Functional Side Chains Research Articles

Versatile N-Methylaminooxy-Functionalized Polypeptides for Preparation of Neoglycoconjugates.

The preparation and characterization of a new set of well-defined polypeptides containing N-methylaminooxy side-chain functionality is described. These functional groups enabled the direct coupling of polypeptides with a variety of unmodified reducing saccharides in water to give neoglycopolypeptides in high yields. The use of different polypeptide scaffolds resulted in neoglycoconjugates with tunable chain conformations, hydrophobicity, and charge. These new neoglycopolypeptides were also found to be stable in aqueous media at pH 7.4 and 37 °C for 1 week. The combination of straightforward synthesis using unmodified saccharides, high yields of saccharide conjugation, and conjugate stability makes these polypeptides attractive candidates for development of degradable glycoprotein mimics.

Phosphoramitoids-A submonomer approach to sequence defined N-substituted phosphoramidate polymers.

There is a growing interest in new methods to generate bio-inspired, chemically diverse, sequence-defined synthetic polymers. Solid-phase submonomer approaches offer facile access to these types of materials, since they take advantage of readily available synthons. Submonomer approaches to date have been applied to peptidomimetics with oligo-amide backbones. Here we extend the approach to a phosphorous-containing backbone, where N-substituted phosphoramidate oligomers are constructed from a set of amine submonomers, diphenyl H-phosphonate, and cyclohexane diol. The key chemical steps in chain elongation are a chain extension reaction based on H-phosphonate (P III) chemistry, and a side chain attachment step based on the Atherton-Todd reaction. Cheap, stable chemical reagents are used without heating, all reaction times are 30 minutes or less and open to air, and no main-chain protecting groups are required. Phosphoramitoid tetramers and pentamers displaying a variety of side chain functionalities were synthesized by a three-step solid-phase submonomer method, typically with >85% crude purities.

Functionalized Helical β-Peptoids.

Peptidomimetic foldamers adopting well-defined three-dimensional structures while being stable toward proteolysis are of interest in biomedical research, chemical biology, and biomimetic materials science. Despite their backbone flexibility, β-peptoids containing N-( S)-1-(1-naphthyl)ethyl ( Ns1npe) side chains can fold into unique triangular prism-shaped helices. We report herein the successful introduction of amino groups onto robustly folded β-peptoid helices by construction and incorporation of novel chiral building blocks. This is the first example of an X-ray crystal structure of a linear β-peptoid containing more than one type of side chain. We thus present a unique foldamer design comprising a robustly folded core with functionalized side chains protruding perpendicular to the helical axis to provide a highly predictable display of functional groups. This work paves the way for development of β-peptoid foldamers with a desired function, such as catalytic properties or as scaffolds enabling polyvalent display.

Conjugated Polymers with Oligoethylene Glycol Side Chains for Improved Photocatalytic Hydrogen Evolution

SummaryConjugated polymers are emerging as promising organic photocatalysts for hydrogen evolution from water. However, it is still very challenging for conjugated polymers to realize highly efficient photocatalytic hydrogen evolution. Herein, we demonstrate an efficient strategy of hydrophilic side chain functionalization to boost the hydrogen evolution rates of conjugated polymers. By functionalizing conjugated polymers with hydrophilic oligo (ethylene glycol) monomethyl ether (OEG) side chains, a 90-fold improvement in hydrogen evolution rate has been achieved than that of alkyl-functionalized conjugated polymer. It is found that the OEG side chains interact robustly with Pt co-catalysts, resulting in more efficient charge transfer. Moreover, OEG side chains in conjugated polymers can adsorb H+ from water, resulting in significantly lowered energy levels on the surfaces of conjugated polymers, which enables cascade energy levels and enhances charge separation and photocatalytic performance. Our results indicate that rational side-chain engineering could facilitate the design of improved organic photocatalysts for hydrogen evolution.

From Hierarchical Helicates to Functional Supramolecular Devices.

