Search

Androgen receptor (AR) has a key role in the development and progression of prostate cancer, and AR antagonists are used for its remedy. Recently, carborane derivatives, which are carbon-containing boron clusters have attracted attention as new AR ligands. Here we determined the force field parameters of 10-vertex and 12-vertex p-carborane to facilitate in silico drug design of boron clusters. Then, molecular dynamics (MD) simulations of complexes of AR-carborane derivatives were performed to evaluate the parameters and investigate the influences of carborane derivatives on the three-dimensional structure of AR. Energy profiles were obtained using quantum chemical calculations, and the force-field parameters were determined by curve fitting of the energy profiles. The results of MD simulations indicated that binding of the antagonist-BA341 changed some hydrogen-bond formations involved in the structure and location of helix 12. Those results were consistent with previously reported data. The determined parameters are also useful for refining the structure of the carborane-receptor complex obtained by docking simulations and development of new ligands with carborane cages not only for AR but also for various receptors.

Tamoxifen, a therapeutic agent for breast cancer, has been associated with genetic polymorphisms in the metabolism of N,N-dialkylaminoethyl substituent, which plays an important role in the expression of selective estrogen receptor modulator (SERM) activity. To solve this problem, we developed a novel estrogen receptor (ER) modulator, Az-01, on the basis of the aromaticity, dipole moment, and isopropyl group of guaiazulene. Az-01 showed four-fold lower binding affinity for ER than E2 but had similar ER-binding affinity to that of 4-hydroxytamoxifen (4-HOtam). Unlike tamoxifen, Az-01 acted as a partial agonist with very weak estrogenic activity at high concentrations when used alone, and it showed potent anti-estrogenic activity in the presence of E2. The cell proliferation and inhibition activities of Az-01 were specific to ER-expressing MCF-7 cells, and no effect of Az-01 on other cell proliferation signals was observed. These findings are important for the development of new types of SERMs without the N,N-dialkylaminoethyl substituent as a privileged functional group for SERMs.

Estrogen receptor (ER) exhibits two subtypes, ERα and ERβ, whose biological functions are quite different despite expression in the same tissues. We developed diiodo-m-carborane derivative 3a, which showed 14-fold selectivity for ERβ with high binding affinity toward ERβ. Interestingly, introduction of an alkyl group into the carbon atom of the m-carborane cage of 3a markedly enhanced the binding affinity toward ERα and decreased affinity toward ERβ. C-n-propyl derivative 3d showed 28-fold selectivity for ERα in an ER binding assay and promoted proliferation of MCF-7 breast cancer cells. Docking simulation studies suggest that the directions of the n-propyl group and the diiodo substituent introduced on the m-carborane cage play important roles for the control of ER subtype selectivity. As 3a and 3d showed ERβ and ERα selectivity with high binding affinity, respectively, these ligands may be useful as biological tools to aid in understanding the different roles of ER subtypes.

Based on the co-crystal structure of bicalutamide with a T877A-mutated androgen receptor (AR), glycerol and aminoglycerol derivatives were designed and synthesized as a novel type of carborane-containing AR modulators. The (R)-isomer of 6c, whose chirality is derived from the glycerol group, showed 20 times more potent cell inhibitory activity against LNCaP cell lines expressing T877A-mutated AR than the corresponding (S)-isomer. Docking studies of both isomers with AR suggested that (R)-6c is in closer spatial proximity to helix-12 of the AR than (S)-6c, which is the most important common motif in the secondary structure of AR for the expression of antagonistic activity.

