Gregory T. Bourne

Exploring privileged structures: the combinatorial synthesis of cyclic peptides.

Head-to-tail cyclic peptides have been reported to bind to multiple, unrelated classes of receptor with high affinity. They may therefore be considered to be privileged structures. This review outlines the strategies by which both macrocyclic cyclic peptides and cyclic dipeptides or diketopiperazines have been synthesised in combinatorial libraries. It also briefly outlines some of the biological applications of these molecules, thereby justifying their inclusion as privileged structures.

Exploring privileged structures: The combinatorial synthesis of cyclic peptides

Head-to-tail cyclic peptides have been reported to bind to multiple, unrelated classesof receptor with high affinity. They may therefore be considered to beprivileged structures. This review outlines the strategies by which bothmacrocyclic cyclic peptides and cyclic dipeptides or diketopiperazines havebeen synthesised in combinatorial libraries. It also briefly outlines someof the biological applications of these molecules, thereby justifying theirinclusion as privileged structures.

Cyclic tetrapeptides via the ring contraction strategy: Chemical techniques useful for their identification

Cyclic tetrapeptides are a class of natural products that have been shown to have broad ranging biological activities and good pharmacokinetic properties. In order to synthesise these highly strained compounds a ring contraction strategy had previously been reported. This strategy was further optimised and a suite of techniques, including the Edman degradation and mass spectrometry/mass spectrometry, were developed to enable characterisation of cyclic tetrapeptide isomers. An NMR solution structure of a cyclic tetrapeptide was also generated. To illustrate the success of this strategy a library of cyclic tetrapeptides was synthesised.

Development and characterization of new inhibitors of the human and mouse hematopoietic prostaglandin D(2) synthases.

The hematopoietic prostaglandin D(2) synthase has a proinflammatory effect in a range of diseases, including allergic asthma, where its product prostaglandin D(2) (PGD(2)) has a role in regulating many of the hallmark disease characteristics. Here we describe the development and characterization of a novel series of hematopoietic prostaglandin D(2) synthase inhibitors with potency similar to that of known inhibitors. Compounds N-benzhydryl-5-(3-hydroxyphenyl)thiophene-2-carboxamide (compound 8) and N-(1-amino-1-oxo-3-phenylpropan-2-yl)-6-(thiophen-2-yl)nicotinamide (compound 34) demonstrated low micromolar potency in the inhibition of the purified enzyme, while only 34 reduced Toll-like receptor (TLR) inducible PGD(2) production in both mouse primary bone marrow-derived macrophages and the human megakaryocytic cell line MEG-01S. Importantly, 34 demonstrated a greater selectivity for inhibition of PGD(2) synthesis versus other eicosanoids that lie downstream of PGH(2) (PGE(2) and markers of prostacyclin (6-keto PGF(1alpha)) and thromboxane (TXB(2))) when compared to the known inhibitors HQL-79 (compound 1) and 2-phenyl-5-(1H-pyrazol-3-yl)thiazole (compound 2). Compound 34 therefore represents a selective hematopoietic prostaglandin D(2) synthase inhibitor.

Isolation and structures of axistatins 1-3 from the Republic of Palau marine sponge Agelas axifera Hentschel .

An investigation begun in 1979 directed at the Republic of Palau marine sponge Agelas axifera Hentschel for cancer cell growth inhibitory constituents subsequently led to the isolation of three new pyrimidine diterpenes designated axistatins 1 (1), 2 (2), and 3 (3), together with the previously reported formamides 4, 5, and agelasine F (6). The structures were elucidated by analysis of 2D-NMR spectra and by HRMS. All of the isolated compounds were found to be moderate inhibitors of cancer cell growth. Axistatins 1-3 (1-3), formamide 4, and agelasine F (6) also exhibited antimicrobial activity.

Topological side-chain classification of β-turns: Ideal motifs for peptidomimetic development

Summaryβ-turns are important topological motifs for biological recognition of proteins and peptides. Organic molecules that sample the side chain positions of β-turns have shown broad binding capacity to multiple different receptors, for example benzodiazepines. β-turns have traditionally been classified into various types based on the backbone dihedral angles (φ2, ψ2, φ3 and ψ3). Indeed, 57–68% of β-turns are currently classified into 8 different backbone families (Type I, Type II, Type I′, Type II′, Type VIII, Type VIa1, Type VIa2 and Type VIb and Type IV which represents unclassified β-turns). Although this classification of β-turns has been useful, the resulting β-turn types are not ideal for the design of β-turn mimetics as they do not reflect topological features of the recognition elements, the side chains. To overcome this, we have extracted β-turns from a data set of non-homologous and high-resolution protein crystal structures. The side chain positions, as defined by Cα–Cβ vectors, of these turns have been clustered using the kth nearest neighbor clustering and filtered nearest centroid sorting algorithms. Nine clusters were obtained that cluster 90% of the data, and the average intra-cluster RMSD of the four Cα–Cβ vectors is 0.36. The nine clusters therefore represent the topology of the side chain scaffold architecture of the vast majority of β-turns. The mean structures of the nine clusters are useful for the development of β-turn mimetics and as biological descriptors for focusing combinatorial chemistry towards biologically relevant topological space.

Synthesis of the Phenylpyridal Scaffold as a Helical Peptide Mimetic

Phenylpyridal- and phenyldipyridal-based scaffolds have been designed and synthesized as novel helical peptide mimetics. The synthesis required optimisation and selective alkylation in producing 2,6-functionalized 3-hydroxypyridine derivatives for a convergent scheme. The pyridine analogues were coupled by a series of Suzuki/Stille types cross-coupling reactions. A series of biaryl and ter-aryl substituted heterocycles were produced. The synthetic approach was concise and high yielding allowing large variability at the wanted side-chain attachment points. A number of compounds were synthesised to show the versatility of the strategy.

Synthesis of a cyclic peptide library based on the somatostatin sequence using the backbone amide linker approach

Herein, we report on the synthesis of a library of cyclic peptides targeted at the somatostatin receptor using the backbone amide linker strategy. After optimising head-to-tail cyclisation and cleavage conditions, a library of discrete cyclic peptides was assembled in high purity and good overall yield.

The development of solid phase protocols for a backbone amide linker and its application to the Boc-based assembly of linear peptides

Herein, we report on the solid phase synthesis of a backbone amide linker. The key step is the acylation of a secondary amide in quantitative yield. To show the application of this methodology we synthesised linear peptides CCK (25-33) and ACP (64-73) using Boc-based protocols in high yields and purity

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

A biphenyl privileged structure library containing three attachment points were synthesized using a catechol-based safety-catch linker strategy. The method requires the attachment of a bromo-acid to the linker, followed by a Pd-catalyzed Suzuki cross-coupling reaction. Further derivatization, activation of the linker with strong acid and aminolysis afforded the respective products in high purity and good overall yield. To show the versatility of the synthesis, a 199-member library was generated. The library samples both conformational and chemical diversity about a well-known privileged substructure.