Catechol ligands with aldehyde, ketone or ester groups attached in 3-position form, in the presence of titanium(IV) triscatecholate, titanium(IV) complexes. If lithium cations are the counterions, they can bind in a successive step to the salicylate units of the complex and form a dimeric triple-lithium-bridged dinuclear helicate. In solution, the dimer is in equilibrium with the monomer and the thermodynamics of the dimerization can be easily evaluated. Thus, the hierarchically assembled titanium(IV) helicates represent a lithium-dependent molecular switch. The investigation of different derivatives of the complex allows for an estimation of the influence of side chain functionalities on the energetics of the dimerization. Thus, the hierarchically assembled helicates can be used as a kind of molecular balance to determine weak interaction energies (solvophobic effects and even dispersive effects). In addition, tethering of two ligands leads to "classical" helicates. Removal or addition of lithium cations allows for a reversible switching between a compressed and expanded state, which in the case of chiral ligands can be even performed stereospecifically.

Romantic Surfaces: A Systematic Overview of Stable, Biospecific, and Antifouling Zwitterionic Surfaces.

This Feature Article focuses on recent advances in the bioconjugation of surface-bound zwitterionic polymers for biospecific antifouling surfaces. Various approaches for the functionalization of antifouling zwitterionic polymers are systematically investigated, such as chain-end and side-chain functionalization. Side-chain functionalization methods can be further classified as those that are achieved through homopolymerization of custom-synthesized zwitterionic monomers equipped with reactive groups, or those that are achieved via synthesis of random or block copolymers combining different monomers with antifouling functionality and others with reactive groups. Several of the pros and cons of these approaches are outlined and discussed. Finally, some perspective and future directions of research are presented toward long-term stable, generically repelling surfaces that strongly and specifically adhere to a single component in a complex mixture.

Chemoselective, Postpolymerization Modification of Bioactive, Degradable Polymers.

Degradable polymers promote sustainability, mitigate environmental impact, and facilitate biological applications. Tailoring degradable polymers is challenging because installing functional group-rich side chains is difficult when the backbone itself is susceptible to degradation. A convenient means of side chain installation is through postpolymerization modification (PPM). In functionalizing polyoxazinones, a class of degradable polymers generated by the ring-opening metathesis polymerization (ROMP), we predictably found PPM challenging. Even the versatile azide-alkyne cycloaddition click reaction was ineffective. To solve this problem, we screened PPM reactions whose efficiencies could be assessed using photochemistry (excimer formation). The mildest, pH-neutral process was functionalization of a ketone-containing polymer to yield either oxime (acid labile)- or alkyoxylamine (stable)-substituted polymers. Using this approach, we equipped polymers with fluorophores, reporter groups, and bioactive epitopes. These modifications imbued the polymers with distinctive spectral properties and biological activities. Thus, polyoxazinones are now tunable through a modular method to diversify these macromolecules' function.

Stereochemical significance of O to N atom interchanges within cationic helicenes: experimental and computational evidence of near racemization to remarkable enantiospecificity.

Oxygen atoms of cationic dioxa and azaoxa [6]helicenes can be exchanged by amino groups to form azaoxa and diaza [6]helicenes respectively. The mild reaction conditions developed herein allow the construction of libraries of derivatives with sensitive and/or functionalized side chains. Using enantioenriched dioxa or azaoxa helicene precursors, these exchanges lead to either near racemization (es 3%) or to a remarkable enantiospecificity (es up to 97%). This unusual behavior is fully characterized via experimental and computational mechanistic evidence. Based on these investigations, the enantiospecificity of the first transformation can be improved to 57-61%.

Computational investigations of the binding mechanism of novel benzophenone imine inhibitors for the treatment of breast cancer.

4-Hydroxytamoxifen (4-OHT), the most common hormone used for the treatment of breast cancer, is a selective estrogen receptor modulator (SERM) inhibitor that acts as an antagonist in breast tissue and a partial agonist in the endometrium. However, the detailed molecular mechanism of 4-OHT structure modification has not been well investigated to date. Herein, molecular docking, molecular dynamics simulations and free energy calculations were performed to explore the mechanisms of the molecular interactions between newly designed benzophenone imines (BIs) and the three forms apo, antagonist and agonist of the human estrogen receptor hERα. The proposed inhibitors were designed by replacing the triarylethylene estrogenic scaffold found in 4-OHT with Schiff base triarylimine derivatives. The antiestrogen scaffold i.e. the O-alkyl side chain in 4-OHT was developed by incorporating an alanine amino acid side chain functionality into the triarylimine scaffold. Docking results reveal that the newly designed BIs bind to the hydrophobic open pocket of the apo and antagonist hERα conformations with higher affinity as compared to the natural and synthetic estrogen estradiol (E2) and 4-OHT. The analysis of the molecular dynamics simulation results based on six different systems of the best docked BI (5c) with hERα receptors demonstrates stable interactions, and the complex undergoes fewer conformational fluctuations in the open apo/antagonist hERα receptors as compared to the case of the closed agonist. In addition, the calculated binding free energies indicate that the main factor that contributes to the stabilization of the receptor–inhibitor complexes is hydrophobic interactions. This study suggests that the development of these Schiff base derivatives may be worth exploring for the preparation of new 4-OHT analogues.

