Facile functionalization of polyesters through thiol-yne chemistry for the design of degradable, cell-penetrating and gene delivery dual-functional agents.
ABSTRACT: Synthesis of polyesters bearing pendant amine groups with controlled molecular weights and narrow molecular weight distributions was achieved through ring-opening polymerization of 5-(4-(prop-2-yn-1-yloxy)benzyl)-1,3-dioxolane-2,4-dione, an O-carboxyanhydride derived from tyrosine, followed by thiol-yne "click" photochemistry with 2-aminoethanethiol hydrochloride. This class of biodegradable polymers displayed excellent cell penetration and gene delivery properties with low toxicities.
Project description:The synthesis of diverse nitric oxide (NO)-releasing network polyesters is described. The melt phase condensation of polyols with a calculated excess of diacid followed by thermal curing generates cross-linked polyesters containing acid end groups. Varying the composition and curing temperatures of the polyesters resulted in materials with tunable thermal and degradation properties. Glass transition temperatures for the synthesized materials range from -25.5 to 3.2 °C, while complete degradation of these polyesters occurs within a minimum of nine weeks under physiological conditions (pH 7.4, 37 °C). Post-polymerization coupling of aminothiols to terminal carboxylic acids generate thiol-containing polyesters, with thermal and degradation characteristics similar to those of the parent polyesters. After nitrosation, these materials are capable of releasing up to 0.81 ?mol NO cm(-2) for up to 6 d. The utility of the polyesters as antibacterial biomaterials was indicated by an 80% reduction of Pseudomonas aeruginosa adhesion compared to unmodified controls.
Project description:Monomethoxy poly(ethylene glycol)-b-poly(Tyr(alkynyl)-OCA), a biodegradable amphiphilic block copolymer, was synthesized by means of ring-opening polymerization of 5-(4-(prop-2-yn-1-yloxy)benzyl)-1,3-dioxolane-2,4-dione (Tyr(alkynyl)-OCA) and used to prepare core cross-linked polyester micelles via click chemistry. Core cross-linking not only improved the structural stability of the micelles but also allowed controlled release of cargo molecules in response to the reducing reagent. This new class of core cross-linked micelles can potentially be used in controlled release and drug delivery applications.
Project description:Eight 4-carboalkoxyvalerolactones (<b>CRVL</b>s), varying in the composition of their alkyl (<b>R</b>) side chains, were synthesized from malic acid and subjected to ring-opening transesterification polymerization (ROTEP) using diphenyl phosphate [DPP, (PhO)<sub>2</sub>PO<sub>2</sub>H] as a catalyst. Each <b>CRVL</b> produced a semicrystalline poly(4-carboalkoxyvalerolactone) (<b>PCRVL</b>), and the nature of the <b>R</b> group impacted the thermal transitions of these polyesters. Bulk polymerizations at 70 °C allowed for preparation of high molar mass samples that contained small amounts of branching, as evidenced by <sup>1</sup>H NMR spectroscopy, MALDI spectrometry, size-exclusion chromatography, and eliminative degradation. Tensile testing of these lightly branched, high molar mass samples revealed that these polyesters are tough (tensile toughness values up to 88 ± 33 MJ•m<sup>-3</sup>) and have Young's moduli (<i>E</i>) up to 186 ± 13 MPa. The acid- and base-catalyzed hydrolytic degradation of the <b>PCRVL</b>s was quantitatively monitored using total organic carbon analysis, and effect of the alkyl chain length on <b>PCRVL</b> hydrolysis rate was determined. Finally, the methyl ester variant of these malic acid-derived thermoplastics is known to be chemically recyclable.
Project description:Chalcones of type 4-XC6H4C(O)CH=CHC6H4(OCH2CCH)-4, where X = Cl, Br or MeO, have been converted to the corresponding 4,5-di-hydro-pyrazole-1-carbo-thio-amides using a cyclo-condensation reaction with thio-semicarbazide. The chalcones 1-(4-chloro-phen-yl)-3-[4-(prop-2-yn-yloxy)phen-yl]prop-2-en-1-one, C18H13ClO2, (I), and 1-(4-bromo-phen-yl)-3-[4-(prop-2-yn-yloxy)phen-yl]prop-2-en-1-one, C18H13BrO2, (II), are isomorphous, and their mol-ecules are linked into sheets by two independent C-H??(arene) inter-actions, both involving the same aryl ring with one C-H donor approaching each face. In each of the products (RS)-3-(4-chloro-phen-yl)-5-[4-(prop-2-yn-yloxy)phen-yl]-4,5-di-hydro-pyrazole-1-carbo-thio-amide, C19H16ClN3OS, (IV), (RS)-3-(4-bromo-phen-yl)-5-[4-(prop-2-yn-yloxy)phen-yl]-4,5-di-hydro-pyrazole-1-carbo-thio-amide, C19H16BrN3OS, (V), and (RS)-3-(4-meth-oxy-phen-yl)-5-[4-(prop-2-yn-yloxy)phen-yl]-4,5-di-hydro-pyrazole-1-carbo-thio-amide, C20H19N3O2S, (VI), the reduced pyrazole ring adopts an envelope conformation with the C atom bearing the 4-prop-2-yn-yloxy)phenyl substituent, which occupies the axial site, displaced from the plane of the four ring atoms. Compounds (IV) and (V) are isomorphous and their mol-ecules are linked into chains of edge-fused rings by a combination of N-H?S and C-H?S hydrogen bonds. The mol-ecules of (VI) are linked into sheets by a combination of N-H?S, N-H?N and C-H??(arene) hydrogen bonds. Comparisons are made with the structures of some related compounds.
