Development of Fully Degradable Phosphonium-Functionalized Amphiphilic Diblock Copolymers for Nucleic Acids Delivery.

To expand the range of functional polymer materials to include fully hydrolytically degradable systems that bear bioinspired phosphorus-containing linkages both along the backbone and as cationic side chain moieties for packaging and delivery of nucleic acids, phosphonium-functionalized polyphosphoester- block-poly(l-lactide) copolymers of various compositions were synthesized, fully characterized, and their self-assembly into nanoparticles were studied. First, an alkyne-functionalized polyphosphoester- block-poly(l-lactide) copolymer was synthesized via a one pot sequential ring opening polymerization of an alkyne-functionalized phospholane monomer, followed by the addition of l-lactide to grow the second block. Second, the alkynyl side groups of the polyphosphoester block were functionalized via photoinitiated thiol-yne radical addition of a phosphonium-functionalized free thiol. The polymers of varying phosphonium substitution degrees were self-assembled in aqueous buffers to afford formation of well-defined core-shell assemblies with an average size ranging between 30 and 50 nm, as determined by dynamic light scattering. Intracellular delivery of the nanoparticles and their effects on cell viability and capability at enhancing transfection efficiency of nucleic acids (e.g., siRNA) were investigated. Cell viability assays demonstrated limited toxicity of the assembly to RAW 264.7 mouse macrophages, except at high polymer concentrations, where the polymer of high degree of phosphonium functionalization induced relatively higher cytotoxicity. Transfection efficiency was strongly affected by the phosphonium-to-phosphate (P+/P-) ratios of the polymers and siRNA, respectively. The AllStars Hs Cell Death siRNA complexed to the various copolymers at a P+/P- ratio of 10:1 induced comparable cell death to Lipofectamine. These fully degradable nanoparticles might provide biocompatible nanocarriers for therapeutic nucleic acid delivery.

Correction: Comparison of the reactivity of ß-thiolactones and ß-lactones toward ring-opening by thiols and amines.

Correction for 'Comparison of the reactivity of ß-thiolactones and ß-lactones toward ring-opening by thiols and amines' by Amandine Noel et al., Org. Biomol. Chem., 2012, 10, 6480-6483.

Self-Reporting Degradable Fluorescent Grafted Copolymer Micelles Derived from Biorenewable Resources.

A series of hydrolytically degradable fluorescent poly(ferulic acid-co-tyrosine)-g-mPEG graft copolymers were synthesized and shown to undergo self-assembly in aqueous media to yield fluorescent micelles. The polymers and their micellar assemblies exhibited greater fluorescence emission intensity than did their small molecular building blocks, which provides a self-reporting character that has potential for monitoring the polymer integrity and also for performing in theranostics applications. The amphiphilic graft-copolymers were synthesized by Cu-assisted azide-alkyne "click" addition of azido-functionalized mPEG polymers onto fluorescent degradable hydrophobic copolymers displaying randomly distributed alkyne side-chain groups along their biorenewably derived poly(ferulic acid-co-tyrosine) backbones. The morphologies and photophysical properties of the supramolecular assemblies generated in aqueous solutions were evaluated by DLS, TEM, AFM, and steady-state optical spectroscopies. The 15-30 nm sized micelles behaved as broad-band emitters in the 350-600 nm range, which highlights their potential as self-reporting nanomaterials for in vitro studies.

Poly(ferulic acid-co-tyrosine): Effect of the Regiochemistry on the Photophysical and Physical Properties en Route to Biomedical Applications.

The photophysical and mechanical properties of novel poly(carbonate-amide)s derived from two biorenewable resources, ferulic acid (FA) and l-tyrosine ethyl ester, were evaluated in detail. From these two bio-based precursors, a series of four monomers were generated (having amide and/or carbonate coupling units with remaining functionalities to allow for carbonate formation) and transformed to a series of four poly(carbonate-amide)s. The simplest monomer, which was biphenolic and was obtained in a single amidation synthetic step, displayed bright, visible fluorescence that was twice brighter than FA. Multidimensional fluorescence spectroscopy of the polymers in solution highlighted the strong influence that regioselectivity and the degree of polymerization have on their photophysical properties. The regiochemistry of the system had little effect on the wettability, surface free energy, and Young's modulus (ca. 2.5 GPa) in the solid state. Confocal imaging of solvent-cast films of each polymer revealed microscopically flat surfaces with fluorescent emission deep into the visible region. Fortuitously, one of the two regiorandom polymers (obtainable from the biphenolic monomer in only an overall two synthetic steps from FA and l-tyrosine ethyl ester) displayed the most promising fluorescent properties both in the solid state and in solution, allowing for the possibility of translating this system as a self-reporting or imaging agent in future applications. To further evaluate the potential of this polymer as a biodegradable material, hydrolytic degradation studies at different pH values and temperatures were investigated. Additionally, the antioxidant properties of the degradation products of this polymer were compared with its biphenolic monomer and FA.

