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[Image: see text] The overactivation of transient receptor potential canonical 3 (TRPC3) is associated with neurodegenerative diseases and hypertension. Pyrazole 3 (Pyr3) is reported as the most selective TRPC3 inhibitor, but it has two inherent structural limitations: (1) the labile ester moiety leads to its rapid hydrolysis to the inactive Pyr8 in vivo, and (2) the alkylating trichloroacrylic amide moiety is known to be toxic. To circumvent these limitations, we designed a series of conformationally restricted Pyr3 analogues and reported that compound 20 maintains high potency and selectivity for human TRPC3 over its closely related TRP channels. It has significantly improved metabolic stability compared with Pyr3 and has a good safety profile. Preliminary evaluation of 20 demonstrated its ability to rescue Aβ-induced neuron damage with similar potency to that of Pyr3 in vitro. Collectively, these results suggest that 20 represents a promising scaffold to potentially ameliorate the symptoms associated with TRPC3-mediated neurological and cardiovascular disorders.

1α,20S-Dihydroxyvitamin D3 [1,20S(OH)2D3], a natural and bioactive vitamin D3 metabolite, was chemically synthesized for the first time. X-ray crystallography analysis of intermediate 15 confirmed its 1α-OH configuration. 1,20S(OH)2D3 interacts with the vitamin D receptor (VDR), with similar potency to its native ligand, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] as illustrated by its ability to stimulate translocation of the VDR to the nucleus, stimulate VDRE-reporter activity, regulate VDR downstream genes (VDR, CYP24A1, TRPV6 and CYP27B1), and inhibit the production of inflammatory markers (IFNγ and IL1β). However, their co-crystal structures revealed differential molecular interactions of the 20S-OH moiety and the 25-OH moiety to the VDR, which may explain some differences in their biological activities. Furthermore, this study provides a synthetic route for the synthesis of 1,20S(OH)2D3 using the intermediate 1α,3β-diacetoxypregn-5-en-20-one (3), and provides a molecular and biological basis for the development of 1,20S(OH)2D3 and its analogs as potential therapeutic agents.

Dialkynylboron chlorides couple smoothly with aryl aldehydes at room temperature to afford 1,4-dialkynes in good to excellent yields. Dialkynylboron halides act simultaneously as Lewis acid and reactant in this coupling reaction.

Reactions of aromatic aldehydes with alkylboron chloride derivatives in the presence of oxygen have been investigated. Dialkylboron chlorides react with aryl aldehydes to produce arylalkylmethanols in good to excellent yields. Under the same reaction conditions, alkylboron dichlorides lead to the formation of arylalkyl chlorides.

Reactions of aryl aldehydes with styrenes in the presence of boron trichloride in CH2Cl2 at 0°C produce 1,3-dichloro-1,3-diarylpropanes in excellent yields. Reactions carried out using boron tribromide generate the corresponding 1,3-dibromo-1,3-diarylpropane in good yields.

The reaction of aryl aldehydes with alkylboron chlorides has been investigated. Monoalkylboron dichlorides react with aryl aldehydes in hexane under reflux conditions to give a mixture of dichloroarylmethane and benzyl chloride. Under the same reaction conditions, dialkylboron chlorides lead to formation of a mixture of benzyl chloride and the chloroalkylation product. In the presence of a base such as 2,6-lutidine, the reactions of monoalkylboron dichlorides with aryl aldehydes yield small amounts of the desired alkylation products at room temperature. Dialkylboron chlorides react with aryl aldehydes in hexane in the presence of base to generate the corresponding arylalkylmethanols in good yields.

The reductive bromination of aromatic aldehydes with isopinocampheyl boron dibromide in hexane at room temperature produces the corresponding benzyl bromides in excellent yields.

Alkoxide C-O bond cleavage occurs readily at room temperature in the presence of titanium(IV) halide. Capture of the resultant carbocation by alkynes provides an efficient route to trisubstituted (E)-alkenyl halides with high stereoselectivity.

