Boron in drug discovery: carboranes as unique pharmacophores in biologically active compounds.
TL;DR: Boron in Drug Discovery: Carboranes as Unique Pharmacophores in Biologically Active Compounds Fatiah Issa, Michael Kassiou, and Louis M. Rendina.
Abstract: Boron in Drug Discovery: Carboranes as Unique Pharmacophores in Biologically Active Compounds Fatiah Issa, Michael Kassiou, and Louis M. Rendina* School of Chemistry, The University of Sydney, Sydney NSW 2006, Australia Discipline of Medical Radiation Sciences, Faculty of Health Sciences, The University of Sydney, Cumberland Campus, Lidcombe NSW 2141, Australia Brain and Mind Research Institute, The University of Sydney, Camperdown NSW 2050, Australia
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TL;DR: This review deals with the redox properties and photoluminescence behavior of this collection of compounds, as well as their influence on the properties of materials and devices whose working principles are related to electron-transfer or electron-promotion phenomena.
Abstract: Icosahedral boranes, carboranes, and metallacarboranes are extraordinarily robust compounds with desirable properties such as thermal and redox stability, chemical inertness, low nucleophilicity, and high hydrophobicity, making them attractive for several applications such as medicine, nanomaterials, molecular electronics, energy, catalysis, environmental chemistry, and other areas. The hydrogen atoms in these clusters can be replaced by convenient groups that open the way to a chemical alternative to conventional "organic" or "organometallic" realms. Icosahedral boron cluster derivatives have been reviewed from different perspectives; however, there is a need for a review dedicated to the redox and photophysical characteristics of easily accessible borane and carborane derivatives, which are excellent materials for a wide range of applications. This review deals with the redox properties and photoluminescence behavior of this collection of compounds, as well as their influence on the properties of materials and devices whose working principles are related to electron-transfer or electron-promotion phenomena. We hope that this review will be of great value to boron cluster scientists and researchers working in the photoluminescence and electrochemistry fields who are interested in exploring the possibilities of these unique and promising systems.
355 citations
TL;DR: This critical review clearly indicates that silver catalysis provides a significant impetus to the rapid evolution of alkyne-based organic reactions, such as alkynylation, hydrofunctionalization, cycloaddition, cycloisomerization, and cascade reactions.
Abstract: Silver is a less expensive noble metal. Superior alkynophilicity due to π-coordination with the carbon-carbon triple bond makes silver salts ideal catalysts for alkyne-based organic reactions. This review highlights the progress in alkyne chemistry via silver catalysis primarily over the past five years (ca. 2010-2014). The discussion is developed in terms of the bond type formed with the acetylenic carbon (i.e., C-C, C-N, C-O, C-Halo, C-P and C-B). Compared with other coinage metals such as Au and Cu, silver catalysis is frequently observed to be unique. This critical review clearly indicates that silver catalysis provides a significant impetus to the rapid evolution of alkyne-based organic reactions, such as alkynylation, hydrofunctionalization, cycloaddition, cycloisomerization, and cascade reactions.
346 citations
TL;DR: The emission process of the o-carborane dyad with anthracene originating from the twisted intramolecular charge transfer (TICT) state in the crystalline state is described and it is proposed that the compact sphere shape of o- carborane would allow for rotation even in the condensed state.
Abstract: The emission process of the o-carborane dyad with anthracene originating from the twisted intramolecular charge transfer (TICT) state in the crystalline state is described. The anthracene-o-carborane dyad was synthesized and its optical properties were investigated. Initially, the dyad had aggregation- and crystallization-induced emission enhancement (AIEE and CIEE) properties via the intramolecular charge transfer (ICT) state. Interestingly, the dyad presented the dual-emissions assigned to both locally excited (LE) and ICT states in solution. From the mechanistic studies and computer calculations, it was indicated that the emission band from the ICT should be attributable to the TICT emission. Surprisingly, even in the crystalline state, the TICT emission was observed. It was proposed from that the compact sphere shape of o-carborane would allow for rotation even in the condensed state.
284 citations
TL;DR: This Perspective presents an overview of the properties of boron clusters that are pertinent for drug discovery, recent applications in the design of various classes of drugs, and the potential use of boreon clusters in the construction of new pharmaceuticals.
Abstract: There are two branches in boron medicinal chemistry: the first focuses on single boron atom compounds, and the second utilizes boron clusters. Boron clusters and their heteroatom counterparts belong to the family of cage compounds. A subset of this extensive class of compounds includes dicarbadodecaboranes, which have the general formula C2B10H12, and their metal biscarboranyl complexes, metallacarboranes, with the formula [M(C2B10H12)2–2]. The unique properties of boron clusters have resulted in their utilization in applications such as in pharmacophores, as scaffolds in molecular construction, and as modulators of bioactive compounds. This Perspective presents an overview of the properties of boron clusters that are pertinent for drug discovery, recent applications in the design of various classes of drugs, and the potential use of boron clusters in the construction of new pharmaceuticals.
243 citations
TL;DR: An o-carborane-based anthracene was synthesized, and single crystals, with incorporated solvent molecules, were obtained from the CHCl3, CH2 Cl2, and C6 H6 solutions that exhibited a variety of emission behaviors such as aggregation-induced emission (AIE), crystallization- induced emission (CIE), aggregation-caused quenching (ACQ), and multichromism.