Xanthine oxidase (XO) is an enzyme that contains molybdenum at the active site and catalyzes the oxidation of purine bases to uric acid. Even though XO inhibitors are widely used for the treatment of hyperuricemia and gout, only very few such compounds are clinically used as drugs for the treatment of these diseases. Given the unique physicochemical properties of tropolone, i.e., its chelating effect and the pKa value that is similar to that of carboxylic acid, we have synthesized 22 5-arylazotropolone derivatives as potential XO inhibitors. In vitro enzyme-inhibitory assays for XO revealed that 3-nitro derivative 1j showed the most potent XO inhibitory activity, which is by one order of magnitude more potent than allopurinol. An enzyme-kinetic study revealed that 1j inhibited the production of uric acid by XO both competitively and non-competitively. A docking-simulation study of 1j with XO suggested that the carbonyl and hydroxyl groups of the tropolone ring interact with the hydroxy group that acts as a ligand for molybdenum and the amino acid residues around the active site of XO.

The development of multitarget anticancer agents is of high interest to medicinal chemists in terms of overcoming drug resistance and preventing cancer-cell migration. Based on the structure of the potent carborane-containing estrogen BE120, non-steroidal multitarget anti-breast cancer agent candidates 1a – 1j were designed and synthesized. Compound 1f shows potent STS-inhibitory activity (IC 50 = 1.8 μM), cell-growth-inhibitory (CGI) activity against 39 human cancer cell lines (MG-MID = 2.8 μM), and tubulin-polymerization-inhibitory (TPI) activity. An analysis of the DNA content for MDA-MB-453 breast cancer cells revealed that 1f arrests the cell cycle in the G2/M phase and induces apoptosis. Accordingly, 1f should be a promising therapeutic agent for hormone-dependent breast cancer.

The female hormone 17 β-estradiol (E2) is synthesized from estrone by steroid sulfatase (STS), and metabolized into 2-methoxyestradiol (2-ME), whereby the biological activity of the latter is substantially different from that of E2. Based on the metabolic pathways of E2, a carborane-containing 2-ME mimic (1c) and its derivatives (1 and 2) were designed and synthesized as novel multitarget anticancer agents. Bissulfamate 1f exhibited potent STS-inhibitory activity and tubulin-polymerization-inhibitory activity. Moreover, the cell-growth-inhibitory (CGI) activity of 1f was similar to that of 2-ME in a panel screening against 39 human cancer cell lines. Accordingly, 1f should be a promising perspective therapeutic agent for hormone-dependent breast tissue.

Amyloid-β aggregation inhibitors are expected to be therapeutic or prophylactic agents for Alzheimer's disease. Rosmarinic acid, which is one of the main aggregation inhibitors derived from Lamiaceae, was employed as a lead compound and its 25 derivatives were synthesized. In this study, the structure-activity relations of rosmarinic acid derivatives for the amyloid-β aggregation inhibitory effect (MSHTS assay), antioxidant properties, and xanthine oxidase inhibition were evaluated. Among the tested compounds, compounds 16d and 19 were found to the most potent amyloid aggregation inhibitors. The SAR revealed that the necessity of the presence of the phenolic hydroxyl on one side of the molecule as well as the lipophilicity of the entire molecule. The importance of these structural properties was also supported by docking simulations.

The selectivity and the binding affinity of previously reported carborane-containing ligands 2 and 3 toward ERβ remains to be optimized. To improve their biological profiles, a series of iodinated carboranyl phenol derivatives ( 4 – 6 ) were designed and synthesized as prospective ERβ-selective ligands with high affinity. Several iodinated carboranyl phenols showed high relative binding affinity (RBA) values for both ERs, and especially for ERβ, due to suitable hydrophobic interactions of the iodine atoms with the hydrophobic amino acid residues of the ERβ ligand-binding domains. Among these derivatives, 9,10-diiodo-m-carborane 5f exhibited a more than 100% increase of the RBA values toward ERβ, a 14-fold increased selectivity for ERβ over ERα, and ER-agonistic activity in MCF-7 cell proliferation assays.

