HIPS-Talk: “Total Synthesis and Functional Exploration of Bioactive Natural Macrocycles“
Macrocyclic secondary metabolites form a diverse group of bioactive natural products, of which many have proven to be important leads for drug discovery and development. This contribution will discuss selected aspects of the synthetic chemistry and biological activity of two macrocyclic natural products, namely the bacterial cyclo-depsipeptide pyridomycin (1) and the marine macrolide (-)-zampanolide (2). Pyridomycin (1) was first isolated from Streptomyces albidofuscus in 1954 and it exhibits significant in vitro activity against Mycobacterium tuberculosis. The molecular target of 1 has recently been revealed as the enoyl-ACP reductase InhA, which is also the target of the clinical anti-TB drug isoniazid. (-)-Zampanolide (2) is a microtubule-stabilizing agent (MSA) and as such is a potent inhibitor of human cancer cell proliferation in vitro.
Structural formulas: cyclo-depsipeptide pyridomycin (1), macrolide (-)-zampanolide (2), analogs of type 3
Our exploration of the biology and medicinal chemistry of pyridomycin (1) has focused on the de novo synthesis of analogs of type 3. Remarkably, although lacking an enol ester moiety, (2R)-3 retained most of the anti-tubercular activity of 1, while (2S)-3 was significantly less active. Based on these findings we have investigated additional analogs derived from (2R)-3, whose synthesis, binding to InhA and antibacterial activity will be discussed in this presentation. As for (-)-zampanolide (2), we have developed an efficient modular total synthesis for this natural product, based on macrocyclic ring-closure by an intramolecular Horner-Wittig-Emmons reaction between C8 and C9. The high resolution crystal structure of the complex of 2 with tubulin has provided fundamentally new insights into the molecular mechanism of MSA-induced tubulin assembly.
 Kuroya, M.; et al. J. Antibiot., Ser. A 1954, 7, 58.
 Hartkoorn, R. C.; et al. EMBO Mol. Med. 2012, 4, 1032.
 Field, J. J.; et al. J. Med. Chem. 2009, 52, 7328.
Gebäude und Raum
Blg E8.1, Seminar Room (Ground floor)
Prof. Dr. Karl-Heinz Altmann
Department of Chemistry and Applied Biosciences, ETH Zürich
Prof. Dr. Rolf Müller