A Versatile Synthetic Approach to Peptidyl Privileged Structures Using a “Safety-Catch” Linker

Abstract

Peptidyl privileged structures have been widely used by many groups to discover biologically active molecules. In this context, privileged substructures are used as "hydrophobic anchors", to which peptide functionality is appended to gain specificity. Utilization of this concept has led to the discovery of many different active compounds at a wide range of biological receptors. A synthetic approach to these compounds has been developed on a "safety-catch" linker that allows rapid preparation of large libraries of these molecules. Importantly, amide bond formation/cleavage through treatment with amines is the final step; it is a linker strategy that allows significant diversification to be easily incorporated, and it only requires the inclusion of an amide bond. In addition, chemistry has been developed that permits the urea moiety to be inserted at the N-terminus of the peptide, allowing the same set of amines (either privileged substructures or amino acid analogues) to be used at both the N- and C-termini of the molecule. To show the robustness of this approach, a small library of peptidyl privileged structures were synthesized, illustrating that large combinatorial libraries can be synthesized using these technologies.

Development and Characterization of New Inhibitors of the Human and Mouse Hematopoietic Prostaglandin D2 Synthases

“…Thus, development of compounds for both receptor and synthase targets will provide unique opportunities to modulate the effects of PGD 2 and is supported by the clinical use of ramatroban, a receptor antagonist, 43 and tranilast, a modest H-PGDS inhibitor, 44 in the control of allergic responses, as well as the therapeutic effect of HQL-79 in animal models of allergic disease. 24,25 We have been interested in the exploitation of privileged substructures [45][46][47] and have used a structure guided approach to develop novel H-PGDS inhibitors based on known inhibitory chemotypes, represented by 1 23 and 2. 26 Compound 8 was created by the fusion of a diphenyl moiety similar to that of 1 to a weak fragment inhibitor 6.…”

“…We have been interested in the exploitation of privileged substructures − and have used a structure guided approach to develop novel H-PGDS inhibitors based on known inhibitory chemotypes, represented by 1 and 2 . Compound 8 was created by the fusion of a diphenyl moiety similar to that of 1 to a weak fragment inhibitor 6 .…”

Library of Biphenyl Privileged Substructures using a Safety-Catch Linker Approach

“…In recent years, we have been interested in establishing solid-phase chemistries that allow the synthesis of various libraries using several purpose built linkers. , The safety-catch linker 9 and 10 in Figure was found to be versatile in producing cyclic peptides and peptoidal compounds …”

“…We decided upon the catechol linker developed in our laboratory. , Unlike most other safety catch linkers that usually require oxidation or alkylation for activation, the catechol safety catch linker 10 only requires simple acid treatment (TFA) for elimination of the t -butyl protecting group. This allows the possible incorporation of thiols, thioureas, and other reactive moieties onto the biphenyl framework.…”

“…22,23 The safetycatch linker 9 and 10 in Figure 2 was found to be versatile in producing cyclic peptides and peptoidal compounds. 24 There are many examples in the literature describing safety-catch linkers. The first safety-catch linker for cyclic peptide synthesis was developed by Marshall and Flannigan.…”