Metal-Binding Q-Proline Macrocycles

Abstract

Herein, we introduce the efficient synthesis of Q-proline (Q-Pro) based, metal-binding macrocycles (QPM), which can display up to nine functional groups. Synthesis of eight QPM was achieved through standard Fmoc-SPPS and peptoid chemistry. QPM are disordered in the absence of a metal cation, as evidenced by NMR and a crystal structure of QPM-3 obtained through racemic crystallization. Addition of metal cations cause these macrocycles to adopt ordered, uniform core structures regardless of the functional groups. Alkylation of QPM allows for addition of reactive functional groups as the final step in a synthesis. Interestingly, the addition of secondary functional groups to the hydantoin amide position (R2) converts the proline ring from C-endo to C-exo, due to steric interactions. 27 Pro 3-2 60 No >98 28 3-4 60 Yes 50 29 3-4 60* Yes >98 QP9 QP9 30 3-4 60* Yes >98 QP15

Metal Cation-Binding Mechanisms of Q-Proline Peptoid Macrocycles in Solution

“…Three spiroligomer-peptoid macrocycle sequences from Northrup et al were studied in this work; all are 3-fold symmetric (Figure ). Two of the sequences, QPM-1 and QPM-3, were found to bind metal cations in solution.…”

“…1 H NMR spectra were measured as described in Northrup et al The complex spectra of peptoid macrocycles in solution in the absence of metal cations suggest several slowly interconverting conformations of the macrocycle at equilibrium. In contrast, spectra that were measured for macrocycles in the presence of 100 mM of monovalent trifluoromethylsulfonate (triflate) salts show a remarkable structuring in solution over the course of 12 h. These NMR experiments were performed with data collection every 3 min for the first 90 min, followed by every half hour up to 300 min, at which point the peaks had largely converged.…”

“…Recently, a new class of peptoid-spiroligomer macrocycle has been synthesized and characterized . Particular sequences were found to acquire remarkable preorganization in the presence of monovalent cations, as seen by monitoring one-dimensional (1D) NMR spectra over time.…”

“…Northrup et al have recently synthesized cyclic hexamers of spiroligomer-peptoid hybrids that can bind monovalent metal cations (Figure ). The architecture of the macrocycle is highly functionalizable, with alternating spiroligomer and peptoid residues. The portion of spiroligomer residues participating in the macrocycle backbone resembles a β-substituted proline, which has led to these structures being called “enhanced prolines” or “Q-prolines,” while complete macrocycles are named “Q-proline macrocycles” (QPM).…”

Reconciling Simulations and Experiments With BICePs: A Review

“…More recently, this approach was used to determine the solution-state structure and ion-binding mechanism of cyclic peptoid-spiroligomer hexamer macrocycles (Hurley et al, 2021 ). Northrup et al found that particular sequences of alternating Q-proline and peptoid residues are able to bind metal cations, forming highly preorganized structures in the process (Northrup et al, 2020 ). To model this process, the BICePs algorithm was used to reconcile conformational populations from implicit-solvent REMD simulations in GAFF, against sparse experimental ROESY correlations.…”