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Ryan D.A.,The Human BioMolecular Research Institute | Okolotowicz K.J.,The Human BioMolecular Research Institute | Mercola M.,Sanford Burnham Institute for Medical Research | Cashman J.R.,The Human BioMolecular Research Institute
Tetrahedron Letters | Year: 2015

An asymmetric synthesis of mexiletine and structural analogs was developed using chiral tert-butanesulfinamide to convert precursor ketones to chiral amines. Starting from α-aryloxy ketones, a two-step condensation-reduction procedure provided chiral N-tert-butanesulfinyl amines as immediate precursors to mexiletine or structural analogs. Reduction of the intermediate N-tert-butanesulfinyl imine showed substrate- and reagent-derived stereoselectivity. Following removal of the chiral auxiliary, mexiletine and structural analogs were obtained in high enantiopurity using this approach. © 2015 Elsevier Ltd. All rights reserved.

Chen S.,The Human BioMolecular Research Institute | Ryan D.A.,The Human BioMolecular Research Institute | Dwyer M.A.,The Human BioMolecular Research Institute | Cashman J.R.,The Human BioMolecular Research Institute
Bone | Year: 2014

Although osteoinductive ceramics can induce osteoblast differentiation in vitro and bone regeneration in vivo, their effects rely solely on the limited number of endogenous stem cells. More recently, ceramic carriers seeded with culture-expanded stem cells have been reported as implants capable of in vivo bone formation. However, effective and safe signaling agents that promote cell differentiation to the osteogenic lineage are still needed. In the present report, two osteogenic small-molecules THQ-1a and PP-9 were identified by testing a series of compounds for Runx2 and BMP2 expression in C2C12 cells. Compounds THQ-1a and PP-9 modulated Wnt signaling and enhanced the expression of molecular markers of osteoblast differentiation. To probe the utility of these compounds for use with ceramic cell implants, the effect of THQ-1a and PP-9 on C2C12 cell osteogenic differentiation was investigated in the presence of a tricalcium phosphate (TCP) ceramic. The effect of THQ-1a and PP-9 on markers such as Osteocalcin and Collagen I was significantly increased in the presence of TCP ceramic. Additionally, THQ-1a or PP-9 in the presence of TCP ceramic gave a synergistic increase in alkaline phosphatase activity in the differentiation of C2C12 cells. Taken together, the results suggest an approach to directing cell lineage commitment for bone regeneration by the application of small-molecule osteogenic agents to cells in the presence of osteoinductive ceramics. © 2014 Elsevier Inc.

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