Poly(carbonate-amide)s Derived from Bio-Based Resources: Poly(ferulic acid-co-tyrosine).

Ferulic acid (FA), a bio-based resource found in fruits and vegetables, was coupled with a hydroxyl-amino acid to generate a new class of monomers to afford poly(carbonate-amide)s with potential to degrade into natural products. l-Serine was first selected as the hydroxyl-amino partner for FA, from which the activated p-nitrophenyl carbonate monomer was synthesized. Unfortunately, polymerizations were unsuccessful, and the elimination product was systematically obtained. To avoid elimination, we revised our strategy and used l-tyrosine ethyl ester, which lacks an acidic proton on the α position of the ethyl ester. Four new monomers were synthesized and converted into the corresponding poly(carbonate-amide)s with specific regioselectivities. The polymers were fully characterized through thermal and spectroscopic analyses. Preliminary fluorescent studies revealed interesting photophysical properties for the monomers and their corresponding poly(carbonate-amide)s, beyond the fluorescence characteristics of l-tyrosine and FA, making these materials potentially viable for sensing and/or imaging applications, in addition to their attractiveness as engineering materials derived from renewable resources.

Chemistry of the ß-thiolactones: substituent and solvent effects on thermal decomposition and comparison with the ß-lactones.

The synthesis of a series of di-, tri-, and tetraalkyl ß-thiolactones and ß-lactones is described as well as their thermal decomposition with extrusion of carbon oxysulfide and carbon dioxide in two solvents of opposite polarities. The ß-thiolactones are considerably more thermally stable than the ß-lactones and require higher temperatures for efficient decomposition in both solvents, whatever the degree of substitution. The results are interpreted in terms of a zwitterionic mechanism for fragmentation with a change in the rate-determining step between the two series.

Highly stereoselective synthesis of primary, secondary, and tertiary α-S-sialosides under Lewis acidic conditions.

N-acetyl 4-O,5-N-oxazolidinone protected sialyl phosphates of either anomeric configuration are excellent donors for the formation of α-S-sialosides at -78 °C in dichloromethane with primary, secondary, and tertiary thiols including galactose 3-, 4-, and 6-thiols. The reactions, which proceed under typical Lewis acid promoted glycosylation conditions, are highly α-selective and do not suffer from competing elimination of the phosphate.

Comparison of the reactivity of ß-thiolactones and ß-lactones toward ring-opening by thiols and amines.

An investigation into the comparative reactivity of simple ß-lactones and ß-thiolactones toward a thiol and a primary amine is reported. A simple 3-mercaptomethyl-2-oxetanone is found to undergo rearrangement in the presence of aqueous base to give the corresponding thietane-3-carboxylic acid rather than the 3-hydroxymethyl-2-thietanone. Implications for the use of ß-thiolactones in bioorganic and medicinal chemistry are discussed.

Stereoselective, electrophilic α-C-sialidation.

5-N-Acetyl-5-N,4-O-oxazolidinone protected α- and ß-sialyl phosphates react with allyltributylstannane and a variety of trimethylsilyl enol ethers to give α-sialyl C-glycosides in high yield and excellent selectivity. Elimination to give the 2,3-glycal is minimized by the presence of the oxazolidinone ring. The oxazolidinone ring can be subsequently cleaved under mild conditions at room temperature leaving in place the native acetamide group.

Carbonyl-inserted organo-hybrids of a Dawson-type phosphovanadotungstate: scope and chemoselective oxidation catalysis.

The Dawson-type polyoxometalate (POM) [P(2)V(3)W(15)O(62)](9-) is a prototype for inclusion of carbonyls of amides, ureas, carbamates, and thiocarbamates into polyoxometallic structures. The carbonyl-inserted POMs catalyze the oxidation of sulfides. Chemoselectivity depends primarily on the proton content of the POM, but it is also influenced by the organic substituent.