Practical polymerization of functionalized lactones and carbonates with Sn(OTf)2 in metal catalysed ring-opening polymerization methods

Stevens, David M.; Watson, Harry A.; LeBlanc, Marc-André; Wang, Ray Y.; Chou, Joanne F.; Bauer, Westley S.; Harth, Eva

doi:10.1039/c3py21119c

Cited by 16 publications

(15 citation statements)

References 25 publications

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“…Poly(α‐allyl‐valerolactone, valerolactone) containing 4% allyl groups was epoxidized with meta‐chloroperoxybenzoic acid (mcpba, 1.2 eq per alkene, Sigma) in CH 2 Cl 2 (0.065 M alkene) for 48 hours and washed with saturated sodium bicarbonate . The resulting polymer was dried under reduced pressure.…”

Section: Methodsmentioning

confidence: 99%

“…(14) Polyester nanoparticle synthesis (NP) Poly(a-allyl-valerolactone, valerolactone) containing 4% allyl groups was epoxidized with meta-chloroperoxybenzoic acid (mcpba, 1.2 eq per alkene, Sigma) in CH 2 Cl 2 (0.065 M alkene) for 48 hours and washed with saturated sodium bicarbonate. (15) The resulting polymer was dried under reduced pressure. 2,2'-ethylenedioxy-bis(ethylamine) (7.5 mL, 0.51 mmol, Sigma) was added to a solution of poly(epoxide-valerolactone, valerolactone) (0.173 g, M n ¼ 3,644 Da) dissolved in CH 2 Cl 2 (21.1 mL).…”

Section: Adenovirus Infection Of Bmscsmentioning

confidence: 99%

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Combined MEK Inhibition and BMP2 Treatment Promotes Osteoblast Differentiation and Bone Healing in Nf1Osx−/− Mice

Ndong

Stevens

Vignaux

et al. 2014

Journal of Bone and Mineral Research

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Neurofibromatosis type I (NF1) is an autosomal dominant disease with an incidence of 1/3000, caused by mutations in the NF1 gene, which encodes the RAS/GTPase-activating protein neurofibromin. Non-bone union following fracture (pseudarthrosis) in children with NF1 remains a challenging orthopedic condition to treat. Recent progress in understanding the biology of neurofibromin suggested that NF1 pseudarthrosis stems primarily from defects in the bone mesenchymal lineage and hypersensitivity of hematopoietic cells to TGFβ. However, clinically relevant pharmacological approaches to augment bone union in these patients remain limited. In this study, we report the generation of a novel conditional mutant mouse line used to model NF1 pseudoarthrosis, in which Nf1 can be ablated in an inducible fashion in osteoprogenitors of post-natal mice, thus circumventing the dwarfism associated with previous mouse models where Nf1 is ablated in embryonic mesenchymal cell lineages. An ex vivo-based cell culture approach based on the use of Nf1flox/flox bone marrow stromal cells showed that loss of Nf1 impairs osteoprogenitor cell differentiation in a cell-autonomous manner, independent of developmental growth plate-derived or paracrine/hormonal influences. In addition, in vitro gene expression and differentiation assays indicated that chronic ERK activation in Nf1-deficient osteoprogenitors blunts the pro-osteogenic property of BMP2, based on the observation that only combination treatment with BMP2 and MEK inhibition promoted the differentiation of Nf1-deficient osteoprogenitors. The in vivo preclinical relevance of these findings was confirmed by the improved bone healing and callus strength observed in Nf1osx−/− mice receiving Trametinib (a MEK inhibitor) and BMP2 released locally at the fracture site via a novel nanoparticle and polyglycidol (PEG)-based delivery method. Collectively, these results provide novel evidence for a cell-autonomous role of neurofibromin in osteoprogenitor cells and insights about a novel targeted approach for the treatment of NF1 pseudoarthrosis.

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Section: Methodsmentioning

confidence: 99%

Section: Adenovirus Infection Of Bmscsmentioning

confidence: 99%

Combined MEK Inhibition and BMP2 Treatment Promotes Osteoblast Differentiation and Bone Healing in Nf1Osx−/− Mice

Ndong

Stevens

Vignaux

et al. 2014

Journal of Bone and Mineral Research

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“…β-butyrolactone, 8,21 ε-caprolactone, 20 and trimethylene carbonate 22 polymerizations have also been achieved by indium catalysts. Although less studied, low catalyst loadings 21 and the potential range of lactone and carbonate monomers 23 make their polymerization a promising area toward finding new biodegradable polymers.…”

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confidence: 99%

High activity of an indium alkoxide complex toward ring opening polymerization of cyclic esters

Quan

Diaconescu

2015

Chem. Commun.

