Structure – Bioactivity Relationship in Cyclic Peptoids: An Overview

Abstract

Cyclic N‐substituted glycines oligomers, also known as cyclic peptoids, constitute a promising class of novel peptidomimetics, capable of simulating bioactive effectors with enhanced proteolytical stability and cell permeability as crucial bonuses. The macrocyclic constraint, essential for the induction of stable secondary structures, determines the biomimetic potential of such molecules, which act as antimicrobials, cytotoxic agents, siderophores, glycosidases inhibitors and so on. The bioactivity can be either attributed to the macrocyclic core (especially chelation) or to the side‐chains (when endowed with specific groups or pharmacophores). The structure‐bioactivity correlations emerging for this class of peptidomimetics, based on the study of conformational order and morphology of the backbone architecture, unravel interesting avenues for the rational design of more effective cyclooligomeric biomimics.

Water-Soluble Chiral Cyclic Peptoids and Their Sodium and Gadolinium Complexes: Study of Conformational and Relaxometric Properties

“…Peptoid macrocycles (N-substituted glycine cyclooligomers) make up an emerging family of peptidomimetics that hold substantial promise for application in biomedicine 1,2 due to their straightforward synthesis, 3,4 vast chemical diversity, and unique structural attributes. 5−7 Efforts to control their conformation have been plagued by the weak intramolecular hydrogen bond network 8 and fast cis/ trans tertiary amide interconversion.…”

“…This result is consistent with our previous finding that it is extremely difficult to achieve the cyclization of tetrameric peptoids bearing all four α-branched side chains. 17 Finally, our designs included the formation of Gd 3+ ion complexes with 2, 4, and 6 hexamer peptoids as we planned 1 H relaxometric investigations to assess their thermodynamic stabilities and relaxivities. This aspect of our study is a continuation of our search for new magnetic resonance imaging (MRI) agents based on cyclic oligoamides.…”

“…[5•9Na] + :1 H NMR (400 MHz, 0.1 M deuterated NaH 2 PO 4 /Na 2 HPO 4 buffer at pH 8.0, single conformational isomer) δ 4.50−3.71 (24H, overlapping signals, 8 × CH 2 and 8 × CH), 1.29 (12H, d, J = 7.1 Hz, CH 3 ), 1.21 (12H, d, J = 7.1 Hz, CH 3 ); 13 C{ 1 H} NMR (150 MHz, 0.1 M deuterated NaH 2 PO 4 / Na 2 HPO 4 buffer at pH 8.0, single conformational isomer) δ 4 × 180.1 (COONa), 4 × 178.8 (COONa), 4 × 171.5 (C�OCH 2 N), 4 × 170.7 (C�OCH 2 N), 8 × 58.2 (NCHCH 3 ), 8 × 55.9 (C�OCH 2 N), 4 × 16.4 (NCHCH 3 ), 4 × 15.2 (NCHCH 3 ); HRMS (MALDI/FTICR) m/z [M + K] + calcd for C 40 H 56 N 8 O 24 K + 1071.3039, found 1071.3125; α D 25 −142.1 (c 0.79, 0.1 M deuterated NaH 2 PO 4 /Na 2 HPO 4 buffer at pH 8.0).…”

“…[7•9Na] + :1 H NMR (600 MHz, 0.1 M deuterated NaH 2 PO 4 /Na 2 HPO 4 buffer at pH 8.0, single conformational isomer) δ ∼4.70 (signal hidden under the HDO signal, 8H, CHH), 4.32 (8H, q, J = 7.0 Hz, CHCH 3 ), 3.72 (8H, d, J = 17.4 Hz, CHH), 1.24 (24H, d, J = 7.0 Hz, CHCH 3 );13 C{ 1 H} NMR (150 MHz, 0.1 M deuterated NaH 2 PO 4 /Na 2 HPO 4 buffer at pH 8.0) δ 8 × 178.7 (C�OONa), 8 × 171.6 (C�O), 8 × 57.6 (NCHCH 3 ), 8 × 46.3 (CH 2 ), 8 × 15.9 (NCHCH 3 ); HRMS (MALDI/FTICR) m/z [M + K] + calcd for C 40 H 56 N 8 O 24 K + 1071.3039, found 1071.2938; α D 25 −202 (c 0.53, 0.1 M deuterated NaH 2 PO 4 /Na 2 HPO 4 buffer at pH 8.0). X-ray Crystallographic Studies of [1•2K].…”

Macrocyclic Triazolopeptoids: A Promising Class of Extended Cyclic Peptoids

“…), scant synthetic effort has been devoted to sequence-defined oligomerization processes . A modular accretion of bifunctional monomers is instead adopted for the synthesis of cyclic peptoids (cyclic oligomers of N-substituted glycines), , a growing class of biomimetic compounds with enormous potential in catalysis, in material chemistry, as bioactive agents, , and as precursors of azamacrocycles . The versatility of their synthetic method allows ample structural flexibility and facile introduction of rigid aromatic spacers into the peptoid oligoamide backbone, producing the valuable “extended peptoids”, , with excellent conformational properties , (despite the absence of intramolecular H-bonding) and metal chelating abilities …”