Abstract: An o-carborane-based anthracene was synthesized, and single crystals, with incorporated solvent molecules, were obtained from the CHCl3 , CH2 Cl2 , and C6 H6 solutions. The anthracene ring in the crystal is highly distorted by the formation of a π-stacked dimer between the anthracene units. The crystals exhibited a variety of emission behaviors such as aggregation-induced emission (AIE), crystallization-induced emission (CIE), aggregation-caused quenching (ACQ), and multichromism.
235 citations
References
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TL;DR: The crystal structures of the LBD of ER in complex with the endogenous oestrogen, 17β-oestradiol, and the selective antagonist raloxifene provide a molecular basis for the distinctive pharmacophore of the ER and its catholic binding properties.
Abstract: Oestrogens are involved in the growth, development and homeostasis of a number of tissues. The physiological effects of these steroids are mediated by a ligand-inducible nuclear transcription factor, the oestrogen receptor (ER). Hormone binding to the ligand-binding domain (LBD) of the ER initiates a series of molecular events culminating in the activation or repression of target genes. Transcriptional regulation arises from the direct interaction of the ER with components of the cellular transcription machinery. Here we report the crystal structures of the LBD of ER in complex with the endogenous oestrogen, 17beta-oestradiol, and the selective antagonist raloxifene, at resolutions of 3.1 and 2.6 A, respectively. The structures provide a molecular basis for the distinctive pharmacophore of the ER and its catholic binding properties. Agonist and antagonist bind at the same site within the core of the LBD but demonstrate different binding modes. In addition, each class of ligand induces a distinct conformation in the transactivation domain of the LBD, providing structural evidence of the mechanism of antagonism.
3,255 citations
TL;DR: Crystal structures of the human estrogen receptor alpha (hER alpha) ligand-binding domain (LBD) and the OHT-LBD complex reveal the two distinct mechanisms by which structural features of OHT promote this "autoinhibitory" helix 12 conformation.
2,581 citations
TL;DR: The differences between the active site of all‐atom minimized structure and the experimental structure are similar to differences observed between crystal structures of the same protein.
Abstract: A study of the binding of the antibacterial agent trimethoprim to Escherichia coli dihydrofolate reductase was carried out using energy minimization techniques with both a full, all-atom valence force field and a united atom force field. Convergence criteria ensured that no significant structural or energetic changes would occur with further minimization. Root-mean-square (RMS) deviations of both minimized structures with the experimental structure with the experimental structure were calculated for selected regions of the protein. In the active site, the all-atom minimized structure fit the experimental structure much better than did the united atom structure. To ascertain what constitutes a good fit, the RMS deviations between crystal structures of the same enzyme either from different species or in different crystal environments were compared. The differences between the active site of all-atom minimized structure and the experimental structure are similar to differences observed between crystal structures of the same protein.
Finally, the energetics of ligand binding were analyzed for the all-atom minimized coordinates. Strain energy induced in the ligand, the corresponding entropy loss due to shifts in harmonic frequencies, and the role of specific residues in ligand binding were examined. Water molecules, even those not in direct contact with the ligand, were found to have significant interaction energies with the ligand. Thus, the inclusion of at least one shell of waters may be vital for accurate simulations of enzyme complexes.
1,812 citations
TL;DR: Thalidomide selectively inhibits the production of human monocyte tumor necrosis factor alpha when these cells are triggered with lipopolysaccharide and other agonists in culture, and may be useful in determining the role of TNF-alpha in vivo and modulating its toxic effects in a clinical setting.
Abstract: Thalidomide selectively inhibits the production of human monocyte tumor necrosis factor alpha (TNF-alpha) when these cells are triggered with lipopolysaccharide and other agonists in culture. 40% inhibition occurs at the clinically achievable dose of the drug of 1 micrograms/ml. In contrast, the amount of total protein and individual proteins labeled with [35S]methionine and expressed on SDS-PAGE are not influenced. The amounts of interleukin 1 beta (IL-1 beta), IL-6, and granulocyte/macrophage colony-stimulating factor produced by monocytes remain unaltered. The selectivity of this drug may be useful in determining the role of TNF-alpha in vivo and modulating its toxic effects in a clinical setting.
1,201 citations
TL;DR: In this paper, a mouse trap mechanism was proposed to reposition the amphi-pathic α-helix of the AF-2 activating domain and form a transcriptionally active receptor.
Abstract: The 2.0-A crystal structure of the ligand-binding domain (LBD) of the human retinoic acid receptor (RAR)-γ bound to all-trans retinoic acid reveals the ligand-binding interactions and suggests an electrostatic guidance mechanism. The overall fold is similar to that of the human RXR-α apo-LBD, except for the carboxy-terminal part which folds back towards the LBD core, contributing to the hydrophobic ligand pocket and 'sealing' its entry site. We propose a 'mouse trap' mechanism whereby a ligand-induced conformational transition repositions the amphi-pathic α-helix of the AF-2 activating domain and forms a transcriptionally active receptor.
1,056 citations