Planta Med 2012; 78 - AL6
DOI: 10.1055/s-0032-1320313

Stictamides – Isolation, synthesis, and biological evaluation of cell invasion inhibitors

P Williams 1, A Preciado 1, Z Liang 1, F Sulzmaier 2, J Ramos 2
  • 1Department of Chemistry, University of Hawaii at Manoa, Honolulu, Hawaii 96822, USA
  • 2University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, Hawaii 96813, USA

γ-Amino-β-hydroxy-acid units are structural motifs often encountered in natural products distributed across diverse taxa. Since their discovery in the microbial secondary metabolite pepstatin there has been widespread interest in this moiety due to its ability to inhibit a broad range of enzymes, primarily by mimicking the transition state of peptide hydrolysis. Classic examples of marine natural products containing this moiety are the didemnins1 that were isolated from a Trididemnum sp., and related metabolites, which continue to be evaluated in clinical trials as anticancer agents. As observed in the structure determination of didemnin A though2, this densely functionalized unit has a manifold of reaction pathways available during the acid hydrolysis protocol, commonly used to determine the absolute and relative configuration of this unit, and many of these either destroy or invert the configuration of the β-hydroxyl group. This ultimately leads to the question “Under what circumstances is the configuration determined from analysis of the hydrolysis reflective of the configuration of the γ-amino-β-hydroxy-acid units?”

Fig.1: Stictamide A

This presentation will discuss our data demonstrating the extent to which this stereochemical erosion of statine units is an issue, our development of a simple 1H NMR method to determine the relative configuration of these units3, and procedural recommendations for their absolute configuration analysis. The utility and validity of the methodology will be demonstrate using a series of recently isolated natural products inhibitors of cell invasion, stictamides A-C4, of which we have recently completed a total synthesis.

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2. Rinehart, K. L.; Sakai, R.; Kishore, V.; Sullins, D. W.; Li, K. M. J. Org. Chem. 1992, 57, 3007–3013.

3. Preciado, A.; Williams, P. G. J. Org. Chem. 2008, 73, 9228–9234.

4. Liang, Z.; Sorribas, A.; Sulzmaier, F. J.; Jiménez, J. I.; Wang, X.; Sauvage, T.; Yoshida, W. Y.; Wang, G.; Ramos, J. W.; Williams, P. G. J. Org. Chem. 2011, 76, 3635–3643.