Receptor tyrosine kinases (RTKs), in response to their growth factor ligands, phosphorylate and activate downstream signals important for physiological development and pathological transformation. Increased expression, activating mutations and rearrangement fusions of RTKs lead to cancer, inflammation, pain, neurodegenerative diseases, and other disorders. Activation or over-expression of ALK, ROS1, TRK (A, B, and C), and RET are associated with oncogenic phenotypes of their respective tissues, making them attractive therapeutic targets. Cancer cDNA array studies demonstrated over-expression of TRK-A and ROS1 in a variety of cancers, compared to their respective normal tissue controls. We synthesized a library of small molecules that inhibit the above indicated RTKs with picomolar to nanomolar potency. The lead molecule GTx-186 inhibited RTK-dependent cancer cell and tumor growth. In vitro and in vivo growth of TRK-A-dependent IMR-32 neuroblastoma cells and ROS1-overexpressing NIH3T3 cells were inhibited by GTx-186. GTx-186 also inhibited inflammatory signals mediated by NFκB, AP-1, and TRK-A and potently reduced atopic dermatitis and air-pouch inflammation in mice and rats. Moreover, GTx-186 effectively inhibited ALK phosphorylation and ALK-dependent cancer cell growth. Collectively, the RTK inhibitor GTx-186 has a unique kinase profile with potential to treat cancer, inflammation, and neuropathic pain.

Reactions of aryl aldehydes with styrene and (E)-β-methylstyrene in the presence of phenylboron dichloride regioselectively generate 1,3-diaryl-3-chloro-1-propanols and 1,3-diaryl-3-chloro-2-methyl-1-propanols in good to excellent yields with high stereoselectivity.

Reactions of aryl aldehydes with alkylboron dichlorides in the presence of oxygen at room temperature produces arylalkyl chlorides in good to excellent yields.

Cp3Yb (Cp = C5H5) reacts with a-naphthol (HNP) in THF to form Cp2Yb(NP)(THF) (1), which crystallizes in the space group P2(1)/n with unit cell dimensions a = 8.084(2), b = 15.996(6), c = 15.973(7) angstrom, beta = 98.95(3), V = 2040.3 angstrom and D(calc.) = 1.69 g cm-3 for Z = 4. Least-squares refinement based on 2242 observed reflections converged to a final R value of 0.081. The average Yb-C(Cp) distance is 2.60(2) angstrom and Yb-O(THF) and Yb-O(NP) distances are 2.30(1) and 2.06(1) angstrom, respectively. The title compound loses the coordinated THF molecule readily by heating under vacuum to give dimeric [Cp2Yb(NP)]2 (2), which undergoes disproportionation to give Cp3Yb and Yb(NP)3 on heating above 230-degrees-C.

The chlorination of aromatic aldehydes with boron trichloride in hexane under reflux conditions produces the corresponding dichloromethyl derivatives in excellent yields.

[reaction: see text] Substitution of benzylic hydroxyl groups with vinyl moieties using vinylboron dihalides has been achieved. The reaction provides a novel method for preparing stereodefined alkenyl halides.

[reaction: see text] A new halopropargylation of alkynes promoted by boron trihalides has been developed. Reactions of (Z)-2-halo-1-vinylboron dihalides (generated in situ via reaction of alkynes with boron trihalides) with lithium propargyloxides in CH(2)Cl(2) at room temperature produce the corresponding (Z)-1-halo-1,4-enynes in modest to good yields.

Reaction of NaCp′ (Cp′ = C5H4CH3) with YbCl3 and YbOCl in THF results in the formation of a new complex, Cp′3Yb4(μ-Cl)6(μ3-Cl)(μ4-O)(THF)3 (1). The X-ray crystal structure of 1 reveals an oxygen-centered tetrahedral arrangement of ytterbium atoms which has μ-Cl groups bridging each edge and a μ3-Cl ligand over the trianglar face composed of Yb atoms with Cp′ groups.

Organoboron chlorides and bromides are valuable reagents for halogenation and alkylation of aromatic aldehydes, addition of aldehydes to alkenes, and dialkenylation of aldehydes. An overview of these newly discovered reactions is presented.

