Multifaceted roles of disulfide bonds. Peptides as therapeutics.

A noticeable increase in molecular complexity of drug targets has created an unmet need in the therapeutic agents that are larger than traditional small molecules. Macrocycles, which are cyclic compounds comprising 12 atoms or more, are now recognized as molecules that “are up to the task” to interrogate extended protein interfaces. However, because macrocycles (particularly the ones based on peptides) are equipped with large polar surface areas, achieving cellular permeability and bioavailability is anything but straightforward. While one might consider this to be the Achilles' heel of this class of compounds, the synthetic community continues to develop creative approaches toward the synthesis of macrocycles and their site-selective modification. This perspective provides an overview of both mechanistic and structural issues that bear on macrocycles as a unique class of molecules. The reader is offered a historical foray into some of the classic studies that have resulted in the current renaissance of macrocycles. In addition, an attempt is made to overview the more recent developments that give hope that macrocycles might indeed turn into a useful therapeutic modality.

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Macrocycles: lessons from the distant past, recent developments, and future directions

Financial support of the Spanish Ministry of Science and
Innovation (CTQ2012-38543-C03) and Generalitat Valenciana
(PROMETEO/2012/020) is acknowledged. V.M.-C. thanks the
Spanish Ministry of Science and Education for a predoctoral
fellowship (FPU AP2007-02562) and Generalitat Valenciana for
a VALi+d postdoctoral fellowship (APOSTD/2013/041).
M.D.P. thanks the Spanish Ministry of Education for a
postdoctoral fellowship and UGC India for a Startup Grant.

Macrocyclization Reactions: The Importance of Conformational, Configurational, and Template-Induced Preorganization

The well-known properties of the carbonyl group render aldehydes and ketones prominent substrates in both C-C and C-heteroatom bond forming methodologies of organic synthesis. In practical syntheses, nitrogen analogues of aldehydes and ketones such as enamines, imines, or hydrazones, acting as synthetic equivalents of the carbonyl * To whom correspondence should be addressed. E-mail: lazny@uwb.edu.pl. Chem. Rev. 2010, 110, 1386–1434 1386

N,N-dialkylhydrazones in Organic Synthesis. From Simple N,N-dimethylhydrazones to Supported Chiral Auxiliaries

Natural peptides show high degrees of specificity in their biological action. However, their therapeutical profile is severely limited by their conformational freedom and metabolic instability. Stapled peptides constitute a solution to these problems and access to these structures lies on a limited number of reactions involving the use of non-natural amino acids. Here, we describe a synthetic strategy for the preparation of unique constrained peptides featuring a covalent bond between tryptophan and phenylalanine or tyrosine residues. The preparation of such peptides is achieved in solution and on solid phase directly from the corresponding sequences having an iodo-aryl amino acid through an intramolecular palladium-catalysed C-H activation process. Moreover, complex topologies arise from the internal stapling of cyclopeptides and double intramolecular arylations within a linear peptide. Finally, as a proof of principle, we report the application to this new stapling method to relevant biologically active compounds.

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New peptide architectures through C–H activation stapling between tryptophan–phenylalanine/tyrosine residues

A general method for constraining peptide conformations via linkage of aromatic sidechains has been developed. Macrocyclization of suitably functionalized tri-, tetra- and pentapeptides via Suzuki–Miyaura cross-coupling has been used to generate side chain to side chain, biaryl-bridged 14- to 21-membered macrocyclic peptides. Biaryl bridges possessing three different configurations, meta–meta, meta–ortho, and ortho–meta, were systematically explored through regiochemical variation of the aryl halide and aryl boronate coupling partners, allowing fine-tuning of the resultant macrocycle conformation. Suzuki–Miyaura macrocyclizations were successfully achieved both in solution and on solid phase for all three sizes of peptide. This approach constitutes a means of constraining peptide conformation via direct carbogenic fusion of side chains of naturally occurring amino acids such as phenylalanine and tyrosine, and so is complementary to strategies involving non-natural, for example, hydrocarbon, bridges.

Biaryl-Bridged Macrocyclic Peptides: Conformational Constraint via Carbogenic Fusion of Natural Amino Acid Side Chains

Mechanism of ozonation reactions. IV. Carbon-nitrogen double bonds

Macrocycle-based drug design represents an exciting new frontier in drug discovery, and consequently there is considerable interest in methodologies for the efficient construction of macrocyclic motifs. However, typical high-dilution macrocyclization conditions are inefficient and impractical in a pharmaceutical setting from cost, capacity and green chemistry perspectives. This critical review reports the results of a comprehensive literature survey of recent macrocyclization reactions and proposes a macrocyclization efficiency index, Emac, which takes into account both reaction yield and concentration. Analysis and discussion of the literature dataset using this novel metric are presented, along with selected examples of high and low efficiency macrocyclizations.

Emac – a comparative index for the assessment of macrocyclization efficiency

Conditions have been identified for the efficient Ullmann macrocyclization of phenol and imidazole nucleophiles with aryl iodides at high reaction concentrations of up to 100 mM and using 5–10 mol % loading of an inexpensive copper catalyst. A range of substitution patterns and ring sizes are tolerated, and the method has been exemplified by the synthesis of a set of druglike macrocycles.

James C. Collins

Papers

Biaryl-Bridged Macrocyclic Peptides: Conformational Constraint via Carbogenic Fusion of Natural Amino Acid Side Chains

Mechanism of ozonation reactions. IV. Carbon-nitrogen double bonds

Emac – a comparative index for the assessment of macrocyclization efficiency

Macrocyclizations for medicinal chemistry: synthesis of druglike macrocycles by high-concentration Ullmann coupling.