The conformational
analysis of macrocycles is a complex and challenging
problem. There are many factors that contribute to this complexity.
These include a large number of degrees of freedom, transannular interactions
such as hydrogen bonds and hydrophobic interactions, and a range of
steric interactions, along with ring strain effects. To a greater
extent than within acyclic molecules, these interactions within macrocycles
are coupled such that changing one dihedral angle can significantly
affect other dihedral angles, further complicating the situation.
However, this coupling of bond rotations and transannular interactions
enables the transmission of three-dimensional information from one
side of a macrocycle to the other. Making relatively small structural
modifications to a macrocycle can result in local conformational changes
that propagate along the ring to affect distal structural features.
The factors that control how such changes can propagate are poorly
understood, and it is difficult to predict which modifications will
result in significant conformational reorganizations of remote regions
of a macrocycle. This review discusses examples where small structural
modifications to macrocyclic scaffolds change the conformational preferences
of structurally remote regions of the ring. We will highlight evidence
provided for conformational changes triggered by remote substituents
and explanations of how these changes might occur in an effort to
further understand the factors that control such phenomena.
Synthetic methods that provide control over macrocycle conformation represent valuable tools for the discovery of bioactive molecules. Incorporation of heterocycles into cyclic peptides may offer a way to stabilize their solution conformations. Herein, we used N-(isocyanimino)triphenylphosphorane (Pinc) to install an oxadiazole ring and an endocyclic amine into peptide macrocycles. To elucidate the conformational effect of this constellation of functionalities, we performed synthesis, variable temperature NMR analysis, and NOE-based molecular dynamics simulation of a range of macrocycles in DMSO. As part of this study, we conducted experiments to compare macrocycle conformation in aqueous and DMSO solutions. The obtained solution structures suggest that the reduced amide bond/heterocycle (RAH) motif can stabilize macrocycle conformations in both water and DMSO, which addresses an enduring challenge in molecular design. The conformational effect of the RAH was used in an effort to mimic the biologically relevant secondary structure of MAdCAM-1. This resulted in the discovery of a novel αβ integrin antagonist.
We
describe the development and use of composite two-dimensional
barriers in macrocyclic backbones. These tunable constructs derive
their mode of action from heterocyclic rearrangements. The Boulton-Katritzky
reaction has been identified as a particularly versatile means to
effect a composite barrier, allowing the examination of the influence
of heterocycle translocation on conformation. Kinetic studies using 1H NMR have revealed that the in-plane atom movement is fast
in 17, 18, 19-membered rings but slows down in 16-membered rings.
The analysis by NMR and MD simulation experiments is consistent with
the maintenance of rare cis-amide motifs during conformational
interconversion. Taken together, our investigation demonstrates that
heterocyclic rearrangement reactions can be used to control macrocyclic
backbones and provides fundamental insights that may be applicable
to the development of a wide range of other conformational control
elements.
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