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Journal of Undergraduate Research

Keywords

undergraduates, intersection of organic synthesis, peptide science

College

Physical and Mathematical Sciences

Department

Chemistry and Biochemistry

Abstract

Our academic goals were threefold. First, we aimed to synthesize building blocks and begin assembling them to construct the anticancer peptide yaku’amide A (YA, Figure 1). Our purposes in synthesizing YA were to develop new chemical reactions suitable for efficiently preparing its unusual amino acids (shown in red and blue in Figure 1), and synthesize simplified analogues for use in studies designed to reveal its biological target and mode of action. Our second academic goal was derived from the first and involved investigating the ability of bulky dehydroamino acids (i.e., the amino acids of YA shown in blue in Figure 1) to stabilize peptides from degradation by enzymes known as proteases. This degradation severely limits the utility of peptides as drugs. Our third academic goal entailed developing microwave-promoted transformations of iminyl radicals. Iminyl radicals are useful precursors to pyrrolidine rings, which are present in several topselling pharmaceuticals and biologically active natural products (Figure 1). Additionally, microwavepromoted reactions are known for their operational simplicity and safety. We have achieved important milestones related to each of these goals. First, we have synthesized three key subunits of YA: a rightcentral nonapeptide representing two-thirds of its structure, a left-hand pentapeptide comprising the remainder of its amino acids, and the N-terminal acyl subunit (shown in green in Figure 1). Thus, completion of the synthesis of YA is within reach. Second, we have found that bulky dehydroamino acids can impart substantial proteolytic stability to peptides that contain the b-turn secondary structure. Third, we have discovered that microwave-promoted iminyl radical cyclizations offer a direct and practical route to substituted pyrroles and pyrrolidines. To date, this work has resulted in the publication of three papers with undergraduate co-authors and one poster presentation by an undergraduate at a national scientific meeting. Thus, we are pleased with our progress and the achievements that have resulted from this mentoring environment.

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