Synthesis and biological activities of some pseudo-peptide analogs of tetragastrin: the importance of the peptide backbone

Abstract

Pseudo-peptide analogues of the C-terminal tetrapeptide of gastrin, in which a peptide bond has been replaced by a CH2-NH bond, i.e. (tert-butyloxycarbonyl)-L-tryptophyl-psi (CH2-NH)-L-leucyl-L-aspartyl-L-phenylalanine amide (8), (tert-butyloxycarbonyl)-L-tryptophyl-L-leucyl-psi (CH2-NH)-L-aspartyl-L-phenylalanine amide (13), (tert-butyloxycarbonyl)-L-tryptophyl-L-leucyl-L-aspartyl-psi (CH2NH)-L-phenylalanine amide (20), were synthesized. The pseudo-peptides 8 and 13 were shown to have the same affinity as (tert-butyloxycarbonyl)-L-tryptophyl-L-leucyl-L-aspartyl-L-phenylalanine amide (21) for the gastrin receptor on isolated mucosal cells. The pseudo-peptide 20 exhibited lower affinity (IC50 congruent to 10(-5) M). The biological activity of these pseudo-peptides was studied on acid secretion in the anesthetized rat. Compound 8 stimulated acid secretion, identically with that of 21. Compound 13 did not exhibit any agonist activity but was able to antagonize the action of gastrin (ED50 = 0.3 mg/kg). Compound 20 did not show any agonist activity but was able to inhibit gastrin-induced acid secretion, with lower potency (ED50 = 15 mg/kg). The importance of the peptide bonds in the mode of action of gastrin is discussed, and a hypothetical approach of the mechanism of action is presented.

Synthesis, biological evaluation and molecular modeling of oxoisoaporphine and oxoaporphine derivatives as new dual inhibitors of acetylcholinesterase/butyrylcholinesterase

“…4-Carboxyl-7-oxo-7H-dibenzo[de,g]quinoline 4 was obtained in 73% yield by decarboxylation of 3 in diphenyl ether at 190 C for 1.5 h. Amidification of 4 when treated with appropriate amines was failed when we used several classical coupling agents such as ethyl chloroformate, DCC-DMAP [19]. However, using PyBOP [20,21] in N,N-dimethyl acetamide (DMA), which generally worked with hindered carboxylic acids, the desired amides 5a-j were obtained in good yields (51-68%). The corresponding quaternary methiodide salts 6a-h were obtained by treatment with CH 3 I in CHCl 3 .…”

Identification of the core residues of the epitope of a monoclonal antibody raised against glycoprotein D of herpes simplex virus type 1 by screening of a random peptide library

“…Tentage1 S AC [24,25] was used as a resin (40-60 mg per peptide, 10 pmol Fmoc amino acid loading). Repetitive couplings of the appropriate protected Fmoc amino acids were performed by adding a mixture of 90 pl 0.67 M benzotriazole-l-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP) [26] in N-methylpyrrolidone (NMF'), 20 pl N-methylmorpholin (NMM) in NMP (20 v/v) and 100 pl of an 0.60 M solution of the appropriate Fmoc amino acid [27] in NMP (sixfold excess) to the reaction vessel. Fmoc-deprotection was performed by adding 0.8 ml piperidineDMA (U4; v/v) three times to the reaction vessel.…”

Synthesis and Proinflammatory Properties of Muramyl Tripeptides Containing Lysine and Diaminopimelic Acid Moieties

“…Sieber Amide resin [42] (13) was swelled in dry dimethylformamide (DMF) and treated with piperidine in DMF (20 %) to remove the Fmoc protecting group of the resin. The resulting amine 14 was coupled with Fmoc-protected derivative 12 by use of benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), [43,44] 1-hydroxy-1H-benzotriazole (HOBt), [45] and N,N-diisopropylethylamine (DIPEA) as the activating reagent to give resin-bound 15. Each reaction component was used in twofold excess with respect to the loading of the resin, and progress of the reaction was monitored by the Kaiser test.…”