Synthesis and Operating Optimization of the PEG Conjugate via CuAAC in scCO₂

Abstract

A new sustainable green protocol for obtaining polyethylene glycol (PEG) conjugates, with a prototype molecule, which in this work was coumarin, by means of click chemistry is presented. The organic solvents commonly used for this type of reaction were replaced by supercritical carbon dioxide (scCO2). The synthesis and characterization of PEG-coumarin were successfully reported using FTIR, 1H NMR, and MALDI TOF. Subsequently, a preliminary study was carried out using the response surface methodology to examine the variables that most affect the use of scCO2 as a reaction medium. The main effects caused by these variables, individually and their binary interaction, have been estimated. The response surface methodology has been used in this work to screen variables using a factorial design 23. The p-values of temperature and pressure were 0.006 and 0.0117, being therefore the most significant variables of the response surface methodology study. Subsequently, a more intensive study has been carried out on the variables that have shown the greatest significant effect on reaction performance where an 82.32% synthesis success was achieved, which broadens the scope of the use of scCO2 as a reaction medium. The conjugated coumarin with mPEG-alkyne and coumarin were evaluated for their in vitro antioxidant activities by the DPPH radical scavenging assay and were found to exhibit substantial activities. The click product showed comparable or even better efficacy than the initial coumarin.

Self-assembled coumarin- and 5-fluorouracil-PEG micelles as multifunctional drug delivery systems

“…1-Azido-5-bromopentane (ABrP) was prepared according to a literature procedure [25,26]. 4-Azidomethyl-7-methoxycoumarin (AMMC) was prepared as described elsewhere by some of us [27]. All other chemicals used for this study were provided by domestic suppliers and were analytical grade.…”

Copper-Containing Catalysts for Azide–Alkyne Cycloaddition in Supercritical CO2

“…However, Cu(CH 3 COO) 2 •H 2 O exhibited an efficient behavior in the same operative reactions conditions and with half the amount of catalyst. The C/A molar ratio of Cu(CH 3 COO) 2 •H 2 O was optimized in a previous work [35] and was therefore set at a ratio of 0.5. The molar ratio for CuBr was one.…”

“…This conjugate can be used in pharmaceutical applications, as it was found to be able to form nanoaggregates to form micelles and exhibits anti-oxidative capacity and fluorescent characteristics for monitoring of disease treatment provided by coumarin [34]. Optimal conditions of pressure and temperature of scCO 2 for the CuAAC reaction were fixed after the previous optimization study [35]. Both homogeneous and heterogeneous catalysts were considered for this work.…”

“…The homogeneous catalysts selected were CuBr and Cu(CH 3 COO) 2 •H 2 O and the heterogeneous catalysts were Cu Wire, a Cu Plate, Cu/β-SiC, Pre-treated Cu Wire and a Pre-treated Cu Plate. Silicon carbide pellets (β-SiC) have been widely employed as catalytic support for heterogeneous catalysis, as they exhibit a high thermal conductivity, a high resistance to oxidation, a high mechanical strength, chemical inertness, and average surface area [35][36][37]. In addition, this work also reports the reusability of the tested catalyst after several cycles in the CuAAC reaction in scCO 2 .…”

“…after the previous optimization study [35]. Both homogeneous and heterogeneous ca lysts were considered for this work.…”