Azaborines: synthesis and use in the generation of stabilized boron-substituted carbocations.

A formal N-heterocyclic carbene insertion into the B-H bond of 9-BBN followed by a ring expansion reaction is reported. NHC-9-BBN adducts were reacted in one or two steps to give the corresponding di- or triazaborines. Hydride abstraction of selected species with [Ph3C]+ is facile, giving rise to 6π-aromatic cations with Lewis acidity comparable to Lewis acids commonly employed in frustrated Lewis pairs.

Functional antagonism of ß-arrestin isoforms balance IGF-1R expression and signalling with distinct cancer-related biological outcomes.

With very similar 3D structures, the widely expressed ß-arrestin isoforms 1 and 2 play at times identical, distinct or even opposing roles in regulating various aspects of G protein-coupled receptors (GPCR) expression and signalling. Recent evidence recognizes the ß-arrestin system as a key regulator of not only GPCRs, but also receptor tyrosine kinases, including the highly cancer relevant insulin-like growth factor type 1 receptor (IGF-1R). Binding of ß-arrestin1 to IGF-1R leads to ligand-dependent degradation of the receptor and generates additional MAPK/ERK signalling, protecting cancer cells against anti-IGF-1R therapy. Because the interplay between ß-arrestin isoforms governs the biological effects for most GPCRs, as yet unexplored for the IGF-1R, we sought to investigate specifically the regulatory roles of the ß-arrestin2 isoform on expression and function of the IGF-1R. Results from controlled expression of either ß-arrestin isoform demonstrate that ß-arrestin2 acts in an opposite manner to ß-arrestin1 by promoting degradation of an unstimulated IGF-1R, but protecting the receptor against agonist-induced degradation. Although both isoforms co-immunoprecipitate with IGF-1R, the ligand-occupied receptor has greater affinity for ß-arrestin1; this association lasts longer, sustains MAPK/ERK signalling and mitigates p53 activation. Conversely, ß-arrestin2 has greater affinity for the ligand-unoccupied receptor; this interaction is transient, triggers receptor ubiquitination and degradation without signalling activation, and leads to a lack of responsiveness to IGF-1, cell cycle arrest and decreased viability of cancer cells. This study reveals contrasting abilities of IGF-1R to interact with each ß-arrestin isoform, depending on the presence of the ligand and demonstrates the antagonism between the two ß-arrestin isoforms in controlling IGF-1R expression and function, which could be developed into a practical anti-IGF-1R strategy for cancer therapy.

Borocation catalysis.

The synthesis, stability and catalytic reactivity of borocations are described in the context of their reaction in frustrated Lewis pair-type processes. The reactivity of these unique Lewis acids can be predicted based on the number of substituents and their ability to stabilize the positive charge on boron. Tricoordiante borenium ions prove to be the most catalytically relevant and their use in the catalytic transformations of organic molecules is described.

Unbalancing p53/Mdm2/IGF-1R axis by Mdm2 activation restrains the IGF-1-dependent invasive phenotype of skin melanoma.

Melanoma tumors usually retain wild-type p53; however, its tumor-suppressor activity is functionally disabled, most commonly through an inactivating interaction with mouse double-minute 2 homolog (Mdm2), indicating p53 release from this complex as a potential therapeutic approach. P53 and the tumor-promoter insulin-like growth factor type 1 receptor (IGF-1R) compete as substrates for the E3 ubiquitin ligase Mdm2, making their relative abundance intricately linked. Hence we investigated the effects of pharmacological Mdm2 release from the Mdm2/p53 complex on the expression and function of the IGF-1R. Nutlin-3 treatment increased IGF-1R/Mdm2 association with enhanced IGF-1R ubiquitination and a dual functional outcome: receptor downregulation and selective downstream signaling activation confined to the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. This Nutlin-3 functional selectivity translated into IGF-1-mediated bioactivities with biphasic effects on the proliferative and metastatic phenotype: an early increase and late decrease in the number of proliferative and migratory cells, while the invasiveness was completely inhibited following Nutlin-3 treatment through an impaired IGF-1-mediated matrix metalloproteinases type 2 activation mechanism. Taken together, these experiments reveal the biased agonistic properties of Nutlin-3 for the mitogen-activated protein kinase pathway, mediated by Mdm2 through IGF-1R ubiquitination and provide fundamental insights into destabilizing p53/Mdm2/IGF-1R circuitry that could be developed for therapeutic gain.

Chapter Seven - When Phosphorylation Encounters Ubiquitination: A Balanced Perspective on IGF-1R Signaling.

Cell-surface receptors govern the critical information passage from outside to inside the cell and hence control important cellular decisions such as survival, growth, and differentiation. These receptors, structurally grouped into different families, utilize common intracellular signaling-proteins and pathways, yet promote divergent biological consequences. In rapid processing of extracellular signals to biological outcomes, posttranslational modifications offer a repertoire of protein processing options. Protein ubiquitination was originally identified as a signal for protein degradation through the proteasome system. It is now becoming increasingly recognized that both ubiquitin and ubiquitin-like proteins, all evolved from a common ubiquitin structural superfold, are used extensively by the cell and encompass signal tags for many different cellular fates. In this chapter we examine the current understanding of the ubiquitin regulation surrounding the insulin-like growth factor and insulin signaling systems, major members of the larger family of receptor tyrosine kinases (RTKs) and key regulators of fundamental physiological and pathological states.

Asymmetric dihydroxylation of olefins using cinchona alkaloids on highly ordered inorganic supports.

[reaction: see text] A modified cinchona alkaloid was grafted onto a mesoporous molecular sieve and onto amorphous silica gel. These heterogeneous ligands were employed in the asymmetric dihydroxylation of olefins under Sharpless conditions. The supported ligands yielded equivalent enantioselectivity compared with that of the homogeneous system and were easily recovered and reused.