Cyclic Octamer Peptoids: Simplified Isosters of Bioactive Fungal Cyclodepsipeptides

Abstract

Cyclic peptoids have recently emerged as an important class of bioactive scaffolds with unique conformational properties and excellent metabolic stabilities. In this paper, we describe the design and synthesis of novel cyclic octamer peptoids as simplified isosters of mycotoxin depsipeptides bassianolide, verticilide A1, PF1022A and PF1022B. We also examine their complexing abilities in the presence of sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (TFPB) salt and explore their general insecticidal activity. Finally, we discuss the possible relationship between structural features of free and Na+-complexed cyclic octamer peptoids and bioactivities in light of conformational isomerism, a crucial factor affecting cyclic peptoids’ biomimetic potentials.

Cation-Induced Molecular Switching Based on Reversible Modulation of Peptoid Conformational States

“…The presence of a two-fold symmetry in conformationally stable homo-oligomers 5 and 6 was given by their 1 H NMR spectra, showing half of the expected signals (Figure ). Inspection of the side chains’ N -CH 2 Δδ (small 1 H NMR Δδ implied trans -amide junctions, larger Δδ indicated cis -peptoid bonds; see Figures S1 and S3 in the Supporting Information), literature data, ,, and density functional theory (DFT) calculations (Figure ; see Supporting Information for computational details of all the theoretically calculated structures) inferred a C 2 -symmetric structure for the ccttcctt peptoid bond sequence in both the oligomers 5 and 6 . Molecular geometry optimization revealed, for the minimum energy conformations, the expected ϕ (∼±90°) and ψ (∼180°) dihedral angles clustering ,,, due to the orthogonal CO i –1 ···C′ i O (i.e., n → π*) ,,, and CO i +1 ···C′ i O (typical of polyproline I and II helix foldings and ribbon conformation of peptoids) interactions (Figures S34 and S35 in the Supporting Information).…”

“…Of the many macrocyclic peptoids synthesized, ,, cyclo-octamer peptoids appear as the most interesting supramolecular species for two main reasons. First, the concurrent intramolecular interactions − ,,, and steric strain force the C 2 -symmetric oligoamide framework of most of the synthesized cyclo-octapeptoids in two conformationally stable enantiomorphous helical spirals (Δ G ⧧ for conformational inversion: ∼15/16 kcal mol –1 ). , Second, their excellent complexing abilities ,, make them ideal platforms to study morphological modifications modulated by ions. Trimeric ,,,, and tetrameric ,,, cyclic peptoids are too rigid as conformationally adaptable hosts (Δ G ⧧ > 19.0 kcal mol –1 ) and generally unable to complex ions, whereas cyclohexameric peptoids ,,,,,,,,− give complex mixtures of rotamers in slow equilibrium on the NMR time scale (Δ G ⧧ ≤ 14.4 kcal mol –1 ) …”

The Challenge of Conformational Isomerism in Cyclic Peptoids

“…These large cyclopeptoids, with alternating dyads of cis and trans amide bonds, reveal C 2 ‐symmetric ccttcctt backbones (ΔG ‡ for conformational inversion: ca. 15/16 kcal mol –1 ), , with ϕ and ψ torsion angles within the expected energetic minima (ϕ ≈ ±70°, ψ ≈ ±175°), as in cyclo‐( N ph‐ N ph‐ N pa‐ N me) 2 , cyclo‐( N pa 8 ), cyclo‐( N spe 8 ), a propylazido derivative, congeners of cyclodepsipeptides, cyclo‐( N me 8 ), 6a / 6b , and cyclo‐(Sar 8 ), ( 8a / 8b , Figure A). It is interesting to note that the two trans ‐amide and the two cis ‐amide bonds of the octameric backbone form independent consecutive PPII and PPI helices, justifying the surprising conformational stability of these large cyclooligomers.…”

“…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 …”

Structural Diversity of Peptoids: Tube-Like Structures of Macrocycles

“…Secondary structures can thus be induced via sequence control [ 41 , 42 ], but the scope of conformational permutations and the influence of certain side chains still have not been fully investigated. To constrain secondary structures, peptoid macrocycles of different sizes have been synthesised [ 1 , 2 , 37 , 38 , 43 , 44 , 45 , 46 , 47 , 48 ]. Among them, octameric macrocycles whose spatial structures were determined via X-ray crystallography and nuclear magnetic resonance (NMR) techniques [ 3 , 37 , 38 , 43 , 44 , 48 , 49 ].…”