Isolation, Modification, and Synthesis of Anticancer Polyketide Natural Products in Discovery of New Anticancer Therapeutics

Justin Hammons

Appointment Period: 2011-2013, Grant Years: [27,28] (Minority Supplement Slot)

The field of natural product chemistry is a vast discipline that ranges from isolation and structure elucidation, total synthesis and analog development, to biological activity and mode of action studies. The structural scaffolds that nature provides is unmatched by humans in creativity. These compounds often have intriguing biological activity, of which we try to take advantage either creating the next antibiotic, antifungal, antiviral, or anticancer agents.

With the protein target identified as the human macrophage migration inhibitory factor (hMIF), we can begin looking at analog development. We are not only looking to increase the activity of the compound but also to identify the key pharmacophores and developed a SAR map of the natural product binding site of the protein. As we begin to understand how our compounds bind to the protein, we can begin examining how our compounds are inhibiting the protein. hMIF plays multiple roles in cellular activity but it appears that spirohexenolide inhibits cellular uptake of hMIF and is not involved in catalytic activity. Learning more about how spirohexenolide affects MIF, we can learn more about MIF's role in cancer development and begin to study this protein as a viable target.

PUBLICATIONS (resulting from this training)

Kang M, Jones BD, Mandel AL, Hammons JC, DiPasquale AG, Rheingold AL, La Clair JJ, Burkart MD. Isolation, structure elucidation, and antitumor activity of spirohexenolides A and B. J Org Chem. (2009) 74:9054-61. PMID: 19883063.

Villa RE, Hammons JC, La Clair JJ, Burkart MD. Preclinical preparation and in vivo analysis of anticancer spliceosome inhibitors. In preparation.

Hammons JC, La Clair JJ, Burkart MD. Total synthesis of spirohexenolide B. In preparation.

Other publications (prior to Training Grant appointment):

Franco JU, Hammons JC, Rios D, Olmstead MM. New tetraazaannulene hosts for fullerenes. Inorg Chem. 2010 Jun 7;49(11):5120-5. PubMed PMID: 20441157.

Kang M, Jones BD, Mandel AL, Hammons JC, DiPasquale AG, Rheingold AL, La Clair JJ, Burkart MD. Isolation, structure elucidation, and antitumor activity of spirohexenolides A and B. J Org Chem. 2009 Dec 4;74(23):9054-61. PubMed PMID:
19883063.

Franco, J.U.; Ell, J.R.; Hilton, A.K.; Hammons, J.C.; Olmstead, M.M. C60Cl6, C60Br8, and C60(NO2)6 as Selective Tools in Organic Synthesis. Fullerenes, Nanotubes, and Carbon Nanostructures 2009. 17, 349-360.  doi:10.1080/15363830903007960

Franco JU, Olmstead MM, Hammons JC. Bis[1-(1-adamantyliminomethyl)-2-naphtholato-Œ∫N,O]cobalt(II). Acta Crystallogr Sect E Struct Rep Online. 2008 Sep 6;64(Pt 10):m1223. PubMed PMID: 21200984; PubMed Central PMCID:  PMC2959448.

Franco, J.U.; Olmstead, M.M.; Hammons, J.C. Tetra- 2-acetato- 8 O:O'-bis{[1-(1- adamantyliminomethyl)-2-naptholato- O]-rhodium(II)}. Acta Cryst. 2007. E63, m2606- 2607. doi:10.1107/S1600536807046302