Hydrogen Sulfide Delivery to Enhance Bone Tissue Engineering Cell Survival.

Though crucial for natural bone healing, local calcium ion (Ca2+) and phosphate ion (Pi) concentrations can exceed the cytotoxic limit leading to mitochondrial overload, oxidative stress, and cell death. For bone tissue engineering applications, H2S can be employed as a cytoprotective molecule to enhance mesenchymal stem cell (MSC) tolerance to cytotoxic Ca2+/Pi concentrations. Varied concentrations of sodium hydrogen sulfide (NaSH), a fast-releasing H2S donor, were applied to assess the influence of H2S on MSC proliferation. The results suggested a toxicity limit of 4 mM for NaSH and that 1 mM of NaSH could improve cell proliferation and differentiation in the presence of cytotoxic levels of Ca2+ (32 mM) and/or Pi (16 mM). To controllably deliver H2S over time, a novel donor molecule (thioglutamic acid-GluSH) was synthesized and evaluated for its H2S release profile. Excitingly, GluSH successfully maintained cytoprotective level of H2S over 7 days. Furthermore, MSCs exposed to cytotoxic Ca2+/Pi concentrations in the presence of GluSH were able to thrive and differentiate into osteoblasts. These findings suggest that the incorporation of a sustained H2S donor such as GluSH into CaP-based bone graft substitutes can facilitate considerable cytoprotection, making it an attractive option for complex bone regenerative engineering applications.

Synthesis of 3-(Arylsulfonyl)-3-pyrrolines from Allenyl Sulfonamides by Silver Ion Catalysis.

Treatment of allenyl sulfonamides with catalytic amounts of silver fluoride in acetonitrile at reflux afforded the corresponding 3-sulfonyl-3-pyrrolines in excellent yields by intramolecular hydroamination via a 5- endo-trig cyclization. The starting allenyl sulfonamides were prepared by lithiation of allenic sulfones and trapping with various N-sulfonylimines.

Aptamer-displaying peptide amphiphile micelles as a cell-targeted delivery vehicle of peptide cargoes.

Peptide amphiphile micelles (PAMs) are attractive vehicles for the delivery of a variety of therapeutic and prophylactic peptides. However, a key limitation of PAMs is their lack of preferential targeting ability. In this paper, we describe our design of a PAM system that incorporates a DNA oligonucleotide amphiphile (antitail amphiphile-AA) to form A/PAMs. A cell-targeting DNA aptamer with a 3' extension sequence (tail) complementary to the AA is annealed to the surface to form aptamer-displaying PAMs (Aptamer~A/PAMs). Aptamer~A/PAMs are small, anionic, stable nanoparticles capable of delivering a large mass percentage peptide amphiphile (PA) compared to targeting DNA components. Aptamer~A/PAMs are stable for over 4 h in the presence of biological fluids. Additionally, the aptamer retains its cell-targeting properties when annealed to the A/PAM, thus leading to enhanced delivery to a specifically-targeted B-cell leukemia cell line. This exciting modular technology can be readily used with a library of different targeting aptamers and PAs, capable of improving the bioavailability and potency of the peptide cargo.

Controlled Ion Release from Novel Polyester/Ceramic Composites Enhances Osteoinductivity.

Due to the growing number of patients suffering from musculoskeletal defects and the limited supply of and sub-optimal outcomes associated with biological graft materials, novel biomaterials must be created that can function as graft substitutes. For bone regeneration, composite materials that mimic the organic and inorganic phases of natural bone can provide cues which expedite and enhance endogenous repair. Specifically, recent research has shown that calcium and phosphate ions are inherently osteoinductive, so controllably delivering their release holds significant promise for this field. In this study, unique aliphatic polyesters were synthesized and complexed with a rapidly decomposing ceramic (monobasic calcium phosphate, MCP) yielding novel polymer/ceramic composite biomaterials. It was discovered that the fast dissolution and rapid burst release of ions from MCP could be modulated depending on polymer length and chemistry. Also, controlled ion release was found to moderate solution pH associated with polyester degradation. When composite biomaterials were incubated with mesenchymal stems cells (MSCs) they were found to better facilitate osteogenic differentiation than the individual components as evidenced by increased alkaline phosphate expression and more rapid mineralization. These results indicate that controlling calcium and phosphate ion release via a polyester matrix is a promising approach for bone regenerative engineering.

Silver-Catalyzed Cyclization of Sulfonyl Allenes to Dihydrofurans.

Treatment of α-hydroxy allenic sulfones with 10 mol % of silver fluoride in acetonitrile at ambient temperature furnished the corresponding 3-tosyl 2,5-dihydrofurans in excellent yields via a 5-endo-trig cyclization. The starting α-hydroxy allenic sulfones were prepared by lithiation of allenic sulfones and trapping with carbonyl compounds.

A Synthesis of Dihydrofuran-3(2H)-ones.

Treatment of readily available α'-hydroxyenones with a catalytic amount of strong acid in refluxing toluene affords the corresponding dihydrofuran-3(2H)-ones in excellent yields via a formal 5-endo-trig cyclization.

Catalytic generation of vinylthionium ions. (4 + 3)-Cycloadditions and Friedel-Crafts alkylations.

A 3-phenylsulfanyl-substituted allylic alcohol and an ester thereof were treated with Brønsted acids or a gold catalyst, respectively, to generate vinylthionium ions. These species react with dienes, primarily substituted furans, to give products of either (4 + 3)-cycloaddition or Friedel-Crafts alkylation. The results are rationalized on the basis of a stepwise mechanism in which the relative rates of ring closure versus proton loss in the intermediate σ-complex determine the course of the reaction.

New synthesis of α'-hydroxydienones.

Herein, attempted oxidation of selected allenols with PCC affording α'-hydroxydienones rather than simple oxidation products is described. The formation of the products observed is rationalized via a series of sigmatropic shifts, followed by hydrolysis.

C-H activation in S-alkenyl sulfoximines: an endo 1,5-hydrogen migration.

Intramolecular redox reaction: heating N-alkyl, N-allyl-, and N-benzyl-substituted S-alkenyl sulfoximines under appropriate conditions results in the formation of NH-S-alkyl sulfoximines. The intramolecular redox reaction involves a hydride transfer that occurs by a 6-endo-trig process. The intermediates in the reaction can also give access to four- and six-membered heterocyclic rings and a new class of chiral dienes.