STABILIZED ANALOGS OF THYMOPENTIN .1. 4,5-KETOMETHYLENE PSEUDOPEPTIDES

The pentapeptide, thymopentin (Arg(1)-Lys(2)-Asp(3)-Val(4)-Tyr(5)) is known for its activity as an immunomodulating drug, but with limited h alf-life in plasma. In this first paper of a series of three studies, the synthesis of analogs stabilized at the peptide bond between the C- terminal amino acids via insertion of a ketomethylene moiety is descri bed. N-Blocked pseudopeptides containing Val(k)Phe, Ala(k)Phe, and Val (k)Val units were prepared and attached to chloromethyl Merrifield res in via the carboxy terminal. Removal of the N-BOC group by trifluoroac etic acid was followed by sequential coupling with N-BOC dipeptides of aspartic acid to yield resin-bound N-BOC pseudotetrapeptides. Removal of N-BOC and coupling with N-BOC-r-N-tosylarginine followed by total cleavage of blocking groups and resin by HF afforded the target pseudo pentapeptides. The analogs were found to compete favorably with thymop entin for binding to CEM cells, but binding was reduced by about 20-30 % on average. All analogs showed significant enhancement of half-life versus thymopentin in mouse serum, but most showed only modest improve ment in human serum. Insertion of proline or norleucine at position 2 in the chain caused a substantial increase in half-life (3-4-fold), wh ile N-methylnorleucine conferred complete stability in the analogs.