Zhenshan Jia

One-Pot Synthesis of Chiral α-Methylene-γ-lactams with Excellent Diastereoselectivities and Enantioselectivities

An efficient one-pot asymmetric synthesis of highly substituted γ-lactams containing α-methylene groups has been successfully developed. A wide range of γ-lactams could be obtained in high yields with excellent diastereomeric ratios of up to 99:1 in favor of trans isomers. In particular, excellent enantioselectivities of the two newly formed stereogenic centers with up to 99% ee were observed.

Reactivity of Fullerene Epoxide: Preparation of Fullerene-Fused Thiirane, Tetrahydrothiazolidin-2-one, and 1,3-Dioxolane

The epoxide moiety in the fullerene-mixed peroxide C60(O)(OOtBu)4 1 reacts readily with aryl isocyanates ArNCS (Ar = Ph, Naph) to form both the thiirane derivative C60(S)(OOtBu)4 and fullerene-fused tetrahydrothiazolidin-2-one. The reaction of 1 with trimethylsilyl isothiocyanate TMSNCS yields the isothiocyanate derivative C60(NCS)(OH)(OOtBu)4, the isothiocyanate and hydroxyl moieties of which could be converted to a fullerene-fused tetrahydrothiazolidin-2-one ring with alumina quantitatively. Treating 1 with BF3.Et2O yields the fullerene-fused [1,3,2]-dioxoborolane derivative C60(O2BOH)(OOtBu)4. In the presence of aldehyde or acetone, BF3.Et2O catalyzes the conversion of epoxide to fullerene-fused 1,3-dioxolane derivatives. The products are characterized by spectroscopic data. Two of the compounds are also characterized by single-crystal X-ray analysis.

Effect of Simvastatin Prodrug on Experimental Periodontitis

BACKGROUND Local application of statins has shown potential in preventing and regenerating bone loss associated with experimental periodontitis. This study evaluates the effect of a novel simvastatin (SIM) prodrug (capable of delivering high doses to periodontitis inflammatory lesion and cells) on experimental periodontitis bone loss and inflammation. METHODS Forty mature female Sprague Dawley rats were subjected to ligature-induced experimental periodontitis between maxillary first and second molars (M1-M2). Equal groups were treated with three weekly doses of: 1) prodrug carrier alone (mPEG); 2) 0.5 mg SIM dose equivalent in carrier (SIM/SIM-mPEG); 3) 1.0 mg SIM/SIM-mPEG; 4) 1.5 mg SIM/SIM-mPEG; or 5) ligature alone. Contralateral molars served as unmanipulated controls. Four weeks after initiation of periodontitis, animals were euthanized, the M1-M2 interproximal was evaluated with microcomputed tomography and histology, and data were analyzed with one-way analysis of variance. RESULTS Ligature alone caused a mean bone loss of 1.01 ± 0.06 mm from the cemento-enamel junction, whereas all doses of SIM/SIM-mPEG reduced bone loss, especially 1.5 mg SIM/SIM-mPEG (0.68 ± 0.05 mm, P <0.001), which was not statistically different from contralateral control (0.47 ± 0.06 mm). A dose of 1.5 mg SIM/SIM-mPEG also reduced percentage of neutrophils compared with carrier alone (2.0% ± 1.0% versus 5.7% ± 1.1%; P <0.05), and increased amount of uninflamed connective tissue in the M1-M2 interproximal area (65.2% ± 3.3% versus 46.3% ± 3.3%; P <0.001). The mPEG carrier alone did not have bone-sparing or anti-inflammatory properties. CONCLUSION Multiple local 1.5-mg doses of a macromolecular SIM prodrug decreases amount of experimental periodontitis bone loss and inflammation in rats.

Pentafluorophenyl transfer reaction: preparation of pentafluorophenyl [60]fullerene adducts through opening of fullerene epoxide moiety with trispentafluorophenylborane.

