Synthesis of Macrocyclic, Potential Protease Inhibitors Using a Generic Scaffold

Abstract

A generic macrocyclic peptide structure 2 was designed as a potential inhibitor of a range of proteinases, by using as a basis for the design the known structures of a series of enzyme-inhibitor complexes. The macrocyclic nature of the target 2 was chosen so as to reduce the entropic advantage in the hydrolytic enzymatic step, and thereby to inhibit the function of the enzyme. The nature of the linking group was identified as a benzoxazole by molecular modeling, so as to preserve the recognized conformation of the peptide chain. The specificity of the potential inhibitor was tuned by variation of the P(1) group (by incorporating phenylalanine, aspartic acid, or lysine), to allow recognition by different enzyme classes. The targets were prepared from the bis-amino acid derivative 5, itself prepared using the Pd-catalyzed coupling of an organozinc reagent with the iodobenzothiazole 7 and subsequent macrocyclization of the open-chain derivatives 22-24 using HATU. None of the macrocylic compounds 25, 28-30, and 32 inhibited their target enzymes. NMR and MS studies on the interaction of macrocycle 29 and chymotrypsin established that compound 29 was in fact a substrate of the enzyme. This result indicated that while the design had been partially successful in identifying a compound that bound, the reduction in entropic advantage due to its macrocyclic nature was not sufficient to allow 29 to act as an inhibitor.

Protein–protein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase

“…The propensity of the eight octapeptides to assume secondary structures correlated with their inhibitory activities. Previous studies have shown entropy-mediated gains in affinity by constraining the conformational freedom of ligands (37)(38)(39)(40)(41)(42). In the present study, spontaneous prestructuring of the peptide might reduce the entropic penalty associated with formation of a peptide/hTS complex.…”

The Synthesis of Macrocycles for Drug Discovery

“…Nonetheless, this chemical approach has been used to advantage to prepare both macrocyclic peptidomimetic and non-peptidic compounds, including renin inhibitors, [23][24][25][26][27] thrombin inhibitors (7, Figure 11.1, ring closure site and reagent used for cyclization indicated), 28,29 human immunodeficiency (HIV) protease inhibitors, 30,31 b-secretase (BACE-1) inhibitors, 32 TNF-a converting enzyme (TACE) inhibitors, 33 selective MMP-8 inhibitors, 34 protease inhibitors, 35 calpain inhibitors, 36 cholecystokinin (CCK)-B antagonists, 37 subtype selective somatostatin analogues, 38 growth factor receptor-bound protein 2 (Grb) Src homology 2 (SH2) domain inhibitors, 39 histone deacetylase (HDAC) inhibitors, 40 heat shock protein 90 (Hsp90) inhibitors, 41 PDZ domain ligands, 42 multicyclic mimics of protein loop structures, 43,44 and a wide variety of structures that target the G-quadruplex (8). [45][46][47] For this latter example, it was actually simultaneous double amide bond formation that created the ring.…”

“…84 A similar strategy was employed for the synthesis of arylthioether-containing macrocycles, where intramolecular S N Ar reactions, in addition to S N 2 processes, provided the key cyclization step in the solid phase parallel synthesis of a set of peptidomimetics. 85 In a standard solution phase S N Ar process, extensive series of macrocyclic piperazinone, pyrrolidinone and imidazole farnesyltransferase (FTase) inhibitors, with 34 as a representative example ( Figure 11.4, site of ring closure indicated) were constructed, [86][87][88] from which were also identified dual inhibitors of FTase and geranylgeranyltransferase-1 (GGTase) (35). 89 Additionally, an S N Ar approach proved useful for the assembly of aminopyrimidine macrocycles (36) that possessed inhibitory activity against both CDK and vascular endothelial growth factor receptor-2 (VEGF-R2) and exhibited in vivo oral activity in a tumour xenograft model.…”

Synthesis of some novel 2-substituted benzoxazoles as anticancer, antifungal, and antimicrobial agents

“…2-Substituted benzoxazoles have also been shown to exert analgesic (Bartsch and Erker, 1991), fungicidal, insecticidal, nematocidal (Yalcin et al, 1992), potent protease inhibitory, and anticancer activities and serve as a topoisomerase I poison (Dumez et al, 2002;Kim et al, 1996).…”