This paper is dedicated to Drs Bruce E. Maryanoff and Cynthia A. Maryanoff for their outstanding contribution to organic chemistry as industrial chemists AbstractThe presence of carboxamide groups is found in a large array of biologically important compounds. Peptides and proteins play an important role in modern biology. A key step in peptide production is the formation of the peptide bond, which involves amide bond formation. Chemical synthesis of large peptides by intermolecular coupling of smaller peptides using conventional peptide bond-forming techniques did not realize its potential advantages until recently. Using an approach based on highly specific and efficient chemical ligation of two peptide segments, the two subunits were ligated to form a new peptide bond. Native chemical ligation extended the concept by creating a native peptide bond and providing new approaches to protein engineering.
A reliable, high yielding cyclization protocol for the macrocycle of tamandarin B is presented. This strategy will facilitate the synthesis of side chain analogues.
The syntheses of three tamandarin B analogs are described. The goal of these studies was to prepare material to determine their relative therapeutic index and to gain an oversight as to their potential for clinical applications.
The synthesis of Lys 3 tamandarin M is described. This analogue can be used as a protein affinity ligand to probe the mechanism of action of this unique class of molecules.The didemnins are a family of marine natural products that were isolated by Rinehart in 1984. 1 They consist of a 23-membered depsipeptide macrocycle with a side chain attached to the threonine nitrogen of the macrocycle. The didemnins (Figure 1) have been the subject of many syntheses. 2 Didemnin B (2) was the first marine natural product to enter into phase II clinical trials, but the trials were terminated due to toxicity issues associated with dosing levels, 3 and didemnin M (3) was later reported by Rinehart in 1994. 4 The difference between didemnins B and M is that the side chain of didemnin M is extended by two additional amino acid residues. It is one of the most potent immunosuppressive reagents known. In 2000, Fenical and Vervoort reported the structure of the structurally related tamandarins A and B 5 ( Figure 1) and both molecules were subsequently synthesized. 6 The main difference between didemnins and tamandarins is that tamandarins A and B posses a structurally simpler hydroxyisovaleryl (Hiv) fragment within a 21-membered ring instead of the α-(α-hydroxyisovaleryl)propionyl fragment within a 23-membered ring. This structural distinction results in minor differences in biological activity, but the absence of the highly epimerizable stereocenter present in the didemnins makes the tamandarins a more accessible synthetic target. Although these compounds have been extensively studied, their mechanism of action remains unclear.Many of the unresolved questions in the didemnin field are related to its mechanism(s) of action. Previous affinity studies have focused exclusively on the macrocycle by attaching a linker to the N-Me-D-Leu residue of didemnin A (1). 7 These studies revealed two binding proteins; elongation factor 1α (EF-1α) and palmitoyl protein thioesterase 1 (PPT1). Although the first study showed that an EF-1α-mediated effect upon protein translation explained certain biochemical effects of didemnins, their potent antiproliferative effect remained unexplained. 8 The relevance of PPT1 in mediating antiprolifrerative activities of didemnins was questioned. 9 Since the residues in both didemnins and tamandarins are the major contributors to the biological activity, it is possible that the molecular targets mjoullie@sas.upenn.edu.
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