This is a resubmission of proposal 2R01 CA40081-05A1. The principal goal of our research program is to develop efficient, stereocontrolled synthetic routes to biologically important cyclodepsipeptides and to study their potential sites of activity. We have previously investigated the chemistry and synthesis of the didemnins. A significant accomplishment during this period was the revision of the stereochemistry of the Hip unit. We have also developed a general synthetic strategies and methodologies that will enable us to make modifications, either in the macrocycle or in the linear side chains. These side chains are of utmost importance for biological activity. Our synthetic approach id eminently suited for modifying amino acids in the peptide chain, and to, therefore, examine specific aspects of the structure-activity relationships (SARs). SARs are important, not only for the design of improved drugs, but also for better understanding of the mechanism of bioactivity. Using molecular modeling programs and chemical intuition, we have designed some analogs as reasonable entry targets and we have devised strategies for their construction. The planned investigations will also contribute to the development of biologically important cyclodepsipeptides. The structural simplicity of the didemnins, their potent and diverse biological activities, and their present scarcity make synthetic investigations of these compounds an important endeavor.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Bio-Organic and Natural Products Chemistry Study Section (BNP)
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University of Pennsylvania
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Joullié, Madeleine M; Berritt, Simon; Hamel, Ernest (2011) Structure-activity relationships of ustiloxin analogues. Tetrahedron Lett 52:2136-2139
Lee, Jisun; Berritt, Simon; Prier, Christopher K et al. (2011) Facile ring-opening of azabicyclic [3.1.0]- and [4.1.0]aminocyclopropanes to afford 3-piperidinone and 3-azepinone. Org Lett 13:1083-5
Lassen, Kenneth M; Joullié, Madeleine M (2010) Total synthesis of Lys(3) tamandarin M: a potential affinity ligand. Org Lett 12:5306-9
Lassen, Kenneth M; Lee, Jisun; Joullié, Madeleine M (2010) An efficient synthesis of the tamandarin B macrocycle. Tetrahedron Lett 51:1635-1638
Lassen, Kenneth M; Lee, Jisun; Joullie, Madeleine M (2010) Synthetic studies of tamandarin B side chain analogues. J Org Chem 75:3027-36
Shangguan, Ning; Joullié, Madeleine (2009) Total Synthesis of Isoroquefortine E and Phenylahistin. Tetrahedron Lett 50:6755-6757
Shangguan, Ning; Joullié, Madeleine (2009) A Copper-Carbodiimide Approach to the Phomopsin Tripeptide Side Chain. Tetrahedron Lett 50:6748-6750
Li, Pixu; Evans, Cory D; Wu, Yongzhong et al. (2008) Evolution of the total syntheses of ustiloxin natural products and their analogues. J Am Chem Soc 130:2351-64
Forbeck, Erin M; Evans, Cory D; Gilleran, John A et al. (2007) A regio- and stereoselective approach to quaternary centers from chiral trisubstituted aziridines. J Am Chem Soc 129:14463-9
Adrio, Javier; Cuevas, Carmen; Manzanares, Ignacio et al. (2007) Total synthesis and biological evaluation of tamandarin B analogues. J Org Chem 72:5129-38

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