Tony Holý Lecture – Karl-​Heinz Altmann

Macrocyclic secondary metabolites are a diverse group of bioactive natural products and many of these compounds have been, and continue to be important leads for drug discovery and development. In this talk, I will discuss selected aspects of the synthetic chemistry, medicinal chemistry and chemical biology of two macrocyclic natural products, the marine macrolide zampanolide (1) and the bacterial metabolite rhizoxin F (WF-1360F) (2). (-)-Zampanolide (1) is a microtubule-stabilizing agent (MSA), while rhizoxin F (WF-1360F) (2) is a tubulin assembly inhibitor; both compounds are potent inhibitors of human cancer cell proliferation in vitro.

For zampanolide (1) macrocyclic ring-closure was achieved by an intramolecular Horner-Wadsworth-Emmons reaction between C8 and C9, which proceeded in high yield and with excellent selectivity. We have also developed an efficient method for the construction of the C20 hemiaminal stereocenter. The synthesis of 2 was based on ring-closure by ring-closing alkyne metathesis (RCAM) between C11 and C12. Conversion of the triple bond into the desired E double bond involved the selective reduction to the Z double bond followed by radical-induced isomerization. For both compounds high resolution crystal structures of their complexes with tubulin have provided insights into the molecular mechanism of MSA-induced tubulin assembly and the suppression of this process by rhizoxin F (2), respectively.