Unlike the extensively studied perfluoroalkyl fullerene adducts, perfluorophenyl fullerene adducts are quite difficult to prepare by known methods. Trispentafluorophenylborane was found to react with fullerene epoxide to form the 1,2-perfluorophenylfullerenol. The method can be applied to both the simple epoxide C60(O) and fullerene multiadducts containing an epoxide moiety. Single crystal X-ray structure analysis confirmed the addition of the pentafluorophenyl group.

Preparation of a 12-membered open-cage fullerendione through silane/borane-promoted formation of ketal moieties and oxidation of a vicinal fullerendiol.

[60]Fullerene mixed peroxide C(60) (OH)(Cl)(OOtBu) reacts with PhMe(2)SiH/B(C(6)F(5))(3) to give oxahomofullerene. Mechanistic investigation indicates that the hydroxyl group in the central pentagon ring is essential to convert the tert-butylperoxo group into a ketal moiety. Migration of the silyl group and transformation of the siloxy group into a phenyl group are observed in the deprotection of the fullerene bound siloxy group. A 12-membered open-cage fullerendione was obtained through oxidation of a [6,6]-fullerendiol. This orifice could be closed to form ketal/hemiketal moieties by BF(3)-catalyzed reaction with methanol. All of the new fullerene derivatives were characterized by spectroscopic data, and structure of the open-cage fullerendione was also confirmed by single-crystal X-ray analysis.

The Evaluation of Therapeutic Efficacy and Safety Profile of Simvastatin Prodrug Micelles in a Closed Fracture Mouse Model

ABSTRACTPurposeTo evaluate the therapeutic efficiency of a micellar prodrug formulation of simvastatin (SIM/SIM-mPEG) and explore its safety in a closed femoral fracture mouse model.MethodsThe amphiphilic macromolecular prodrug of simvastatin (SIM-mPEG) was synthesized and formulated together with free simvastatin into micelles. It was also labeled with a near infrared dye for in vivo imaging purpose. A closed femoral fracture mouse model was established using a three-points bending device. The mice with established closed femoral fractures were treated with SIM/SIM-mPEG micelles, using free simvastatin and saline as controls. The therapeutic efficacy of the micelles was evaluated using a high-resolution micro-CT. Serum biochemistry and histology analyses were performed to explore the potential toxicity of the micelle formulation.ResultsNear Infrared Fluorescence (NIRF) imaging confirmed the passive targeting of SIM/SIM-mPEG micelles to the bone lesion of the mice with closed femoral fractures. The micelle was found to promote fracture healing with an excellent safety profile. In addition, the accelerated healing of the femoral fracture also helped to prevent disuse-associated ipsilateral tibia bone loss.ConclusionSIM/SIM-mPEG micelles were found to be an effective and safe treatment for closed femoral fracture repair in mice. The evidence obtained in this study suggests that it may have the potential to be translated into a novel therapy for clinical management of skeletal fractures and non-union.

The Development of Drug-free Therapy for Prevention of Dental Caries

ABSTRACTPurposeThe purpose of this study was to develop a novel, drug-free therapy that can reduce the over-accumulation of cariogenic bacteria on dental surfaces.MethodsWe designed and synthesized a polyethylene glycol (PEG)-based hydrophilic copolymer functionalized with a pyrophosphate (PPi) tooth-binding anchor using “click” chemistry. The polymer was then evaluated for hydroxyapatite (HA) binding kinetics and capability of reducing bacteria adhesion to artificial tooth surface.ResultsThe PPi-PEG copolymer can effectively inhibit salivary protein adsorption after rapid binding to an artificial tooth surface. As a result, the in vitro S. mutans adhesion study showed that the PPi-PEG copolymer can inhibit saliva protein-promoted S. mutans adhesion through the creation of a neutral, hydrophilic layer on the artificial tooth surface.ConclusionsThe results suggested the potential application of a PPi-PEG copolymer as a drug-free alternative to current antimicrobial therapy for caries prevention.