Protein aggregation is the principal component of numerous protein misfolding pathologies termed proteinopathies, such as Alzheimer’s disease, Parkinson’s disease, prion disease, and AA amyloidosis with unmet treatment needs. Protein aggregation inhibitors have great potential for the prevention and treatment of proteinopathies. Here we report the development of an automated real-time microliter-scale high throughput screening (MSHTS) system for amyloid aggregation inhibitors using quantum-dot nanoprobes. Screening 504 crude extracts and 134 low molecular weight aromatic compounds revealed the relationship of amyloid-β (Aβ) aggregation inhibitory activities of plant extracts using a plant-based classification. Within the eudicots, rosids, Geraniales and Myrtales showed higher activity. Screening low molecular weight aromatic compounds demonstrated that the structure of tropolone endows it with potential Aβ aggregation inhibitory activity. The activity of the most active tropolone derivative was higher than that of rosmarinic acid. MSHTS also identified three chaperone molecules as tau aggregation inhibitors. These results demonstrate that our automated MSHTS system is a novel and robust tool that can be adapted to a wide range of compounds and aggregation-prone polypeptides.

Targeting cancer with small molecule prodrugs should help overcome problems associated with conventional cancer-targeting methods. Herein, we focused on lysine-specific demethylase 1 (LSD1) to trigger the controlled release of anticancer drugs in cancer cells, where LSD1 is highly expressed. Conjugates of the LSD1 inhibitor trans-2-phenylcyclopropylamine (PCPA) were used as novel prodrugs to selectively release anticancer drugs by LSD1 inhibition. As PCPA-drug conjugate (PDC) prototypes, we designed PCPA-tamoxifen conjugates 1 a and 1 b, which released 4-hydroxytamoxifen in the presence of LSD1 in vitro. Furthermore, 1 a and 1 b inhibited the growth of breast cancer cells by the simultaneous inhibition of LSD1 and the estrogen receptor without exhibiting cytotoxicity toward normal cells. These results demonstrate that PDCs provide a useful prodrug method that may facilitate the selective release of drugs in cancer cells.

We have previously reported that the carborane compound BE360, a novel selective estrogen receptor modulator, has a therapeutic potential against dementia. This study aimed to explore the effects and underlying mechanisms of BE360 on depression-like behaviors in ovariectomized (OVX) mice subjected to subchronic stress, which are postmenopausal depression models. BE360 was subcutaneously administrated using a mini-osmotic pump, for 2 weeks. Depression-like behaviors were evaluated using the forced swimming test. Neurogenesis in the hippocampal dentate gyrus (DG) was measured by analyzing cells expressing doublecortin (DCX) following 5-bromo-2’-deoxyuridine (BrdU) uptake. The levels of phosphorylated cyclic-AMP response element-binding protein (p-CREB), brain-derived neurotrophic factor (BDNF), and Bcl-2 were measured using immunohistochemistry or immunoblotting. Depression-like behaviors in OVX + Stress-exposed mice improved after chronic treatment with BE360. BE360 treatment in OVX + Stress-exposed mice increased p-CREB, BDNF, and Bcl-2 expressions in the hippocampus. Immunohistochemistry showed that the number of BrdU/DCX double-positive cells in the DG of the hippocampus, which decreased significantly in OVX + Stress-exposed mice, increased after subchronic treatment with BE360. The present study demonstrates that BE360 exerts antidepressant effects via hippocampal neurogenesis, potentially activated through CREB/BDNF, Bcl-2 signaling pathways. These results indicate that BE360 may have therapeutic potential against postmenopausal depression.

