Related Experiment Video
Updated: Aug 4, 2025
11:09
Constructing Thioether/Vinyl Sulfide-tethered Helical Peptides Via Photo-induced Thiol-ene/yne Hydrothiolation
Published on: August 1, 2018
10.8K
Conformationally Controlled sp3 -Hydrocarbon-Based α-Helix Mimetics.
Lydia I Dewis1, Madhavachary Rudrakshula1, Christopher Williams1
1School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, UK.
Angewandte Chemie (International Ed. in English)
|April 5, 2023
Summary
Researchers developed novel hydrocarbon scaffolds that mimic alpha-helices, offering a new strategy for drug discovery. These conformationally controlled molecules show promise as therapeutic agents by inhibiting protein-protein interactions.
Area of Science:
- Medicinal Chemistry
- Organic Synthesis
- Structural Biology
Background:
- Alpha-helices are crucial in protein-protein interactions, making alpha-helix mimetics a key therapeutic strategy.
- Controlling the conformation of mimetics is essential for maximizing efficacy but current methods are often restrictive.
- Nature utilizes syn-pentane interactions to control conformation, but this is synthetically challenging for lead optimization.
Purpose of the Study:
- To develop a novel synthetic strategy for creating conformationally defined alpha-helix mimetics.
- To explore the use of alternating syn-anti configured hydrocarbons to mimic alpha-helical structures.
- To demonstrate the therapeutic potential of these novel scaffolds in drug discovery.
Main Methods:
- Assembly-line synthesis of contiguously substituted hydrocarbons.
- Nuclear Magnetic Resonance (NMR) spectroscopy for structural analysis.
- Computational analysis to understand conformational preferences.
- Design and testing of a p53 mimetic targeting Mdm2.
Main Results:
- Alternating syn-anti hydrocarbons adopt well-defined conformations by avoiding syn-pentane interactions.
- These scaffolds successfully present functional groups in an alpha-helix-mimicking arrangement.
- A p53 mimetic demonstrated moderate to good binding affinity to Mdm2.
Conclusions:
- Novel hydrocarbon scaffolds offer a synthetically accessible route to conformationally controlled alpha-helix mimetics.
- These findings present a promising new class of molecules for therapeutic intervention in diseases involving protein-protein interactions.
- The developed scaffolds hold significant therapeutic promise, exemplified by the p53-Mdm2 interaction inhibitor.
Related Concept Videos
02:02Chair Conformation of Cyclohexane
14.8K
The chair conformation is the most stable form of cyclohexane due to the absence of angle and torsional strain. The absence of angle strain is a result of cyclohexane’s bond angle being very close to the ideal tetrahedral bond angle of 109.5° in its chair conformer. Similarly, the torsional strain is also absent owing to the perfectly staggered arrangement of bonds.
The hydrogen atoms linked to carbons are arranged in two different axial and equatorial orientations to achieve this...
The hydrogen atoms linked to carbons are arranged in two different axial and equatorial orientations to achieve this...
14.8K
00:52¹H NMR of Conformationally Flexible Molecules: Temporal Resolution
893
At room temperature, the chair conformer of cyclohexane undergoes rapid ring flipping between two equivalent chair conformers at a rate of approximately 105 times per second. These two chair conformers are in equilibrium. The rapid ring flipping results in the interconversion of the axial proton to an equatorial proton and an equatorial to the axial proton. Such interconversions are too rapid and cannot be detected on the NMR timescale. Hence, the NMR spectrometer cannot distinguish between the...
893
02:11Conformations of Cyclohexane
12.7K
Cyclohexane does not exist in a planar form due to the high angle and torsional strain it would experience in the planar structure. Instead, it adopts non-planar chair and boat conformations.
The chair form is the most stable and derives its name from its resemblance to the “easy chair.” In the chair conformation, two carbon atoms are arranged out-of-plane — one above and one below, minimizing the torsional strain. In the chair form, the bond angle is very close to the ideal...
The chair form is the most stable and derives its name from its resemblance to the “easy chair.” In the chair conformation, two carbon atoms are arranged out-of-plane — one above and one below, minimizing the torsional strain. In the chair form, the bond angle is very close to the ideal...
12.7K
02:18Conformations of Ethane and Propane
14.1K
In an organic molecule, free rotation about the carbon-carbon single bond results in energetically different conformers of the molecule. Due to this rotation, called the internal rotation, ethane has two major conformations — staggered and eclipsed.
Staggered conformation is a low energy and more stable conformation with the C-H bonds on the front carbon placed at 60°dihedral angles relative to the C-H bonds on the back carbon, leading to a reduced torsional strain. In staggered...
Staggered conformation is a low energy and more stable conformation with the C-H bonds on the front carbon placed at 60°dihedral angles relative to the C-H bonds on the back carbon, leading to a reduced torsional strain. In staggered...
14.1K
01:15¹H NMR of Conformationally Flexible Molecules: Variable-Temperature NMR
1.1K
The axial and equatorial protons in cyclohexane can be distinguished by performing a variable-temperature NMR experiment. In this process, except for one proton, the remaining eleven protons are replaced by deuterium. The deuterium substitution avoids the possible peak splitting caused by the spin-spin coupling between the adjacent protons. The remaining proton flips between the axial and equatorial positions.
1.1K
02:30Stability of Substituted Cyclohexanes
12.7K
This lesson discusses the stability of substituted cyclohexanes with a focus on energies of various conformers and the effect of 1,3-diaxial interactions.
The two chair conformations of cyclohexanes undergo rapid interconversion at room temperature. Both forms have identical energies and stabilities, each comprising equal amounts of the equilibrium mixture. Replacing a hydrogen atom with a functional group makes the two conformations energetically non-equivalent.
For example, in...
The two chair conformations of cyclohexanes undergo rapid interconversion at room temperature. Both forms have identical energies and stabilities, each comprising equal amounts of the equilibrium mixture. Replacing a hydrogen atom with a functional group makes the two conformations energetically non-equivalent.
For example, in...
12.7K