PGM-Free ORR Catalysts Designed by Templating PANI-Type Polymers Containing Functional Groups with High Affinity to Iron

In this work, a coordination-chemistry approach was used to increase the content of nitrogen-coordinated iron moieties (Fe-Nx) in platinum group metal-free (PGM-free) catalysts for oxygen reduction reaction (ORR). The catalysts were derived from a series of polyaniline (PANI)-type precursors with N-containing functional side chains having high affinity to iron. The PGM-free ORR catalysts synthesized using such polymeric templates were characterized by scanning electron microscopy, X-ray diffractometry, and tested in an electrochemical cell and H2-air fuel cell for ORR activity. X-ray photoelectron spectroscopy (XPS) analysis showed that, in spite of similar nitrogen contents, catalysts obtained using PANI-type polymers containing side chains with high affinity to iron had higher Fe content than PANI-derived catalyst. These PGM-free catalysts showed improved ORR activity in an electrochemical cell and in H2-air fuel cell testing, compared to the PANI-derived catalyst. A correlation between the content of Fe-Nx moieties and the fuel cell performance was observed in these PGM-free ORR catalysts.

Alkali stability of anion exchange membrane

Anion exchange membrane fuel cells (AEMFCs) are attractive alternatives to proton exchange membrane fuel cells due to using non-noble metal catalysts and faster cathode reaction kinetics. Anion exchange membranes (AEMs) are one of the key materials composed of AEMFCs. The hydroxide conductivity of AEMs has been able to meet operating requirements of fuel cells. Although the hydroxide conductivity is no longer a problem, the stability of AEMs is still a notable challenge. This work mainly introduces the development of alkaline stability of AEMs. AEMs mainly consist of functional groups, side chains and polymer backbones. The degradation of functional groups causes by attacking of hydroxide ion through Hofmann elimination, nucleophilic substitution and ylide-intermediate degradation pathways. Numerous functional groups have been developed in order to improve the alkaline stability of AEMs. The introductions of appropriate electron donors and steric shielding are effective ways to weaken the attack of hydroxide ion. Developing new functional groups is a very important way. In addition, the development of novel stable groups is an important way for long-lived AEMs. For example, hetero-cycloaliphatic quaternary ammonium cations (QAs) are proved to be especially stable in both model compound studies and even AEM studies. The most commonly studied AEMs were synthesized by chloromethylation/bromination of the aromatic backbones, followed by a Menshutkin reaction to introduce QAs. Benzylic groups, electron-withdrawing groups, are prone to degrade by nucleophilic substitution on the benzylic carbon/α-carbon, Hofmann elimination and N-ylide intermediate formation in the presence of hydroxide ion. Therefore, the tethering linkage between the polymer backbone and functional groups is quite important. Recent studies have mainly introduced long side chains between functional groups and polymer backbones, leaving functional groups away from the benzene ring of the polymer backbone. The all-alkyl, amine- and ether-containing branched-chain structures are proved to be stable. Poly(arylene ether)s have been extensively studied in AEMs due to the advantages of good thermal stability, high mechanical property and easy modification. Frequently employed polyaromatic electrolytes are quaternized poly(aryl ether sulfone)s, which are prepared via the nucleophilic polycondensation reaction. The introduction of functional groups leads to degrade of these main chains containing aryl ether bonds, which are unable to avoid in the polycondensation reaction. It is necessary that main chains are devoid of aryl ether bonds so as to develop AEMs with excellent alkaline stability. Diels-Alder reaction, coupling reaction and acid-catalyzed Friedel-Craft polycondensation are effective methods for synthesizing aromatic backbones devoid of aryl ether bonds. In addition, aliphatic backbones, such as poly(ethylene-co-tetrafluoroethylene), are proved to have good stability in alkaline conditions, so its modification for AEMs has also become an important research direction. At present, the alkaline stability of AEMs has made great progress. Three major aspects have been studied in an effort to develop stable AEMs: (1) screening stable functional groups such as five- or six-membered cyclic amines, substituted imidazoles; (2) developing effective linkages between functional groups and polymer backbones; (3) designing aryl ether-free aromatic backbones and stable aliphatic backbones. The designed AEMs can remain for hundreds of hours without degradation in alkaline solution, which is a significant advancement in increasing alkaline stability of AEMs.

