Synthesis and Bioevaluation of Methionine Depletion Agents

The native polyamines (putrescine, spermidine, and spermine) are low molecular weight amines that exist as polycations at physiological pH. These polycations interact with DNA, RNA, and influence many cellular processes. Intracellular polyamine levels are maintained via a balance of polyamine biosynthesis, catabolism, and transport. Ornithine, an amino acid obtained from L-arginine, is decarboxylated by ornithine decarboxylase (ODC) to form putrescine. The biosynthesis of the higher polyamines, spermidine and spermine, requires the addition of an amino-propyl group donated by decarboxylated S-adenosylmethionine (dc-SAM), which itself is derived from the amino acid L-methionine (Met). Tumor cells are heavily reliant on methionine because it is required for the translation of proteins, methylation of biomolecules and anabolic processes like polyamine biosynthesis. Pancreatic ductal adenocarcinoma cells (PDAC) are heavily reliant upon polyamines, and one way to affect the growth of PDAC cells is to reduce their intracellular methionine pools. LAT1 is the principal transporter of methionine into human cells and this thesis describes the discovery of a new methionine efflux agonist, which uses LAT1 to export methionine into the extracellular space. As expected, this agonist reduced both intracellular methionine and polyamines levels and inhibited cell growth of L3.6pl human pancreatic cancer cells. The agonist contains two chiral centers. Utilizing organic synthesis, the four possible stereoisomers (RR, SS, SR, and RS) were synthesized and. evaluated for their ability to inhibit L3.6pl cell growth, deplete intracellular methionine levels, and reduce intracellular polyamine pools. A success here may lead to new drugs which target pancreatic cancers via methionine starvation