A novel two-step aldehyde homologation procedure for the preparation of methyl ketones has been developed, which involves the use of 1,1-dibromo-1-alkenes as precursors and zinc metal as mediator in near-critical water.

Reactions of aldehydes with 2 equiv of alkyne in the presence of TiX(4) (X = Cl, Br) regioselectively generated 1,5-dihalo-1,4-dienes in moderate to good yields with high (E,Z)-stereoselectivity. [reaction: see text]

[reaction: see text]. The reactions of aryl aldehydes with 2 equiv of arylacetylenes in the presence of boron trichloride yield (E,Z)-1,3,5-triaryl-1,5-dichloro-1,4-pentadienes. Reactions carried out in the presence of boron tribromide generate the corresponding (Z,Z)-1,3,5-triaryl-1,5-dibromo-1,4-pentadienes.

M(NMe(2))(4) (M = Ti, Zr, Hf) were found to react with H(2)SiR'Ph (R' = H, Me, Ph) to yield H(2), aminosilanes, and black solids. Unusual amide hydride complexes [(Me(2)N)(3)M(mu-H)(mu-NMe(2))(2)](2)M (M = Zr, 1; Hf, 2) were observed to be intermediates and characterized by single-crystal X-ray diffraction. [(Me(2)N)(3)M(mu-D)(mu-NMe(2))(2)](2)M (1-d(2), 2-d(2)) were prepared through reactions of M(NMe(2))(4) with D(2)SiPh(2). Reactions of (Me(2)N)(3)ZrSi(SiMe(3))(3) (5) with H(2)SiR'Ph were found to give aminosilanes and (Me(2)N)(2)Zr(H)Si(SiMe(3))(3) (6). These reactions are reversible through unusual equilibria such as (Me(2)N)(3)ZrSi(SiMe(3))(3) (5) + H(2)SiPh(2) right arrow over left arrow (Me(2)N)(2)Zr(H)Si(SiMe(3))(3) (6) + HSi(NMe(2))Ph(2). The deuteride ligand in (Me(2)N)(2)Zr(D)Si(SiMe(3))(3) (6-d(1)) undergoes H-D exchange with H(2)SiR'Ph (R' = Me, H) to give 6 and HDSiR'Ph. The reaction of Ti(NMe(2))(4) with SiH(4) in chemical vapor deposition at 450 degrees C yielded thin Ti-Si-N ternary films containing TiN and Si(3)N(4). Ti(NMe(2))(4) reacts with SiH(4) at 23 degrees C to give H(2), HSi(NMe(2))(3), and a black solid. HNMe(2) was not detected in this reaction. The reaction mixture, upon heating, gave TiN and Si(3)N(4) powders. Analyses and reactivities of the black solid revealed that it contained -H and unreacted -NMe(2) ligands but no silicon-containing ligand. Ab initio quantum chemical calculations of the reactions of Ti(NR(2))(4) (R = Me, H) with SiH(4) indicated that the formation of aminosilanes and HTi(NR(2))(3) was favored. These calculations also showed that HTi(NH(2))(3) (3b) reacted with SiH(4) or H(3)Si-NH(2) in the following step to give H(2)Ti(NH(2))(2) (4b) and aminosilanes. The results in the current studies indicated that the role of SiH(4) in its reaction with Ti(NMe(2))(4) was mainly to remove amide ligands as HSi(NMe(2))(3). The removal of amide ligands is incomplete, and the reaction thus yielded "=Ti(H)(NMe(2))" as the black solid. Subsequent heating of the black solid and HSi(NMe(2))(3) may then yield TiN and Si(3)N(4), respectively, as the Ti-Si-N materials.

[reaction: see text] Aryl aldehydes react with alkylboron chloride derivatives in the presence of base to generate the corresponding arylalkylmethanols in good yields. A variety of alkylboron chlorides can be utilized in the new alkylation reaction.

Stilbenes are readily prepared in good yields via homocoupling of aryl aldehyde tosylhydrazones in the presence of lithium tert -butoxide and trimethyl borate under reflux in THF.