A bifunctional conjugated polyelectrolyte for the interfacial engineering of polymer solar cells

In this work a novel combination of side chain functionalities, alkyl-phosphonate (EP) and alkyl-ammonium bromide (NBr) groups, on a polyfluorene backbone (PF-NBr-EP) was studied as cathode interfacial material (CIM) in polymer-based solar cells. The devices were made with a conventional geometry, with PTB7:PC71 BM as active layer and aluminum as metal electrode. The CIM showed good solubility in ethanol and film forming ability onto the active layer so that its deposition could be finely tuned. The interface engineering imparted by this CIM was assessed and discussed through kelvin probe force microscopy (KPFM), impedance spectroscopy, charge recombination and electron transport characterizations. To discriminate between the interfacial modifications imparted by the interlayer and its solvent, we included in this study a surface ethanol treated device. In the optimized conditions an average power conversion efficiency of 7.24% was obtained, which is about 60% higher when compared to devices made with bare Al and 26% when compared to devices made with a standard calcium/aluminum cathode. Besides performances, some insights about the devices shelf life stability are also presented. A good persistency through aging was found for the cathode interfacial engineering capabilities of PF-NBr-EP.

Tuning the Binding Affinity and Selectivity of Perfluoroaryl-Stapled Peptides by Cysteine-Editing.

A growing number of approaches to "staple" α-helical peptides into a bioactive conformation using cysteine cross-linking are emerging. Here, the replacement of l-cysteine with "cysteine analogues" in combinations of different stereochemistry, side chain length and beta-carbon substitution, is explored to examine the influence that the thiol-containing residue(s) has on target protein binding affinity in a well-explored model system, p53-MDM2/MDMX, which is constituted by the interaction of the tumour suppressor protein p53 and proteins MDM2 and MDMX, which regulate p53 activity. In some cases, replacement of one or more l-cysteine residues afforded significant changes in the measured binding affinity and target selectivity of the peptide. Computationally constructed homology models indicate that some modifications, such as incorporating two d-cysteine residues, favourably alter the positions of key functional amino acid side chains, which is likely to cause changes in binding affinity, in agreement with measured surface plasmon resonance data.

Pyrrole-Mediated Peptide Cyclization Identified through Genetically Reprogrammed Peptide Synthesis.

Flexible in vitro translation (FIT) was used as a screening method to uncover a new methodology for peptide constraining based on the attack of a nucleophilic side-chain functionality onto an oxidized furylalanine side chain. A set of template peptides, each containing furylalanine as furan-modified amino acid and a nucleophilic residue (Cys, His, Lys, Arg, Ser, or Tyr), was produced through FIT. The translation mixtures were treated with N-bromosuccinimide (NBS) to achieve selective furan oxidation and subsequent MALDI analysis demonstrated Lys and Ser as promising residues for cyclisation. Solid-phase peptide synthesis (SPPS) was used to synthesize suitable amounts of material for further in-depth analysis and characterisation. It was found that in the case of the peptide containing lysine next to a furylalanine residue, a one-pot oxidation and reduction reaction leads to the generation of a cyclic peptide featuring a pyrrole moiety as cyclisation motif, resulting from the attack of the lysine side chain onto the oxidized furylalanine side chain. Structural evidence was provided via NMR and the generality of the methodology was explored. We hereby expand the scope of our previously developed furan-based peptide labeling and crosslinking strategy.