The identification of novel drug targets for the treatment of ischemic stroke is currently an urgent challenge. Recent experimental findings have highlighted the neuroprotective potential of immunomodulatory strategies, based on polarization of myeloid cells toward non-inflammatory, beneficial phenotypes. Given the role of retinoid X receptors (RXR) in myeloid cells differentiation and polarization, here we have explored the neuroprotective potential of the RXR agonist bexarotene in mice subjected to focal cerebral ischemia. Acute administration of bexarotene significantly reduced blood brain barrier leakage, brain infarct damage and neurological deficit produced by transient middle cerebral artery occlusion in mice, without affecting cerebral blood flow. The rexinoid exerted neuroprotection with a wide time-window, being effective when administered up to 4.5h after the insult. The amelioration of histological outcome, as well as the ability of bexarotene to revert middle cerebral artery occlusion (MCAo)-induced spleen atrophy, was antagonised by BR1211, a pan-RXR antagonist, or by the selective peroxisome proliferator-activated receptor (PPAR)γ antagonist bisphenol A diglycidyl ether (BADGE), highlighting the involvement of the RXR/PPARγ heterodimer in the beneficial effects exerted by the drug. Immunofluorescence analysis revealed that bexarotene elevates Ym1-immunopositive N2 neutrophils both in the ipsilateral hemisphere and in the spleen of mice subjected to transient middle cerebral artery occlusion, pointing to a major role for peripheral neutrophil polarization in neuroprotection. Thus, our findings suggest that the RXR agonist bexarotene exerts peripheral immunomodulatory effects under ischemic conditions to be effectively repurposed for the acute therapy of ischemic stroke.

Candidates for highly selective estrogen receptor-beta (ERβ) ligands (6a-c, 7a-c, 8a and 8b) were designed and synthesized based on carborane-containing ER ligands 1 and 2 as lead compounds. Among them, p-carboranylcyclohexanol derivatives 8a and 8b exhibited high ERβ selectivity in competitive binding assay: for example, 8a showed 56-fold selectivity for ERβ over ERα. Docking studies of 8a and 8b with the ERα and ERβ ligand-binding domains (LBDs) suggested that the p-carborane cage of the ligands is located close to key amino acid residues that influence ER-subtype selectivity, that is, Leu384 in the ERα LBD and Met336 in the ERβ LBD. The p-carborane cage in 8a and 8b appears to play a crucial role in the increased ERβ selectivity.

We designed and synthesized novel m-carborane-containing selective estrogen receptor modulator (SERM) candidates using previously reported m-carborane-containing ER partial agonist 1 as the lead compound. Biological activities were evaluated by means of ERα competitive binding assay and MCF-7 cell proliferation assay. Re-positioning the N,N-dimethylaminoethyloxy group at the para position of 1 to the meta position enhanced the ERα-binding affinity, and 4c showed the highest relative binding affinity (RBA: 83 vs 17β-estradiol = 100) among the tested compounds. Compound 4b showed the most potent ER-agonist activity (EC50: 1.4 nM) and the lowest maximal efficacy (Emax: 50%) in MCF-7 cell proliferation assay. Inhibition of 0.1 nM 17β-estradiol-induced MCF-7 cell proliferation by 4b (IC50: 0.4 μM) was at least 10 times more potent than that of the lead compound 1.

We have reported the design and synthesis of novel estrogen receptor (ER) agonists with a diphenylamine skeleton, which has several advantages over the formerly used diphenylmethane skeleton for drug development. Here, we confirmed the versatility of the diphenylamine skeleton by designing and synthesizing ER antagonist candidates bearing a basic alkylamino side chain on one of the two phenol groups of the diphenylamine agonist core structure. Among the tested compounds, cyclic alkylamine-containing derivatives showed more potent ER-antagonistic activity than the corresponding acyclic derivatives in cell proliferation assay using the MCF-7 cell line. Compound 5e showed the most potent antiestrogenic activity (IC50: 1.3×10(-7)M), being 10times more potent than tamoxifen.

The two subtypes of estrogen receptor (ER), ERα and ERβ, differ greatly in expression pattern and biological functions, and ERβ-selective ligands candidates to treat immune-related disorders. ERβ-selective ligands have mostly been designed based the idea of introducing a substituent that interferes sterically with the ligand's interaction with Met421 to selectively decrease the affinity for ERα (the equivalent residue in ERβ is Ile373). Therefore, we designed and synthesized a series of carboranyl phenol derivatives bearing an aliphatic substituent as candidate ERβ-selective ligands. Introduction of a longer aliphatic substituent into the carboranyl moiety enhanced the ERβ selectivity of o-carboranyl phenol derivatives 4, but not m-carboranyl bisphenol derivatives 5. Compound 4c showed 7.4-fold ERβ selectivity in ER-binding assay and exhibited moderate estrogenic activity in cell proliferation assay using MCF-7 cell line.

