TY - JOUR

T1 - Increasing the Functional Group Diversity in Helical beta-Peptoids

T2 - Achievement of Solvent- and pH-Dependent Folding

AU - Wellhofer, Isabelle

AU - Beck, Janina

AU - Frydenvang, Karla

AU - Brase, Stefan

AU - Olsen, Christian A.

PY - 2020

Y1 - 2020

N2 - We report the synthesis of a series of bis-functionalized beta-peptoid oligomers of the hexamer length. This was achieved by synthesizing and incorporating protected amino- or azido-functionalized chiral building blocks into precursor oligomers by a trimer segment coupling strategy. The resulting hexamers were readily elaborated to provide target compounds displaying amino groups, carboxy groups, hydroxy groups, or triazolo-pyridines, which should enable metal ion binding. Analysis of the novel hexamers by circular dichroism (CD) spectroscopy and H-1-C-13 heteronuclear single quantum coherence nuclear magnetic resonance (HSQC NMR) spectroscopy revealed robust helical folding propensity in acetonitrile. CD analysis showed a solvent-dependent degree of helical content in the structural ensembles when adding different ratios of protic solvents including an aqueous buffer. These studies were enabled by a substantial increase in solubility compared to previously analyzed beta-peptoid oligomers. This also allowed for the investigation of the effect of pH on the folding propensity of the amino- and carboxy-functionalized oligomers, respectively. Interestingly, we could show a reversible effect of sequentially adding acid and base, resulting in a switching between compositions of folded ensembles with varying helical content. We envision that the present discoveries can form the basis for the development of functional peptidomimetic materials responsive to external stimuli.

AB - We report the synthesis of a series of bis-functionalized beta-peptoid oligomers of the hexamer length. This was achieved by synthesizing and incorporating protected amino- or azido-functionalized chiral building blocks into precursor oligomers by a trimer segment coupling strategy. The resulting hexamers were readily elaborated to provide target compounds displaying amino groups, carboxy groups, hydroxy groups, or triazolo-pyridines, which should enable metal ion binding. Analysis of the novel hexamers by circular dichroism (CD) spectroscopy and H-1-C-13 heteronuclear single quantum coherence nuclear magnetic resonance (HSQC NMR) spectroscopy revealed robust helical folding propensity in acetonitrile. CD analysis showed a solvent-dependent degree of helical content in the structural ensembles when adding different ratios of protic solvents including an aqueous buffer. These studies were enabled by a substantial increase in solubility compared to previously analyzed beta-peptoid oligomers. This also allowed for the investigation of the effect of pH on the folding propensity of the amino- and carboxy-functionalized oligomers, respectively. Interestingly, we could show a reversible effect of sequentially adding acid and base, resulting in a switching between compositions of folded ensembles with varying helical content. We envision that the present discoveries can form the basis for the development of functional peptidomimetic materials responsive to external stimuli.

KW - SOLID-PHASE SYNTHESIS

KW - ASYMMETRIC-SYNTHESIS

KW - CHIRAL AMINES

KW - SIDE-CHAIN

KW - CIRCULAR-DICHROISM

KW - FOLDAMERS

KW - PEPTIDE

KW - BACKBONE

KW - SUBSTITUENTS

KW - STABILITY

U2 - 10.1021/acs.joc.0c00780

DO - 10.1021/acs.joc.0c00780

M3 - Journal article

C2 - 32806085

VL - 85

SP - 10466

EP - 10478

JO - Journal of Organic Chemistry

JF - Journal of Organic Chemistry

SN - 0022-3263

IS - 16

ER -