often turn out as lead structures in clinical investigation of those drug candidates. Our endeavours to synthesize Lysolipin I a member of the family of polycyclic xanthone natural products (PXNPs) with promising antibiotic activity against multi-drug resistant bacteria stems led to the development of a synthetic route to access closely related natural product scaffolds along a short sequence. The high modularity of this approach allows for the access of a large number of related molecules which along their ongoing biological investigation in the collaboration with renowned research laboratories in the US will lead to an in depth structure activity relationship (SAR) investigation. This SAR combined with our work on revealing the yet unknown mode of action (MoA) of Lysolipin I has potential of opening new therapeutic strategies in the fight against multi-drug resistant bacteria stems, so-called superbugs, responsible for the death of thousands of patients annually.