Design of novel inhibitors of aminopeptidases. Synthesis of peptide-derived diamino thiols and sulfur replacement analogs of bestatin

Abstract

Investigations were directed toward inhibition of an aminopeptidase, isolated from rat brain, which has been implicated in the metabolic inactivation of enkephalins. The design rationale and synthesis of novel peptidyl diamino thiol inhibitors of rat brain aminopeptidase are presented, along with accompanying structure-activity analysis. Some of the reported compounds are highly active aminopeptidase inhibitors and possess enzyme inhibitory potency in the nanomolar range (62; I50 = 1 nM). Analysis of the data permits speculations on possible modes of binding of diamino thiols to aminopeptidase. Other investigations were directed toward understanding the mode of enzyme binding of the naturally occurring aminopeptidase inhibitor bestatin. On the basis of published models of enzyme binding, replacement of the C-2 hydroxyl group of bestatin by a sulfhydryl group was anticipated to lead to enhanced inhibition due to a strengthened interaction of this group with enzymic zinc. Contrary to expectations, "thiobestatin" inhibited rat brain aminopeptidase with only the same degree of effectiveness as the corresponding alcohol. Speculations on the possible mode of enzyme-inhibitor binding of bestatin are offered.

Ring closing metathesis of α- and β-amino acid derived dienes

“…Arndt-Eistert homologation [35,36] of N-Cbz-(S)-phenylalanine 10, followed by stereocontrolled allylation or methylation, gave 18 and 14, respectively [37,38]. The disubstituted b-amino acid 14 was then allylated to give a,a-disubstituted 15.…”

Leukotriene A4 hydrolase: a critical role of glutamic acid-296 for the binding of bestatin

“…Furthermore, it has been suggested that a Zn# + ion and an acidic residue are involved in the binding of the drug to the active site [20,22]. Because bestatin is a prototype for an aminopeptidase inhibitor and many newly synthesized com-…”

Peptidomimetics and metalloprotease inhibitors as anticancer drugs

“…Inhibitors with similar binding mode mainly includes: (1) modified or reformed compounds based on Bestatin, e.g. α-Thiobestatin (K i : 4.4 μmol/L), Bestatin thioamide (K i : 40.3 μmol/L) [29] , Lapstatin (IC50: 203 μmol/L) [30] , and para-hydroxybestatin, etc. (Figure 19, 33-35); (2) AHPA derivatives, e.g.…”