Synthesis, Biological Testing, and Stereochemical Assignment of an End Group Modified Retro-Inverso Bombesin C-Terminal Nonapeptide

Article abstract of DOI:10.1021/jo00297a039

The end group modified retro-inverso bombesin C-terminal nonapeptide 3 and its diastereomer 4 have been synthesized.The absolute configurations at the substituted malonamic acid residues in 3 and 4 were determined by chemical correlations with D- and L-2-aminobutyric acids of known absolute configuration.Thus, the absolute configuration at the substituted malonic acid residues in each diastereomer of 25a were determined by Raney nickel desulfurization followed by Hofmann degradation to give the dipeptide derivatives 30 and 31 having established absolute configurations.Hydrolysis of 25a then gave the diastereomeric acids 25b having defined stereochemistries.Coupling of the diastereomer of 25b having the R configuration at the substituted malonamic acid residue to the hexapeptide 27 then gave a stereochemically defined diastereomer of 19, which was converted to 20b.Deprotection of 20a and 20b gave 3 and 4, respectively.As shown by an assay that measures the increase in inositol phosphates in GH3 rat pituitary cells stimulated by bombesin-like peptides, the retro-inverso peptide 3, having an absolute configuration at the substituted malonic acid residue corresponding to that of the methionine residue in bombesin, was essentially inactive as an agonist, whereas peptide 4, having the opposite configuration at the substituted malonamic acid residue, had weak agonist activity when compared to that of bombesin.Neither 3 nor 4 had any bombesin antagonist activity.