Design, synthesis, anti-inflammatory, cytotoxic and cell based studies of some novel side chain analogues of myrrhanones A & B isolated from the gum resin of Commiphora mukul

Myrrhanones A (1) and B (2), isolated from the gum resin of Commiphora mukul, were reported to exhibit anticancer and anti-inflammatory activities. In view of their interesting skeletal features and biological activities they have been chemically modified by exploiting their side chain functionalities to synthesise 29 diverse analogues. All the synthesized analogues were screened for their cytotoxic potential against a panel of five human cancer cell lines which include DU145 (Prostate), HT-29 (Colon), MCF-7 (Breast), Hela (Cervical) and U87MG (Glioblastoma) along with a normal cell line (L132). The synthesized analogues were also screened for anti-inflammatory activity against TNF-α and IL-1β using LPS induced inflammation model employing U937 cells. The biological screening results revealed that compounds 4b (piperidine analogue), 9d (linear aliphatic four member amide analogue) and 9i (N-methyl piperazine analogue) displayed significant cytotoxic activity against MCF-7, HT-29 and DU145 [IC50 (μM): 4.65 ± 1.28, 5.48 ± 0.13 and 6.63 ± 1.39] respectively. These analogues were further taken up for apoptotic assay, which confirmed that compounds 4b, 9d and 9i induced apoptosis in MCF-7, HT-29, DU145 cells and arrested in G0/G1 phase. Further, compounds 9c and 9g found to exhibit good anti-inflammatory activity against TNF-α with IC50 (μM) values of 10.02 ± 2.13 and 10.53 ± 0.48 respectively, while compound 2 exhibited strong inhibitory activity against both TNF-α (IC50: 9.39 ± 0.44 μM) and IL-1β (IC50: 12.15 ± 1.36 μM).

Mesomorphic and structural properties of liquid crystalline side-chain polymethacrylates: from smectic C* to columnar phases

ABSTRACTThe chiral methacrylate monomers with photosensitive azobenzene group possessing the orthogonal smectic A* and tilted smectic C* (Sm-C*) phases have been synthesised and characterised. The monomers have been used as functional side chains for the design of corresponding polymethacrylates. X-ray diffraction has been applied to elucidate the structure and phase behaviour of liquid-crystalline side-chain polymethacrylates with azobenzene-containing central core, chiral fragments and aliphatic spacers and tails of different length. X-ray patterns of polymethacrylates oriented fibres impose the tilted Sm-C* order as a basic structure of these materials. This is complemented by a regular pattern of small-angle diffuse spots, which implies complex positional order on the local scale and serves as a precursor for the formation of a columnar phase. The increase of the total length of the aliphatic tail and spacer of the side-chain fragments leads to formation of the tilted columnar phase (Coltilt*) with two-dimensional monoclinic lattice. For the polymer containing 10 methylene units in both, spacer and aliphatic tail, the Coltilt* precedes the formation of the Sm-C* phase. The observed structural changes are explained as due to coupling between the smectic ordering of the mesogenic side groups and the polymer backbone conformation.

Synthesis of poly(Nε‐phenoxycarbonyl‐l‐lysine) by polycondensation of activated urethane derivative and its application for selective modification of side chain with amines

ABSTRACTWe report a methodology for the synthesis of Nε‐phenoxycarbonyl‐protected poly(l‐lysine) on the side chain by chain growth polycondensation of Nα,Nε‐bis(phenoxycarbonyl)‐l‐lysine proceeded through the selective elimination of phenol and CO2 from the Nα phenoxycarbonyl moiety at 50 °C in N,N‐dimethylacetamide in the presence of a primary amine used as an initiator. After optimization of reaction condition, the addition of acetic acid during polycondensation proved effective for the realization of the predicted molecular weight and narrow dispersity of the corresponding polypeptide by adjusting the feed ratio of monomer to the amine initiator because of the suppression of interchain coupling that occurs between the amino terminus of poly(l‐lysine) and the Nε‐phenoxycarbonyl group on the polymer side chains. Furthermore, taking advantage of the potentially reactive Nε‐phenoxycarbonyl moiety on the side chain, post‐polymerization modification was effectively achieved by the nucleophilic reaction of amine compounds including primary, secondary, and aromatic amines through the formation of urea linkage, providing a useful platform for synthesis of selective side chain functionalization of poly(l‐lysine) samples. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018, 56, 2522–2530

Structural exploration of cinnamate-based phosphonic acids as inhibitors of bacterial ureases

