Elsevier

Tetrahedron

Volume 68, Issue 23, 10 June 2012, Pages 4501-4505
Tetrahedron

Double-sided α-helix mimetics

https://doi.org/10.1016/j.tet.2011.11.010Get rights and content

Abstract

The design and synthesis of substituted bis- and tris-benzamides is reported in which the projection of side-chain residues on both sides of an α-helix is reproduced. The scaffold is conformationally constrained by a series of intramolecular hydrogen bonds, allowing for spatial and angular mimicry of the i, i+2, i+4 and i+6 side-chains in the case of the bis-benzamide, and may be extended to higher-order oligomers.

Introduction

Protein–protein interactions (PPIs) are responsible for diverse biological functions ranging from signal transduction to immune response.1 Among protein secondary structures, α-helices form the largest class and are responsible for a multitude of PPIs and the stability of higher-order structures.2 Hence, the design of α-helix mimetics as inhibitors of aberrant interactions is a promising strategy that has attracted wide attention from the synthetic community. There are many reports in which both peptidic3 and non-peptidic4, 4(a), 4(b), 4(c), 4(d), 4(e), 4(f) oligomers project substituents in the correct spatial and angular orientation to mimic the side-chains of one face of an α-helix—frequently those of the i, i+4 and i+7 residues. Non-peptidic scaffolds include indanes, terphenyls, terpyridyls and polycylic ethers.4e In a related approach, hydrogen-bond-constrained scaffolds including enaminones,5 benzoylureas, tris-pyridylamides and tris-benzamide have been developed as more accessible mimetics in which the syntheses are simplified and the biological properties improved (Fig. 1a,b, Ref. 4b and refs therein).

Whilst there are a growing number of synthetic scaffolds for the mimicry of side-chains on a single face of an α-helix, there have been very few examples in which the side-chain projection of two faces is reproduced.6 Of these approaches, many do not allow extension to higher-order oligomers in which more than three or four side-chains are mimicked. The side-chains projecting from the exterior face of an α-helix have been widely implicated in the binding of multiple proteins and in bacterial cell wall sensing. Hrs-UIM (hepatocyte growth factor-regulated tyrosine kinase substrate-ubiquitin interacting motif),7 golgi associated protein Arf-GAP18 and glucagon like peptide-1 (GLP-1)9 depend of residues of both faces of the α-helix for their function. Antimicrobial peptides (magainins, defensins and protegrins) have one side of their backbone composed of cationic groups to interact with anionic phospholipids and lipopolysaccharides on the bacterial cell wall, and another side composed of hydrophobic groups to facilitate penetration of the bacterial membrane.10

With the goal of creating a novel scaffold for simultaneous mimicry of two faces of an α-helix, we have designed a series of double-sided mimetics based on our benzamide scaffold11 (Fig. 1c). We anticipated that this design would adopt a constrained conformation due to intramolecular H-bonding between the amide N–H and ortho-alkoxy group, and mimic of the i, i+2, i+4 and i+6 residues of an α-helix. The two oligomer precursors originate from a common intermediate and may be connected via nucleophilic attack of an aromatic amine on an activated carboxyl group. A range of acyl groups, potentially including amino acids, may be incorporated in the i+2 and i+6 positions.

Section snippets

Results and discussion

Synthesis of carboxylic acid monomer 3 from 2-amino-5-hydroxybenzoic acid or 4-chloro-2-methylaniline was poor yielding; however a robust three-step procedure was established starting from m-cresidine in 50% overall yield (Scheme 1). Esterification of the carboxylic acid and reduction of the nitro-group gave amine 5 in 85% yield, setting the stage for coupling with 3 to form bis-benzamide 10.

Activation of 3 as an acid chloride, or the use of coupling agents such as DCC, EDCI, HATU, gave an

Conclusions

In summary, we have designed a modular and scalable route to conformationally constrained double-sided benzamide α-helix mimetics and have efficiently synthesized a range of hetero-dimeric bis-benzamides and a tris-benzamide bearing six side-chains. The synthesis is amenable to extension of these mimetics to higher oligoamides and to molecules with a broad array of N-acyl groups.

General

Reactions were carried out under a nitrogen or argon atmosphere in oven-dried glassware unless otherwise stated. Standard inert atmosphere techniques were used in handling all air and moisture sensitive reagents. Anhydrous tetrahydrofuran and dichloromethane (from commercial sources) were obtained by filtration through activated alumina (powder ∼150 mesh, pore size 58 Å, basic, Sigma–Aldrich) columns, or were dried on an MB-SPS-800 dry solvent system. Other solvents and reagents were used

Acknowledgements

We thank Dr. Martin D. Smith (Oxford) for helpful discussions and The University of Oxford for funding (S.T.).

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