Stabilized analogs of thymopentin. 2. 1,2- and 3,4-ketomethylene pseudopeptides.
In this second paper in a series of three studies of stable analogs of thymopentin (Arg1-Lys2-Asp3-Val4-Tyr5), the synthesis of analogs stabilized at peptide bonds 1,2 and 3,4 via insertion of ketomethylene units is described. A tris(carbobenzyloxy)arginyl(k)norleucine pseudopeptide was synthesized and coupled to Asp-Val-Phe-resin units followed by HF cleavage to prepare Arg(k)Nle-Asp-Val-Phe analogs. Preparation of N-BOC Asp(k)Val and N-BOC Asp(k)Ala units followed by coupling to Phe- or Tyr-resin units provided resin-bound pseudotripeptide substrates for attachment of various arginyl dipeptides. Cleavage from the resin afforded 3,4-ketomethylene-stabilized pseudopeptide analogs of thymopentin. The Arg-Lys-Asp(k)Val-Phe and Arg-Lys-Asp(k)Val-Tyr analogs were more strongly bound to CEM cells than thymopentin itself. There was significant enhancement of stability in serum for the analogs, especially those containing Arg(k)Nle or Arg-NMeLys moieties at the 1,2-peptide bond.
DeGraw
J I
JI
Bio-Organic Chemistry Laboratory, SRI International, Menlo Park, California 94025, USA.
Almquist
R G
RG
Hiebert
C K
CK
Judd
A K
AK
Dousman
L
L
Smith
R L
RL
Waud
W R
WR
Uchida
I
I
D000276:Adjuvants, Immunologic / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D004355:Drug Stability; D006207:Half-Life; D006801:Humans; D007536:Isomerism; D007659:Ketones / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry*; D011869:Radioligand Assay; D016339:Spectrometry, Mass, Fast Atom Bombardment; D016305:Thymopentin / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology
D000276:Adjuvants, Immunologic; D007659:Ketones; D009842:Oligopeptides; D016305:Thymopentin