Tertiary-Butylbenzene Functionalization as a Strategy for β-Sheet Polypeptides

Abstract

β-Sheet forming polypeptides are one of the least explored synthetic systems due to their uncontrolled precipitation in the ring-opening polymerization (ROP) synthetic methodology. Here, a new t-butylbenzene functionalization approach is introduced to overcome this limitation by sterically controlling the propagating polymer chains, and homogeneous polymerization with good control over chain growth was accomplished. New bulky N-carboxyanhydride monomers were designed having t-butylbenzene pendant by multistep organic synthesis, and N-heterocyclic carbene was explored as a catalyst to make high-molecular-weight and narrow polydisperse soluble polypeptides. This ROP process was successfully demonstrated for two β-sheet forming polypeptides such as poly­(l-serine) and poly­(l-cysteine). These new t-butylbenzene-functionalized polypeptides were found to be readily soluble in tetrahydrofuran, chloroform, and so forth, and they were produced in high molecular weights having M n = 32 kDa with dispersity D̵ ≤ 1.3. ROP kinetics were studied by real-time Fourier transform infrared and 1H NMR to determine the actual content of the secondary structures in the propagating chains. These studies established that the α-helical conformational front in the propagation chain was speeding up the polymerization kinetics with good degree of control in the ROP process. Reversible-conformational transitions in the post-polymerization deprotection were found to restore the β-sheet secondary structures in poly­(l-serine)­s. The newly developed t-butylbenzene-substituted steric-hindrance approach is valuable in yielding soluble polymers, and this approach could be useful for exploring new polypeptide architectures for long-term impact.

Comparison of Thermoresponsive Behavior between Polyproline and Periodically Grafted Polyproline toward Hofmeister Ions: An Explanation of Its Conformational Origin

“…21 In a recent work, Nisal and coworkers demonstrated a steric bulk functionalization strategy for the synthesis of high molecular weight β-sheet forming polypeptides. 33 Few years ago, Kumin and co-workers identified the mechanism by which side-chain functional groups in oligopolyprolines stabilize biologically relevant PPII conformations. 34 In comparison with all other homopolypeptides, polyproline is unique for its strained cyclic side chain and lack of N−H amide group.…”

“…Following this, researchers explored the possibility of attaching non-natural residues as side chains to control the secondary structure and function of the polypeptide. − For example, Song and co-workers modified the secondary structure of poly­( l -glutamic acid) by incorporating donor–acceptor H-bonding ligands in the side chains that had interesting cell-penetrating properties . In a recent work, Nisal and co-workers demonstrated a steric bulk functionalization strategy for the synthesis of high molecular weight β-sheet forming polypeptides . Few years ago, Kümin and co-workers identified the mechanism by which side-chain functional groups in oligopolyprolines stabilize biologically relevant PPII conformations …”

Poly(l-alanine-co-l-threonine succinate) as a Biomimetic Cryoprotectant

“…The FTIR peaks centered at 1620 and 1560 cm −1 are from the carbonyl stretching of β-sheet peptides and carboxylate of PATs, respectively. 38,39 The absorbance of carboxylate peaks centered at 1560 cm −1 relative to that of peptide peaks at 1620 cm −1 was in the order of PATs-4 ∼ PATs-2>PATs-3>PATs-1, which was correlated to the degree of succinylation (Figure 4a). The absorbance of peaks centered at 1620 cm −1 relative to that of carboxylate peaks at 1560 cm −1 was in the order of PATs-1> PATs-3> PATs-4>PATs-2, which was also well correlated with the magnitude of the ellipticity centered at 223−226 nm of the CD spectra, indicating that the negative CD bands come from β-sheet conformation (Figure 4b).…”

Melt Polycondensation Strategy for Amide-Functionalized l-Aspartic Acid Amphiphilic Polyester Nano-assemblies and Enzyme-Responsive Drug Delivery in Cancer Cells

“…The deuterated chloroform was used as solvent and trimethylsilane was used as internal standard; the residual proton peak appears at 7.26 ppm. Monomers and polymers were characterized using the following analytical instruments: HRMS-ESI-Q-time of flight LCMS, Applied Biosystems 4800 PLUS MALDI TOF, ATR-FTIR, and Viscotek size exclusion chromatography in the THF RI detector (Viscotek columns T6000M), as reported earlier . TA Q20 Differential Scanning Calorimeter and PerkinElmer thermal analyzer were used for the analysis of thermal decomposition and thermal phase transitions ( T g , T m and T c ) at 10 °C/min under a nitrogen atmosphere as reported earlier .…”

“…l -Amino acids are natural bio-derived monomers associated with significant structural diversity to help in the design and development of biodegradable polymers. ,, ROP of N-carboxylic anhydride monomers is one of the most studied synthetic strategies to build α-helical − and β-sheet polypeptides , and their block copolymers. l -Amino acids were converted into α-hydroxy acids, and their cyclic monomers were subjected to ROP to produce poly­(α-hydroxy acid)­s. , The polycondensation strategy has been reported to build non-peptide polymer analogues from l -amino acid resources such as poly­(ester-amide)­s, − poly­(acetal-urethane)­s, poly­(disulfide-urethane)­s, poly­(disulfide amide)­s, polycarbonates, − and poly­(ester-urea-urethanes) .…”