Selenoprotein W engages in overactive osteoclast differentiation in multiple myeloma.

BACKGROUND: Patients with multiple myeloma exhibit malignant osteolytic bone disease due to excessive osteoclast formation and function. We recently identified that osteoclastogenic stimulator selenoprotein W (SELENOW) is upregulated via ERK signaling and downregulated via p38 signaling during receptor activator of nuclear factor (NF)-κΒ ligand (RANKL)-induced osteoclast differentiation. In the intrinsic physiological process, RANKL-induced downregulation of SELENOW maintains proper osteoclast differentiation; in contrast, forced overexpression of SELENOW leads to overactive osteoclast formation and function. METHODS AND RESULTS: We observed that SELENOW is highly expressed in multiple myeloma-derived peripheral blood mononuclear cells (PBMCs) and mature osteoclasts when compared to healthy controls. Also, the level of tumor necrosis factor alpha (TNFα), a pathological osteoclastogenic factor, is increased in the PBMCs and serum of patients with multiple myeloma. ERK activation by TNFα was more marked and sustained than that by RANKL, allowing SELENOW upregulation. Excessive expression of SELENOW in osteoclast progenitors and mature osteoclasts derived from multiple myeloma facilitated efficient nuclear translocation of osteoclastogenic transcription factors NF-κB and NFATc1, which are favorable for osteoclast formation. CONCLUSION: Our findings suggest a possibility that feedforward signaling of osteoclastogenic SELENOW by TNFα derived from multiple myeloma induces overactive osteoclast differentiation, leading to bone loss during multiple myeloma.

Counter-rotatable dual cinchona quinuclidinium salts and their phase transfer catalysis in enantioselective alkylation of glycine imines.

Dual cinchona quinuclidinium salts with a diphenyl ether linker were synthesized and used as powerful asymmetric phase transfer catalysts in the α-alkylation of imines of glycine and alanine ester with 0.01-0.1 mol% loading (17 examples, 92-99% ee). Skewed conformers of dual quinuclidiniums at TS were proposed to rationalize their high efficiency via DFT calculations.

Photochemical Approach for the Preparation of N-Alkyl/Aryl Substituted Fulleropyrrolidines: Photoaddition Reactions of Silyl Group Containing α-Aminonitriles with Fullerene C60.

The photochemical reactions of C60 with N-(trimethylsilyl)methyl substituted and N-alkyl/aryl substituted α-aminonitriles were explored to evaluate the scope and reaction efficiency depending on the structural nature of amine substrates. The results showed that photoreactions of C60 with trimethylsilyl group containing N-alkyl amines produced predominantly both trimethylsilyl and cyano group containing trans-pyrrolidine ring fused fulleropyrrolidines in a chemo- and stereoselective manner. Interestingly, photoreactions of C60 with N-branched alkyl substituted amines led to exclusive formation of non-silyl containing cycloadducts. In contrast to those of N-alkyl substituted α-aminonitriles, photoreactions of N-(trimethylsilyl)methyl and N-aryl substituted α-aminonitriles gave rise to the formation of both trans- and cis-isomeric fulleropyrrolidines with an inefficient and non-stereoselective manner. The feasible mechanistic pathways leading to generation of fulleropyrrolidines are 1,3-dipolar cycloaddition of the azomethine ylides, generated by either a single electron transfer (SET) (under N2-purged conditions) or H atom abstraction (under O2-purged conditions) process, to fullerene C60. The stereoselectivities of photoproducts depending on the nature of amines are likely to be associated with conformational stabilities of in situ generated azoemthine ylides.

Dimeric cinchona ammonium salts with benzophenone linkers: enantioselective phase transfer catalysts for the synthesis of α-amino acids.

Chiral phase transfer catalysts of dimeric cinchona ammonium salts linked with a benzophenone bridge showed high enantioselectivity in the α-alkylation of a glycinate ester under mild industry-applicable conditions: 0.5 mol% PTC and near equivalents of alkyl halide. A dual function of the dimeric quinuclidiniums was proposed for the high efficiency.