Ring expansion reactions of anti-aromatic boroles: a promising synthetic avenue to unsaturated boracycles.

Conjugated boron heterocycles have emerged as attractive synthetic targets due to their potential in medicinal chemistry and as electronic materials. However, the development of unsaturated boracycles has been hampered by difficulties in their preparation. Recently, a new synthetic avenue to access these species has been developed that takes advantage of the high reactivity of boroles. These five-membered anti-aromatic heterocycles can react with substrates to furnish ring expansion products via the insertion of one, two, or three atoms into the boracyclic ring. The ring expansion can occur via two pathways, the first exploits the activated diene moiety of the heterocycle in Diels-Alder chemistry with the resulting bicyclic species undergoing further rearrangements. The second reaction pathway is initiated by the coordination of the Lewis basic site of a substrate to the highly Lewis acidic boron center rendering the endocyclic B-C bond of the borole nucleophilic, inducing the formation of larger boracycles via attack at the electrophilic site of the substrate. This review summarizes the current state of this chemistry and details the mechanisms leading to the products. The methodologies described herein could very well be extended to other substrates, as well as applied to other anti-aromatic heterocycles.

1,2-Phosphaborines: hybrid inorganic/organic P-B analogues of benzene.

Photolysis of the cyclic phosphine oligomer [PPh]5 in the presence of pentaarylboroles leads to the formation of 1,2-phosphaborines by the formal insertion of a phenylphosphinidene fragment into the endocyclic CB bond. The solid-state structure features a virtually planar central ring with bond lengths indicating significant delocalization. Appreciable ring current in the 1,2-phosphaborine core, detected in nuclear independent chemical shift (NICS) calculations, are consistent with aromatic character. These products are the first reported 1,2-BPC4 conjugated heterocycles and open a new avenue for BP as a valence isoelectronic substitute for CC in arene systems.

Robust cyclometallated Ir(III) catalysts for the homogeneous hydrogenation of N-heterocycles under mild conditions.

Cyclometallated Cp*Ir(N^C)Cl complexes derived from N-aryl ketimines are highly active catalysts for the reduction of N-heterocycles under ambient conditions and 1 atm H2 pressure. The reaction tolerates a broad range of other potentially reducible functionalities and does not require the use of specialised equipment, additives or purified solvent.

Synthetic retinoids: structure-activity relationships.

Retinoid signalling pathways are involved in numerous processes in cells, particularly those mediating differentiation and apoptosis. The endogenous ligands that bind to the retinoid receptors, namely all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid, are prone to double-bond isomerisation and to oxidation by metabolic enzymes, which can have significant and deleterious effects on their activities and selectivities. Many of these problems can be overcome through the use of synthetic retinoids, which are often much more stable, as well as being more active. Modification of their molecular structures can result in retinoids that act as antagonists, rather than agonists, or exhibit a large degree of selectivity for particular retinoid-receptor isotypes. Several such selective retinoids are likely to be of value as pharmaceutical agents with reduced toxicities, particularly in cancer therapy, as reagents for controlling cell differentiation, and as tools for elucidating the precise roles that specific retinoid signalling pathways play within cells.

Proteomic profiling of the stem cell response to retinoic acid and synthetic retinoid analogues: identification of major retinoid-inducible proteins.

The natural retinoid, all-trans retinoic acid (ATRA), is widely used to direct the in vitro differentiation of stem cells. However, substantial degradation and isomerisation of ATRA in response to UV-vis light has serious implications with regard to experimental reproducibility and standardisation. We present the novel application of proteomic biomarker profiling technology to stem cell lysates to rapidly compare the differentiation effects of ATRA with those of two stable synthetic retinoid analogues, EC19 and EC23, which have both been shown to induce differentiation in the embryonal carcinoma cell line TERA2.cl.SP12. MALDI-TOF MS (matrix-assisted laser desorption ionisation time-of-flight mass spectrometry) protein profiles support previous findings into the functional relationships between these compounds in the TERA2.cl.SP12 line. Subsequent analysis of protein peak data enabled the semi-quantitative comparison of individual retinoid-responsive proteins. We have used ion exchange chromatographic protein separation to enrich for retinoid-inducible proteins, thereby facilitating their identification from SDS-PAGE gels. The cellular retinoid-responsive proteins CRABP-I, CRABP-II, and CRBP-I were up-regulated in response to ATRA and EC23, indicating a bona fide retinoid pathway response to the synthetic compound. In addition, the actin filament regulatory protein profilin-1 and the microtubule regulator stathmin were also elevated following treatment with both ATRA and EC23. The up-regulation of profilin-1 and stathmin associated with retinoid-induced neural differentiation correlates with their known roles in cytoskeletal reorganisation during axonal development. Immunological analysis via western blotting confirmed the identification of CRABP-I, profilin-1 and stathmin, and supported their observed regulation in response to the retinoid treatments.

Synthesis and evaluation of synthetic retinoid derivatives as inducers of stem cell differentiation.

All-trans-retinoic acid (ATRA) and its associated analogues are important mediators of cell differentiation and function during the development of the nervous system. It is well known that ATRA can induce the differentiation of neural tissues from human pluripotent stem cells. However, it is not always appreciated that ATRA is highly susceptible to isomerisation when in solution, which can influence the effective concentration of ATRA and subsequently its biological activity. To address this source of variability, synthetic retinoid analogues have been designed and synthesised that retain stability during use and maintain biological function in comparison to ATRA. It is also shown that subtle modifications to the structure of the synthetic retinoid compound impacts significantly on biological activity, as when exposed to cultured human pluripotent stem cells, synthetic retinoid 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylethynyl)benzoic acid, 4a (para-isomer), induces neural differentiation similarly to ATRA. In contrast, stem cells exposed to synthetic retinoid 3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylethynyl)benzoic acid, 4b (meta-isomer), produce very few neurons and large numbers of epithelial-like cells. This type of structure-activity-relationship information for such synthetic retinoid compounds will further the ability to design more targeted systems capable of mediating robust and reproducible tissue differentiation.