Cyclic Peptoids as Mycotoxin Mimics: An Exploration of Their Structural and Biological Properties

Abstract

Cyclic peptoids have recently emerged as important examples of peptidomimetics for their interesting complexing properties and innate ability to permeate biological barriers. In the present contribution, experimental and theoretical data evidence the intricate conformational and stereochemical properties of five novel hexameric peptoids decorated with N-isopropyl, N-isobutyl, and N-benzyl substituents. Complexation studies by NMR, in the presence of sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaTFPB), theoretical calculations, and single-crystal X-ray analyses indicate that the conformationally stable host/guest metal adducts display architectural ordering comparable to that of the enniatins and beauvericin mycotoxins. Similarly to the natural depsipeptides, the synthetic oligolactam analogues show a correlation between ion transport abilities in artificial liposomes and cytotoxic activity on human cancer cell lines. The reported results demonstrate that the versatile cyclic peptoid scaffold, for its remarkable conformational and complexing properties, can morphologically mimic related natural products and elicit powerful biological activities.

Macrocyclization enhances affinity of chemokine‐binding peptoids

“…To our knowledge, the only heptameric peptoid that has been reported comprised 3 bipyridine moieties in alternating positions that coordinated a ruthenium ion so that the position of the respective side chains was defined by complex formation . In analogy, the hydrophobic core and positively charged substituents of TAMRA could sequester some of the hydrophobic and negatively charged side chains while the others would face the other side of the macrocycle or assume an equatorial position.…”

The Challenge of Conformational Isomerism in Cyclic Peptoids

“…The directionality of the amide bonds (and therefore the intrinsic unlikelihood to have mirror symmetry in cyclic peptoids), combined with the rigidity of the cyclic peptoid oligomers, determines the formation enantiomorphous conformers. This is the case of asymmetric cyclohexamers 5a / 5b (i.e. : cyclo‐[( cis , p S ) N Phe 1 ‐( cis , p R ) N Val 1 ‐( trans , p R ) N Phe 2 ‐( cis , p R ) N Val 2 ‐( cis , p S ) N Phe 3 ‐( trans , p S ) N Val 3 ], cyclo‐[( cis , p R ) N Phe 1 ‐( cis , p S ) N Val 1 ‐( trans , p S ) N Phe 2 ‐( cis , p S ) N Val 2 ‐( cis , p R ) N Phe 3 ‐( trans , p R ) N Val 3 ], respectively) and of C 2 ‐symmetric octamers 6a / 6b (Figure ).…”

“…In more than ten years from the brilliant work by Kent Kirshenbaum and co‐workers, cyclic peptoids gained the status of key bioactive/biomimetic agents, efficient catalysts, promising supramolecular building‐blocks, and rigid scaffold/topological templates …”

Peptoids as tools and sensors

“…Only the derivative with the benzoyl function at the 4‐hydroxy position was shown to be a sodium ion transporter, being able to transport other, larger alkali metal cations too. Ion transportation in a range of cyclo‐hexapeptoids was put to use as a cytotoxin in human cancer cell lines, displaying cytotoxicity in A375 human melanoma; A549 human lung carcinoma and HEK293 human embryonic kidney cell lines. It was reasoned that lipophilicity plays a significant role in transmembrane ion transportation ability and that the active molecule discovered had an optimal log P = 4 (octan‐1‐ol:water partition coefficient).…”