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Abstract. An indium complex supported by a ferrocene-derived Schiff base ligand has an unprecedented high activity toward ε-caprolactone, δ-valerolactone, and β-butyrolactone. L-lactide, D,L-lactide, and trimethylene carbonate polymerizations also showed moderate to high activity.Over the past two decades, the ring-opening polymerization of cyclic esters has been increasingly studied because of the promise to produce biodegradable polymers from biomass. In our recent studies, a cerium complex supported by a Schiff base ligand with a ferrocene backbone polymerized L-lactide in a controlled fashion. 24 Phosphinimine analogues with yttrium and indium also demonstrated good activity in lactide and trimethylene carbonate polymerizations. 22 Therefore, we decided to combine indium's activity with the Schiff base, ferrocene-derived ligand in order to study the activity of the resulting complexes toward a broad range of cyclic ester polymerizations. Additional motivation was found from recent studies that point to the biocompatibility, robustness, and high activity of indium catalysts in the ring opening polymerization of cyclic esters. 10,25 Herein, we report a ferrocene-derived Schiff base indium complex that possesses a remarkable range of activity toward cyclic esters and exceptionally fast polymerization rates with lactones. Compound (salfen)In(O t Bu) (salfen = 1,1'-di(2,4-di-tert-butyl-6-iminephenoxy)ferrocene) represents the first indium precatalyst capable of δ-valerolactone polymerization and the most active indium catalyst to date in the polymerization of β-butyrolactone and ε-caprolactone. The polymerization rates of ε-caprolactone are even competitive with those of current industrial catalysts.Compound (salfen)In(O t Bu) was synthesized from the reaction of (salfen)InCl and freshly sublimed KO t Bu. In turn, (salfen)InCl was synthesized by combining InCl3 with K2(salfen), which was generated from H2(salfen) and two equivalents of KH (Eq 1). Needle crystals of (salfen)InCl were isolated from a diethyl ether solution. The solid state molecular structure (Figure 1) shows a distorted octahedral indium center and a THF molecule coordinated trans to the chloride ligand. Similarly to the phosphinimine indium chloride analogue previously reported by us, 22 a long In-Fe distance (3.98 Å) and a staggered configuration of the Cp rings were apparent. Elongation of the In-heteroatom distances compared to other compounds, such as (salen)InCl (salen = N,N ' -bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine (rac-or (R,R)-H2(ONNO))) 9 and (phosfen)In(OPh) (phosfen = 1,1'-di(2-tert-butyl-6-diphenylphosphiniminophenoxy)ferrocene), 22 by about 0.25 Å possibly compensates for the distortion caused by the staggered Cp rings.

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“…41–44 The initiator 3-methyl-1-butanol was employed because its distinctive 1 H-NMR peaks allowed for good characterization. 45 Using a monomer concentration of 2 M, high conversion and good control over molecular weight was achieved, with Đ = 1.08, a degree of polymerization (DP) of 36, and a number average molecular weight of 5,600 Da by 1 H NMR and 5,400 by gel permeation chromatography (pCL-allyl 40 , Table 1). Initially, polymers were purified by dialysis in DCM/MeOH.…”

Section: Resultsmentioning

confidence: 99%

Substituted Polyesters by Thiol–Ene Modification: Rapid Diversification for Therapeutic Protein Stabilization

2017

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Many proteins, especially those used as therapeutics, are unstable to storage and shipping temperatures, leading to increased costs in research and industry. Therefore, the design and synthesis of novel stabilizers is an important area of investigation. Herein we report new degradable polymers that stabilize proteins to environmental stressors such as refrigeration and elevated temperature. Specifically, polycaprolactones with different pendant groups were synthesized and surveyed for their ability to stabilize an important therapeutic protein to storage and shipping conditions. Ring-opening polymerization (ROP) of an allyl-substituted caprolactone monomer was carried out using the organocatalyst 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) to yield a well-defined, alkene-substituted degradable polymer, which was used as a common backbone to control for degree of polymerization. Relevant side chains such as trehalose, lactose, glucose, carboxybetaine and oligo(polyethylene glycol) were installed via post-polymerization thiol-ene reactions. These degradable polymers were then employed as excipients for the stabilization of the therapeutic protein granulocyte colony-stimulating factor (G-CSF) against storage at 4 °C and shipping temperatures of 60 °C. The best stabilization was observed using the trehalose- and zwitterion-substituted polyesters. Both the trehalose- and carboxybetaine-substituted pCL were further investigated with regard to molecular weight dependence, and it was found that the molecular weight was minimally important for stabilization to refrigeration, but critical for G-CSF stabilization at elevated temperatures. Both high performing zwitterionic and trehalose polyesters were also degraded and the polymers and degradation products shown to be non-cytotoxic. This work provides potential biocompatible polymers for stabilization of the important therapeutic G-CSF, as well as a general platform for the future discovery of new polymeric protein stabilizers.

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Practical polymerization of functionalized lactones and carbonates with Sn(OTf)2 in metal catalysed ring-opening polymerization methods

Cited by 16 publications

References 25 publications

Combined MEK Inhibition and BMP2 Treatment Promotes Osteoblast Differentiation and Bone Healing in Nf1Osx−/− Mice

Combined MEK Inhibition and BMP2 Treatment Promotes Osteoblast Differentiation and Bone Healing in Nf1Osx−/− Mice

High activity of an indium alkoxide complex toward ring opening polymerization of cyclic esters

Substituted Polyesters by Thiol–Ene Modification: Rapid Diversification for Therapeutic Protein Stabilization

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