Standardized rat model testing effects of inflammation and grafting on extraction healing

BACKGROUND Loss of alveolar ridge width and height after tooth extraction is well documented, but models to evaluate ridge preservation are neither standardized nor cost-effective. This rat model characterizes the pattern of bone turnover and inflammation after extraction and bone grafting with or without local simvastatin (SIM). METHODS Fifty retired-breeder rats underwent extraction of the maxillary right first molar and standard surgical defect creation under inhalation/local anesthesia. The left side of each animal served as unmanipulated control. Untreated groups (n = 8 to 9 per group) were compared (analysis of variance, t test) at days 0, 7, 14, and 28 for alveolar ridge height and width and for markers of inflammation and bone turnover by microcomputed tomography, histology, and enzyme-linked immunosorbent assay. Seventeen additional specimens had defects grafted with either bone mineralized matrix (BMM) or a BMM+SIM conjugate. RESULTS Extraction-induced bone loss (BL) was noted on buccal, palatal, and interproximal height (P <0.05) and ridge width (P <0.01). Week 1 inflammation positively correlated with ridge height; thereafter, a more intense inflammatory reaction corresponded to reduction in alveolar bone height and density (r = 0.74; P <0.05; Spearman). BMM+SIM preserved the most interproximal bone height (P <0.01), increased ridge width and bone density (P <0.01), enhanced 7-day prostaglandin E2 (P <0.01), and reduced 28-day inflammation density (P <0.05). CONCLUSIONS The standard defect used in the current study paralleled human postextraction alveolar BL. Defect grafting, especially BMM+SIM, reduced inflammation and preserved bone.

Local Application of Pyrophosphorylated Simvastatin Prevents Experimental Periodontitis

PurposeSimvastatin (SIM), a HMG-CoA reductase inhibitor widely prescribed for hypercholesterolemia, has been reported to ameliorate inflammation and promote osteogenesis. Its clinical applications on these potential secondary indications, however, have been hampered by its lack of osteotropicity and poor water solubility. To address this challenge, we propose to design and evaluate the therapeutic efficacy of a novel simvastatin prodrug with better water solubility and bone affinity.MethodThe prodrug (SIM-PPi) was synthesized by directly conjugating a SIM trimer to a pyrophosphate (PPi). It was characterized and evaluated in vitro for its water solubility, osteotropicity, toxicity, anti-inflammatory and osteoinductive properties. It was then tested for anti-inflammatory and osteoinductive properties in vivo by three weekly injections into gingiva of a ligature-induced experimental periodontitis rat model.ResultsIn vitro studies showed that SIM-PPi has greatly improved water-solubility of SIM and shows strong binding to hydroxyapatite (HA). In macrophage culture, SIM-PPi inhibited LPS-induced pro-inflammatory cytokines (IL-1β, IL-6). In osteoblast culture, it was found to significantly increase alkaline phosphatase (ALP) activity with accelerated mineral deposition, confirming the osteogenic potential of SIM-PPi. When tested in vivo on an experimental periodontal bone-loss model, SIM-PPi exhibited a superior prophylactic effect compared to dose equivalent SIM in reducing inflammatory cells and in preserving alveolar bone structure, as shown in the histological and micro-CT data.ConclusionSIM-PPi may have the potential to be further developed for better clinical management of bone loss associated with periodontitis.

Bone-targeting liposome formulation of Salvianic acid A accelerates the healing of delayed fracture Union in Mice

Delayed fracture union is a significant clinical challenge in orthopedic practice. There are few non-surgical therapeutic options for this pathology. To address this challenge, we have developed a bone-targeting liposome (BTL) formulation of salvianic acid A (SAA), a potent bone anabolic agent, for improved treatment of delayed fracture union. Using pyrophosphorylated cholesterol as the targeting ligand, the liposome formulation (SAA-BTL) has demonstrated strong affinity to hydroxyapatite in vitro, and to bones in vivo. Locally administered SAA-BTL was found to significantly improve fracture callus formation and micro-architecture with accelerated mineralization rate in callus when compared to the dose equivalent SAA, non-targeting SAA liposome (SAA-NTL) or no treatment on a prednisone-induced delayed fracture union mouse model. Biomechanical analyses further validated the potent therapeutic efficacy of SAA-BTL. These results support SAA-BTL formulation, as a promising therapeutic candidate, to be further developed into an effective and safe clinical treatment for delayed bone fracture union.