The conjugated system of cinnamic acid, α-substituted with a phosphonoalkyl residue, was previously validated as a scaffold that provided one of the most potent organophosphorus inhibitors of bacterial urease. Following the idea of using Morita-Baylis-Hillman adducts to introduce the terminal phosphonic side chain functionality to the α,β-unsaturated system, we currently report the synthesis and activity of an extended series of compounds. Cinnamates modified with 3-phosphonopropyl and 4-phosphonobutyl side chains were obtained in a convenient two-step procedure, which involved Pd-mediated transformations of the Morita-Baylis-Hillman bromides as the key substrates. The introduction of a terminal alkenyl fragment, which was achieved by Stille coupling with stannanes, was followed by a tandem C-P bond formation/oxidation process. A submicromolar ligand of Sporosarcina pasteurii urease (Ki = 0.509 μM) was identified among the active molecules. In addition, inhibitors of Proteus mirabilis urease affected bacterial growth at the micromolar level. Based on the structure-activity relationship and the mechanism of inhibition, we suggest a nontypical mixed mode of action for the slow binding compounds. We presume that the molecular distance between the phosphonic group and the backbone double bond allows a dual activity: complexation of the acidic group with nickel ions and Michael addition of a cysteine forming the active site lid.

Efficient biodegradation of low-density polyethylene by cyanobacteria isolated from submerged polyethylene surface in domestic sewage water.

Two dominant cyanobacterial species, Phormidium lucidum and Oscillatoria subbrevis, isolated from submerged polyethylene carry bags in domestic sewage water were found to be capable of degrading low-density polyethylene (LDPE) sheets efficiently. The FT-IR, SEM, NMR, CHN content, thermal, and tensile strength of PE were monitored for structural, morphological, and chemical changes of PE. The CHN analysis corroborated about 4% carbon utilization by the cyanobacterial species from the PE. The rapid growth of cyanobacterial species on the PE surface suggested that the microorganisms continued to gain energy from the PE. The reduction in lamellar thickness, weight, and crystallinity of the cyanobacterial-treated PE pointed to an efficient biodegradation process without any pro-oxidant additives or pretreatment. Alteration in bond indices computed from FT-IR spectroscopy revealed changes in functional group and side chain features indicating biodegradation. The enhanced laccase and manganese peroxidase activity corroborated the biodegradation. The 13C-NMR spectroscopy of the PE is consistent with short branching providing further evidence of biodegradation. Scanning electron microscopy and optical microscopy exhibited large grooves on the surface suggesting significant disruption of polyethylene structure.

Exploring Local Disorder within CAU-1 Frameworks Using Hyperpolarized 129Xe NMR Spectroscopy.

The sorption properties of metal-organic frameworks (MOFs) can be influenced by introducing covalently attached functional side chains, which make this subclass of porous materials promising for applications as diverse as gas storage and separation, catalysis, and drug delivery. The incorporation of side groups usually comes along with disorder, as the synthesis procedures rarely allow for one specific position among a larger group of equivalent sites to be selected. For a series of isoreticular CAU-1 frameworks, chosen as model compounds, one out of four positions at every linker is modified with equal probability. Here, we investigate the influence of this disorder on Ar sorption and 129Xe nuclear magnetic resonance spectroscopy using hyperpolarized 129Xe gas. Models used for predicting the pore dimensions as well as their distributions were derived from the unfunctionalized framework by replacing one proton at every linker with either an amino, an acetamide, or a methyl urea functionality. The resulting structures were optimized using density functional theory (DFT) calculations. Results from void analyses and Monte Carlo force field simulations suggest that for available Ar nonlocal DFT (NLDFT) kernels, neither the pore dimensions nor the distributions induced by the side-chain disorder are well-reproduced. By contrast, we found the 129Xe chemical shift analysis for the shift observed at high temperature to be well-suited to develop a detailed fingerprint of the porosity and side-chain disorder within the isoreticular CAU-1 series. After calibrating the 129Xe limiting shift of the amino-functionalized framework with DFT calculations, the downfield shifts for the other two derivatives are an excellent measure for the reduction of the accessible pore space and reveal a strong preference for the side chains toward the octahedral voids for both cases. We expect that the strategy presented here can be commonly applied to disorder phenomena within MOFs in the future.