Improving the Sustainability of Peptide and Polymer Chemistry

This thesis explores methods for improving the sustainability of peptide and polymer chemistry, using alternative solvents and bio-based platform molecules. Cyclic carbonates were first investigated as replacements for reprotoxic polar aprotic solvents in peptide chemistry. Using the solution-phase approach several tetrapeptides were first synthesised utilising propylene carbonate as the only reaction solvent. Good to excellent yields were observed in all cases for both coupling (65-91%) and deprotection (80-99%) steps. The use of propylene carbonate for solid-phase peptide synthesis was then demonstrated, through the total synthesis of the natural vasodilator bradykinin in an excellent 77% crude purity. Extending this work, the use of alternative solvents in solid-phase organic synthesis was then explored. The suitability of green solvents for solid-phase organic synthesis was determined by their ability to solvate polymeric supports. In all cases, a solvent was identified that was able to swell a desired resin to 4.0 mL g-1. The outcomes of this investigation were then used to build a computational model of resin swelling using the HSPiP software and verify resin/solvent compatibility through the multicomponent Ugi reaction. The second half of this thesis then explored the ring-opening metathesis polymerisation of amide derivatives of a novel oxanorbornene-lactone. A number of homo- and random co-polymers were prepared, which were found to possess good molecular weights (Mn = 10,763-28,100) and narrow dispersities (Đ = 1.02-1.11). Thermal analysis also revealed the polymers to be amorphous, possessing high thermal degradation (>300 °C) and glass transition (115-203 °C) temperatures. It was also possible to synthesise a block copolymer, but only when the second monomer was added following 80% conversion of the first monomer. Finally, kinetic data showed that the pendant side chains had a minimal influence on propagation rate (2.3×10-3 s-1 - 3.1×10-4 s-1). Finally, the synthesis and application of spirocyclic oxanorbornene-imides were investigated. These monomers were found to be unsuitable for ROMP, but LLAMA analysis showed that the hydrogenated variants were highly promising lead-like compounds. The data suggests they lay perfectly within lead-like space (-1 ≤ cLogP ≤ 3 and Mw = 200-350 Da), are fairly three-dimensional by PMI analysis and had 0% likeness to a random 2% selection of the ZINC database

Greener solvents for solid-phase synthesis

The use of a variety of green solvents to swell a diverse range of resins used in solid-phase synthesis is investigated. Good swelling is shown to depend on the structure of the resin and the solvent. A modelling approach based on use of a training set of solvents is used to predict which green solvents will, and will not, swell a particular resin. The chemical relevance of the swelling results is confirmed by an experimental study of a solid-supported Ugi reaction carried out in green solvents

Ring-opening metathesis polymerization of tertiary amide monomers derived from a bio-based oxanorbornene

Ring-opening metathesis polymerization (ROMP) of biobased oxanorbornene amides by Grubbs second generation catalyst was used to prepare a range of well-defined homo- and copolymers. A series of 11 amide monomers, featuring a variety of functionalities including amino acids and peptides, have been synthesized from a biobased oxanorbornene acid, prepared through the 100% atom economical tandem Diels–Alder lactonization between itaconic anhydride and furfuryl alcohol. The polymerization has been shown to be well-controlled, with the prepared homo- and copolymers possessing controlled molecular weights with narrow polydispersities

Comparison between the accuracy of echography and chest radiography for determining the position of the superior vena cava catheters in children

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Tuning the Cloud-Point and Flocculation Temperature of Poly(2-(diethylamino)ethyl methacrylate)-Based Nanoparticles via a Postpolymerization Betainization Approach

[Image: see text] The ability to tune the behavior of temperature-responsive polymers and self-assembled nanostructures has attracted significant interest in recent years, particularly in regard to their use in biotechnological applications. Herein, well-defined poly(2-(diethylamino)ethyl methacrylate) (PDEAEMA)-based core–shell particles were prepared by RAFT-mediated emulsion polymerization, which displayed a lower-critical solution temperature (LCST) phase transition in aqueous media. The tertiary amine groups of PDEAEMA units were then utilized as functional handles to modify the core-forming block chemistry via a postpolymerization betainization approach for tuning both the cloud-point temperature (T(CP)) and flocculation temperature (T(CFT)) of these particles. In particular, four different sulfonate salts were explored aiming to investigate the effect of the carbon chain length and the presence of hydroxyl functionalities alongside the carbon spacer on the particle’s thermoresponsiveness. In all cases, it was possible to regulate both T(CP) and T(CFT) of these nanoparticles upon varying the degree of betainization. Although T(CP) was found to be dependent on the type of betainization reagent utilized, it only significantly increased for particles betainized using sodium 3-chloro-2-hydroxy-1-propanesulfonate, while varying the aliphatic chain length of the sulfobetaine only provided limited temperature variation. In comparison, the onset of flocculation for betainized particles varied over a much broader temperature range when varying the degree of betainization with no real correlation identified between T(CFT) and the sulfobetaine structure. Moreover, experimental results were shown to partially correlate to computational oligomer hydrophobicity calculations. Overall, the innovative postpolymerization betainization approach utilizing various sulfonate salts reported herein provides a straightforward methodology for modifying the thermoresponsive behavior of soft polymeric particles with potential applications in drug delivery, sensing, and oil/lubricant viscosity modification

Synthesis of cytotoxic spirocyclic imides from a biomass-derived oxanorbornene

N-Substituted derivatives of cantharimide and norcantharimide represent a promising but underutilized motif for therapeutic applications. Herein, we report a divergent strategy for the preparation of secondary amides and norcantharimide-resembling spirocyclic imides from a biomass-derived oxanorbornene and assess their biological activity. Computational modelling suggests these compounds fall perfectly within lead-like chemical space (200 Da < RMM < 350 Da, −1 < AlogP < 3), with the spirocyclic imides preferred due to their lack of reactive functionalities. Biological analysis of the spirocyclic imides revealed that the compounds displayed antiproliferative activity against a range of human cancer cells (A549, HCT 116, OVCAR-3, MDA-MB-231, MCF7 and PC-3) with the N-octyl derivative displaying the greatest potential as a potent broad-spectrum anticancer drug. Dose-response curves for the N-octyl spirocyclic imide found EC50 values of 56–95 μM dependent on the cell line, with highest activity against human colorectal carcinoma cells (HCT 116)

The greening of peptide synthesis

The synthesis of peptides by amide bond formation between suitably protected amino acids is a fundamental part of the drug discovery process. However, the required coupling and deprotection reactions are routinely carried out in dichloromethane and DMF, both of which have serious toxicity concerns and generate waste solvent which constitutes the vast majority of the waste generated during peptide synthesis. In this work, propylene carbonate has been shown to be a green polar aprotic solvent which can be used to replace dichloromethane and DMF in both solution- and solid-phase peptide synthesis. Solution-phase chemistry was carried out with Boc/benzyl protecting groups to the tetrapeptide stage, no epimerisation occurred during these syntheses and chemical yields for both coupling and deprotection reactions in propylene carbonate were at least comparable to those obtained in conventional solvents. Solid-phase peptide synthesis was carried out using Fmoc protected amino acids on a ChemMatrix resin and was used to prepare the biologically relevant nonapeptide bradykinin with comparable purity to a sample prepared in DMF