Design, synthesis and biological evaluation of ring-fused pyrazoloamino pyridine/pyrimidine derivatives as potential FAK inhibitors.

We report herein the synthesis of novel ring-fused pyrazoloamino pyridine/pyrimidine derivatives as potential FAK inhibitors and the evaluation of pharmaceutical activity against five cancer cell lines (MDA-MB-231, BXPC-3, NCI-H1975, DU145 and 786O). Generally, the majority of compounds displayed strong anti-FAK enzymatic potencies (IC50 < 1 nM) and could effectively inhibit several class of cancer cell lines within the concentration of 3 µM in comparison with GSK2256098 as a reference. Among them, compound 4o is considered to be the most effective due to high sensitivity in antiproliferation. In culture, 4o could not only inhibit FAK Y397 phosphorylation in MDA-MB-231 cell line, but also trigger apoptosis in a dose-dependent manner. Furthermore, computational docking analysis also suggested that 4o and TAE-226 displayed the similar interaction with FAK kinase domain.

Unique Steric Effect of Geminal Bis(silane) To Control the High Exo-selectivity in Intermolecular Diels-Alder Reaction.

The unique steric effect of geminal bis(silane) [(R3Si)2CH] allows an exo-selective intermolecular Diels-Alder reaction of geminal bis(silyl) dienes with α,ß-unsaturated carbonyl compounds. The approach shows good generality to form ortho-trans cyclohexenes in good yields with high exo-selectivity and high enantioselectivity in some asymmetric cases. The excellent exo-stereocontrol aptitude of (R3Si)2CH group is highlighted by comparing with R3SiCH2 and R3Si groups, which leads to endo-selectivity predominantly. The conformational analysis of dienes suggests that (R3Si)2CH group effectively shields both sides of the diene moiety, ensuring the desired exo-selectivity. Moreover, the geminal bis(silane) can be further functionalized to transform the resulting ortho-trans cycloadducts into useful synthons, which makes the approach hold great potential for organic synthesis.

The Current Status and Perspectives of Delivery Strategy for Boronbased Drugs.

Boron-containing compounds are essential micronutrients for animals and plants despite their low-level natural occurrence. They can strengthen the cell walls of the plants and they play important role in supporting bone health. However, surprisingly, boron-containing compounds are seldom found in pharmaceutical drugs. In fact, there are no inherent disadvantages reported so far in terms of the incorporation of boron into medicines. Indeed, drugs based on boron-containing compounds, such as tavaborole (marked name Kerydin) and bortezomib (trade name Velcade) have been investigated and they are used in clinical treatment. In addition, following the advanced development of boron neutron capture therapy and a new emerging proton boron fusion therapy, more boron-containing medicinals are to be expected. This review discusses the current status and perspectives of delivery strategy for boron-containing drugs.

Visible light-promoted radical cyclization of silicon-tethered alkyl iodide and phenyl alkyne. An efficient approach to synthesize benzosilolines.

An efficient approach to synthesize benzosiloline has been developed using a visible light-promoted radical cyclization reaction of silicon-tethered alkyl iodide and phenyl alkyne.

1,4-Hydroiodination of dienyl alcohols with TMSI to form homoallylic alcohols containing a multisubstituted Z-alkene and application to Prins cyclization.

A regioselective 1,4-hydroiodination of dienyl alcohols has been developed using trimethylsilyl iodide as Lewis acid and iodide source. A range of homoallylic alcohols containing a multisubstituted Z-alkene was synthesized with good to excellent configurational control. The approach was applied in sequential hydroiodination/Prins cyclization to afford multisubstituted tetrahydropyrans diastereoselectively.

[1,5]-Anion relay via intramolecular proton transfer to generate 3,3-bis(silyl) allyloxy lithium: a useful scaffold for syn-addition to aldehydes and ketones.

A [1,5]-anion relay has been achieved in 3,3-bis(silyl) benzyl enol ether. Deprotonation at the sterically more accessible benzyl position triggers an intramolecular proton transfer to generate the thermodynamically more stable 3,3-bis(silyl) allyloxy lithium. This endo-oriented allyl anion is stable at -78 °C and undergoes diastereoselective syn-addition at the γ-position with aldehydes and ketones to give monobenzyl-substituted 1,2-diols.

[1,5]-Brook rearrangement: an overlooked but valuable silyl migration to synthesize configurationally defined vinylsilane. The unique steric and electronic effects of geminal bis(silane).

An unusual [1,5]-Brook rearrangement of the lithium alkoxide of geminal bis(silyl) homoallylic alcohol is described. The unique steric and electronic effects of geminal bis(silane) were found to be crucial for promoting this long-range silyl migration, as well as for facilitating the subsequent γ/Z-selective addition of silyl allyllithium with carbonyl compounds to synthesize diverse configurationally defined Z-vinylsilanes.

Bissilyl enal: a useful linchpin for synthesis of functionalized vinylsilane species by anion relay chemistry.

Bissilyl enal, prepared by a Mannich reaction of 3,3-bissilyl aldehyde with formaldehyde, has proven to be a useful linchpin in an efficient three-component coupling process. The reaction features a [1,4]-Brook rearrangement to generate the silylallyl anion, which adopts a predominant endo-orientation and can undergo addition to electrophiles in a regio- and stereoselective manner, giving various E-vinylsilane species in good yields.