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Esters and amides of several a-aza-amino-acids (carbazic acids), and intermediates of use in the introduction into peptides of a- aza-gtycyl, -alanyl, -valyl, -1eucyl. -isoleucyl, -phenylalanyl, -tyrosyl, -tryptophyl, -prolyl, -aspartyl. -asparaginyl, -glutamyl, -glutaminyl, and -pyroglutaminyl residues are described. t-Butyl 3-alkyl-or -aralkyl carbazates, obtained by catalytic hydrogenation of the corresponding hydrazones, were the most versatile intermediates ; they were converted in high yield into a-aza-amino-acid esters and amides, gave a-aza-dipeptide esters when treated with at-isocyanato-esters, and afforded ' active esters ' of N-t-butoxycarbonyl-a-aza-aminoacids when treated with 2,4,5-trichlorophenyI chloroformate.REPLACEMENT in peptides, of the a-CH groups of aminoacid residues by N has little effect on the overall polarity of the molecule and the relative spacing of side-chain residues, but would be expected to induce new chemical and biological properties by virtue of the changed conformational situation at the residue or residues concerned. Our interest over the past six years in analoguesof this type (a-aza-peptides) has led us to establish general methods for the synthesis of a-aza-amino-acid derivatives and the incorporation of a-aza-amino-acid residues into peptides. This aspect of our work is described in the present paper. Subsequent papers in the series will deal with the use of this methodology in the synthesis of a-aza-analogues of biologically active peptides and model enzyme substrates.a-Aza-amino-acid derivatives and a-aza-peptides have hitherto been little explored. Ethyl esters of a-azaphenylalanine, -alanine, -leucine, and -methionhe were prepared by Ronco et aL2 by alkylation/aralkylation of ethyl carbazate, using biacetyl for amino-protection (Scheme 1). Kurtz and Nieman found the methodReagents: see caption, Scheme 2 unattractive for the preparation of N-acetyl-a-azaphenylalanine ethyl ester preferring the ethoxycarbonylation of methyl 3-benzylcarbazate. Gante, in extensive studies: developed methods for the incorporation of aza-glycyl residues into peptides, and demonstrated that a-aza-alanine and -phenylalanine may be incorporated by selective acylation of methyl-and benzyl-hydrazine. Hess, Moreland, and Laubach prepared an analogue of bovine angiotensin I1 in which the 5-valyl residue is replaced by a-aza-valyl ; the incorporation of aza-valine involved the reaction of t-butyl-3-isopropylcarbazate with the adjacent amino-acid residue (tyrosine) as its N-carbonyl ethyl ester. Niedrich and his co-workers prepared a-aza-asparagine and aza-glycine analogues of oxytocin 6 and of eledoisin 7 octapeptide, and a-azaalanine analogues of eledoisin hexa-and penta-peptides ; the incorporation of a-aza-asparagine and -alanine involved selective acylation of hydrazinoacetamide or methylhydrazine.Our own work has shown that the most useful and versatile intermediates are t-butyl 3-alkyl-or -aralkylcarbazates (4). Carbazates of this type, suitable for the synthesis of aza-valine, -leucine, -...

Small, N‐ to C‐terminal cyclized peptides containing the leucyl‐aspartyl‐valine (LDV) motif from fibronectin connecting segment‐1 (CS‐1) have been investigated for their effects on the adhesion of human T‐lymphoblastic leukaemia cells (MOLT‐4) to human plasma fibronectin in vitro mediated by the integrin Very Late Antigen (VLA)‐4 (α4β1, CD49d/CD29). Cyclo(‐isoleucyl‐leucyl‐aspartyl‐valyl‐aminohexanoyl‐) (c(ILDV‐NH(CH2)5CO)) was approximately 5 fold more potent (IC50 3.6±0.44 μM) than the 25‐amino acid linear CS‐1 peptide. Cyclic peptides containing two more or one less methylene groups had similar potency to c(ILDV‐NH(CH2)5CO) while a compound containing three less methylene groups, c(ILDV‐NH(CH2)2CO), was inactive at 100 μM. c(ILDV‐NH(CH2)5CO) had little effect on cell adhesion mediated by two other integrins, VLA‐5 (α5,β1, CD49e/CD29) (K562 cell adhesion to fibronectin) or Leukocyte Function Associated molecule‐1 (LFA‐1, αLβ2, CD11a/CD18) (U937 cell adhesion to Chinese hamster ovary cells transfected with intercellular adhesion molecule‐1) at concentrations up to 300 μM. c(ILDV‐NH(CH2)5CO) inhibited ovalbumin delayed‐type hypersensitivity or oxazolone contact hypersensitivity in Balb/c mice when dosed continuously from subcutaneous osmotic mini‐pumps (0.1–10 mg kg−1 day−1). Maximum inhibition (approximately 40%) was similar to that caused by the monoclonal antibody PS/2 (7.5 mg kg−1 i.v.) directed against the α4 integrin subunit. c(ILDV‐NH(CH2)5CO) also inhibited oxazolone contact hypersensitivity when dosed intravenously 20 h after oxazolone challenge (1–10 mg kg−1). Ear swelling was reduced at 3 h and 4 h but not at 1 h and 2 h post‐dose (10 mg kg−1). Small molecule VLA‐4 inhibitors derived from c(ILDV‐NH(CH2)5CO) may be useful as anti‐inflammatory agents. British Journal of Pharmacology (1999) 126, 1751–1760; doi:

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