Stabilized Analogs of Thymopentin. 2. 1,2- and 3,4-Ketomethylene Pseudopeptides

• Published in: Journal of medicinal chemistry Vol. 40; no. 15; pp. 2398 - 2406
• Main Authors: DeGraw, Joseph I, Almquist, Ronald G, Hiebert, Charles K, Judd, Amrit K, Dousman, Linda, Smith, R. Lane, Waud, William R, Uchida, Itsuo
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 18.07.1997; Amer Chemical Soc
• Subjects: Adjuvants, Immunologic - blood; Adjuvants, Immunologic - chemistry; Adjuvants, Immunologic - pharmacology; Animals; Biological and medical sciences; Chemistry, Medicinal; Drug Stability; Half-Life; Humans; Immunomodulators; Isomerism; Ketones - chemistry; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Medical sciences; Mice; Oligopeptides - chemistry; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Radioligand Assay; Science & Technology; Spectrometry, Mass, Fast Atom Bombardment; Thymopentin - analogs & derivatives; Thymopentin - blood; Thymopentin - pharmacology; KETOMETHYLENE; Human; Biological fluid; Stability; Peptides; Rodentia; Thymopentin; Ketone; In vitro; Blood; Blood plasma; Pseudopeptide; Immunomodulator; Vertebrata; Mammalia; Aminoketone; Structure activity relation; Mouse; Animal; Peptide synthesis; Solid phase; Chemical synthesis; Pentapeptide
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9508043

In this second paper in a series of three studies of stable analogs of thymopentin (Arg-Lys-Asp-Val-Tyr), the synthesis of analogs stablized 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.