Project description:Strong, flexible, and transparent materials have garnered tremendous interest in recent years as materials and electronics manufacturers pursue devices that are bright, flexible, durable, tailorable, and lightweight. Depending on the starting components, polymers fabricated using thiol-yne chemistry have been shown to be exceptionally strong and/or flexible, while also being amenable to modification by the incorporation of nanoparticles. In the present work, novel ligands were synthesized and used to functionalize quantum dots (QDs) of various diameters. The functionalized QDs were then incorporated into thiol-yne prepolymer matrices. These matrices were subsequently polymerized to form QD thiol-yne nanocomposite polymers. To demonstrate the versatility of the fabrication process, the prepolymers were either thermally cured or photopolymerized. The resulting transparent nanocomposites expressed the size-specific color of the QDs within them when exposed to ultraviolet irradiation, demonstrating that QDs can be incorporated into thiol-yne polymers without significantly altering QD expression. With the inclusion of QDs, thiol-yne nanocomposite polymers are promising candidates for use in numerous applications including as device display materials, optical lens materials, and/or sensor materials.
Project description:The first example of an intermolecular thiol-yne-ene coupling reaction is reported for the one-pot construction of C-S and C-C bonds. Thiol-yne-ene coupling opens a new dimension in building molecular complexity to access densely functionalized products. The employment of Eosin Y/DBU/MeOH photocatalytic system suppresses hydrogen atom transfer (HAT) and associative reductant upconversion (via C-S three-electron σ-bond formation). Investigation of the reaction mechanism by combining online ESI-UHRMS, EPR spectroscopy, isotope labeling, determination of quantum yield, cyclic voltammetry, Stern-Volmer measurements and computational modeling revealed a unique photoredox cycle with four radical-involving stages. As a result, previously unavailable products of the thiol-yne-ene reaction were obtained in good yields with high selectivity. They can serve as stable precursors for synthesizing synthetically demanding activated 1,3-dienes.
Project description:Hyperbranched polyesters with a range of exterior thiol modifications were synthesized through a Michael addition thiol-ene reaction. <i>S</i>-Nitrosothiol nitric oxide (NO) donors were subsequently introduced onto the scaffolds to yield NO-releasing polyesters with total NO storage of ~2.0 μmol mg<sup>-1</sup>. Multiple decomposition pathways (i.e., use of light, copper ions, and heat) triggered <i>S</i>-nitrosothiol NO donor breakdown and NO release under physiological conditions (37 °C, pH 7.4). The NO-releasing polyesters were characterized as a function of chemical modification and scaffold size or generation. The approaches described herein expand the scope of biodegradable NO-releasing materials with large NO payloads.
Project description:Precision functionalized polyesters, with defined monomer sequences, are prepared using an orthogonal post-polymerization strategy. These polyesters can be synthesized from bio-derived monomers and are targeted to degrade, by hydrolysis processes, to biocompatible diols and diacids; the new structures enabled by this methodology would be very difficult to synthesize by alternative strategies. A series of 9 well-defined highly alternating AB-type copolyesters, containing terminal and internal alkene functionalities, are synthesized in high conversions by the ring-opening copolymerization of epoxides and cyclic anhydrides. Firstly, the polyesters are functionalized by a selective hydroboration-oxidation reaction to exclusively and quantitatively hydroxylate the terminal alkenes, leaving the alternating internal alkenes unreacted. Subsequently, the internal alkenes are quantitatively transformed into carboxylic acid, amine, alkyl and oligo-ether groups, by thiol-ene reactions, to afford AB polyesters with alternating functional substituents. Three polyesters showing alternating hydrophilic/hydrophobic side-chain sequences self-assemble in solution to form nanostructures that are characterized using transmission electron microscopy and dynamic light scattering methods (R h = 100-300 nm). The selective patterning methodology provides facile, efficient and orthogonal functionalization of alternating polyesters with near-quantitative (AB) n repeat sequences. The method is expected to be generalizable to other polymers and provides access to completely new AB alternating structures with the potential to exploit ligand multi-valency and adjacency to enhance properties.
Project description:We report herein the design, synthesis and biological evaluation of new antioxidant and neuroprotective multitarget directed ligands (MTDLs) able to block Ca<sup>2+</sup> channels. New dialkyl 2,6-dimethyl-4-(4-(prop-2-yn-1-yloxy)phenyl)-1,4-dihydropyridine-3,5-dicarboxylate MTDLs <b>3a</b>-<b>t</b>, resulting from the juxtaposition of nimodipine, a Ca<sup>2+</sup> channel antagonist, and rasagiline, a known MAO inhibitor, have been obtained from appropriate and commercially available precursors using a Hantzsch reaction. Pertinent biological analysis has prompted us to identify the MTDL 3,5-dimethyl-2,6-dimethyl-4-[4-(prop-2-yn-1-yloxy)phenyl]-1,4-dihydro- pyridine- 3,5-dicarboxylate (<b>3a</b>), as an attractive antioxidant (1.75 TE), Ca<sup>2+</sup> channel antagonist (46.95% at 10 ?M), showing significant neuroprotection (38%) against H<sub>2</sub>O<sub>2</sub> at 10 ?M, being considered thus a hit-compound for further investigation in our search for anti-Alzheimer's disease agents.