Stereoselective Fluorination Alters the Geometry of a Cyclic Peptide: Exploration of Backbone‐Fluorinated Analogues of Unguisin A

Peptidomimetics, non-natural mimicries of bioactive peptides, comprise an important class of drug molecules. The essence of the peptidomimetic design is to mimic the key conformation assumed by the bioactive peptides upon binding to their targets. Regulation of the conformation of peptidomimetics is important not only to enhance target binding affinity and selectivity, but also to confer cell-membrane permeability for targeting protein-protein interactions in cells. The rational design of peptidomimetics with suitable three-dimensional structures is challenging, however, due to the inherent flexibility of peptides and their dynamic conformational changes upon binding to the target biomolecules. In this Minireview, a three-dimensional structural diversity-oriented strategy based on the characteristic structural features of cyclopropane to address this challenging issue in peptidomimetic chemistry is described.

Section: Sequencementioning

confidence: 99%

From Peptides to Peptidomimetics: A Strategy Based on the Structural Features of Cyclopropane

Mizuno

Matsui

Shuto

2017

“…Among the properties of the CÀFb ond, [5] its capacityt oe ngage in charge-dipole interactions, dipole-dipole interactions, as well as hyperconjugation have all been exploited to fine-tune the conformation of aw ide range of biomolecules including fatty acids, [6] alpha, [7] beta, [8] and gamma [9] amino acids and their oligomers. [11] Based on these precedents andi nv iew of the importance of macrocyclesi nd rug discovery, [12] we becamei nterested in the possibility of using a-fluoroalkoxyaryl groups [13] as a potentialm anifold to increases haped iversity of macrocyclic scaffolds.I ndeed, while in the absence of steric hindrance alkoxyphenyl groups are known to align in the plane of the aryl ring, a-fluoroalkoxyaryl groups ArOCF 2 Ra nd ArOCF 3 have been shown to reduce the in-plane conformational preferences (Fig-ure 1). [10] Furthermore, Hunter and co-workersh ave elegantly demonstrated the pronounced impact that the gauchee ffect of av icinal difluorinated alkyl chain has on the conformation of derivatives of Unguisin A.…”

mentioning

confidence: 99%

Synthesis of Diverse α‐Fluoroalkoxyaryl Derivatives and Their Use for the Generation of Fluorinated Macrocycles

Cogswell

Dahlén

Knerr

2018

Introduction of difluorinated functionality has emerged as ap owerful meansf or conformational design with minimal steric footprint. Synthetic approaches for the preparation of aryl difluoromethylene etherc ontaining novel buildingblocks wereestablished, enabling the inclusion of the aryl difluoromethylene ether systemi nto macrocyclics caffoldsfor the first time.The rational introductiono ff luorine atoms has becomeakey tool for organic chemists to modulate not only the physicochemicalb ut also the conformational properties of am olecule. With the tremendous progress made to extend the variety of synthetic fluorination methods [1] available,i ti sn os urprise to see the increasing impact of fluorination in contemporary catalysis, [2] pharmaceutical, [3] and agrochemical [4] design. Among the properties of the CÀFb ond, [5] its capacityt oe ngage in charge-dipole interactions, dipole-dipole interactions, as well as hyperconjugation have all been exploited to fine-tune the conformation of aw ide range of biomolecules including fatty acids, [6] alpha, [7] beta, [8] and gamma [9] amino acids and their oligomers. Some of these approaches have recently been applied to the modulation of the conformation of macrocyclic scaffolds.O 'Hagan and co-workers have, for example, probed

“…However, incorporation of two fluoro substituents at the vicinal 2‐ and 3‐positions restricts the number of low‐energy conformations of GABA more severely due to distinct preferences for backbone conformations of the threo and erythro stereoisomers . Although such GABA analogues could be effectively used as peptide foldamers,, the four stereoisomers also showed clearly differentiated biological activity at GABA A‐C receptors, which is remarkable in view of the strong basicity lowering of the amino group by nearby fluoro substituents. Our discussion of the bicyclo[3.2.0]heptane core system adds another potentially interesting case to the list of aliphatic GABA analogues, and its use with different modes of GABA incorporation and the consequent well‐defined conformational fixation could serve as an important tool to unravel preferred interaction modes at the binding sites of target proteins.…”

Section: Resultsmentioning

confidence: 99%

Bicyclo[3.2.0]heptane as a Core Structure for Conformational Locking of 1,3‐Bis‐Pharmacophores, Exemplified by GABA

Vorberg

Trapp

Carreira

et al. 2017

The synthesis and X-ray crystal structures of syn and anti 4-N-Boc-aminobicyclo[3.2.0]heptane-1-carboxylic acids are described. The placement of the N-Boc-amino groups in the two stereoisomers in either pseudo-equatorial or pseudo-axial positions renders the molecules conformationally locked, with N-Boc-protected γ-aminobutyric acid (GABA) embedded within the bicyclic core. Despite the different conformations of the urethane and distinct crystal packing, the bicyclic core units of the two stereoisomers adopt virtually identical structures. They correspond to in silico models of the parent bicyclic core and a systematic array of disubstituted derivatives. The study documents an intrinsic property of the bicyclo[3.2.0]heptane core to favor adoption of a boat-like conformation, which is largely unaffected by various substitution patterns. The structural concepts are useful in the design of molecules with spatial and directional fixation of pharmacophoric groups.