Pyridomycin; Cancer; Tuberculosis; Natural products; Natural product synthesis; Zampanolide; SAR
Dong Maryline, Pfeiffer Bernhard, Altmann Karl-Heinz (2017), Recent developments in natural product-based drug discovery for tuberculosis., in Drug discovery today
, 22(3), 585-591.
Altmann Karl-Heinz, Brütsch Tobias Glauser Simon, On The Chemistry and Biology of the Marine Macrolides Zampanolide and Dactylolide
, Taylor & Francis, Boca Raton, FL, USA.
Zampanolide and pyridomycin are macrocyclic natural products of marine and bacterial origin, respectively, with significant biological activity against proteins that are clinically validated drug targets in cancer and tuberculosis. Zampanolide is a microtubule-stabilizing agent with potent in vitro antiproliferative activity against human cancer cells; pyridomycin is a potent inhibitor of the growth of Mycobacterium tuberculosis and it targets the mycobacterial NADH-dependent enoyl-[acyl-carrier-protein] reductase (InhA; also known as FabI) which is also the target of the anti-tuberculosis drugs isoniazid and ethionamide.While the chemistry of zampanolide has been investigated in some detail, much less effort has been expended on the synthesis of pyridomycin or related structures. More importantly, only limited data on structure-activity relationships (SAR) are currently available in both cases and the structural parameters governing target interactions and pharmacological activity are not well understood. The work proposed in this grant application aims at the elucidation of some key aspects of the zampanolide and pyridomycin SAR. These studies will build on prior work in our laboratory on the total synthesis of zampanolide and of a limited number of zampanolide and pyridomycin analogs. For zampanolide, this will include simplified, monocyclic structures derived from desTHP-zampanolide, which we have previously shown to retain sub-uM antiproliferative activity for the inhibition of cancer cell growth in vitro. The work on pyridomycin analogs will largely be based on the 2-1'-dihydropyridomicin structural template, which essentially retains all of the antimycobacterial activity of the natural product, but does not contain a synthetically challenging enol ester moiety. All zampanolide analogs will be assessed for interactions with the tubulin/microtubule system and the inhibition of human cancer cell proliferation in vitro; pyridomycin analogs will be tested for InhA-inhibitory activity and the inhibition of mycobacterial growth. Overall, the studies proposed in this grant application will (1) widen the scope of the synthetic chemistry around zampanolide- and pyridomycin-type structures and they will (2) expand our understanding of the structural parameters that govern the biological activity of these compounds. As such they could provide the basis for the development of new antitumor or antimycobacterial agents with improved pharmacological properties or technical feasibility over the natural products zampanolide and pyridomycin.