Based on structure–activity relationship studies of the benzoic acid part of diphenylamine-based retinoids, the potent RXR agonist 4 was derivatized to obtain retinoid agonists, synergists, and an antagonist. Cinnamic acid derivatives 5 and phenylpropionic acid derivatives 6 showed retinoid agonistic and synergistic activities, respectively. The difference of the activities is considered to be due to differences in the flexibility of the carboxylic acid-containing substituent on the diphenylamine skeleton. Compound 7 , bearing a methyl group at the meta position to the carboxyl group, was an antagonist, dose-dependently inhibiting HL-60 cell differentiation induced by 3.3 × 10 −10 M Am80.

1-(4-Methoxyphenyl)-12-hydroxymethyl-p-carborane (2a), which is a precursor to the previously developed potent carborane-containing ER agonist BE120, exhibited weak cell growth inhibitory activity against four human cancer cell lines (MCF-7, MDA-MB-453, LNCaP, and PC-3). The biological evaluation of a series of derivatives of 2a revealed that an increased number of methoxy groups on the benzene ring of 2a enhanced the cell growth inhibitory activity. Trimethoxyphenyl derivative 2g afforded the most potent cell growth inhibitory activity (mean GI50 value: 5.8 μM) in a panel screening using 39 human cancer cell lines. Moreover, 2g induced for MDA-MB-453 breast cancer cell lines an arrest of the cell cycle in the G2/M phase and apoptosis mediated by caspase-3/7.

Based upon the structure–activity relationships of diphenylamine derivatives with retinoid synergistic activity (RXR agonists), novel diphenylamine derivatives with a long alkyl chain (9a and 9b) or a benzyl group (10a–f) as the N-substituent were designed and synthesized. All the synthesized compounds dose-dependently inhibited HL-60 cell differentiation induced by 3.3 × 10−10 M Am80. Among them, compound 10f showed the most potent inhibitory activity, and the mechanism was shown, by means of transactivation assay for RARs and RXRs, to involve antagonism against RARs. The N-substituent of the diphenylamine skeleton plays an important role in determining the receptor selectivity for RARs or RXRs, as well as the agonist or antagonist nature of the activity.

Background Omega-3 polyunsaturated fatty acids, including docosahexaenoic acid (DHA), have antidepressant and promnemonic functions. The mechanisms of such activities are still elusive and may involve retinoid X receptors (RXRs), transcription factors known to bind DHA in vitro. Methods Promnemonic and antidespair activities of acute DHA treatment were tested in BALBcByJ mice using spontaneous alternation and forced swim test, respectively. The involvement of retinoid receptors in such DHA activities was investigated using RXR and/or retinoic acid receptor (RAR) agonists to mimic DHA activities or a synthetic pan-RXR antagonist to block them. Involvement of RXR isotypes was analyzed using the same tasks and delayed nonmatch to place for working memory in RXRγ knockout mice. Results Docosahexaenoic acid decreased despair behavior and improved working memory in BALBcByJ mice. Such effects were suppressed by co-treatment with BR1211, a pan-RXR antagonist, whereas a pan-RXR agonist, UVI2108, mimicked DHA activities. Retinoic acid (RA), a natural ligand of RXRs, also reduced despair behavior and improved working memory and such activities did not require activation of RARs, as RA effects were abolished by co-treatment with BR1211 and they were not reproduced by TTNPB, a pan-RAR agonist. The RXRγ knockout mice displayed increased despair and deficits in working memory, which were insensitive to DHA and pan-RXR agonist treatments, whereas DHA or UVI2108 reversed these deficits in RXRγ heterozygous mice. Conclusions Our data suggest that RXRs are a converging point in mediating DHA and RA modulations of despair behavior and working memory and that RXRγ is the predominant RXR isotype in these regulations.

A 1,3,5-substituted benzene platform has been widely used in the fields of supramolecular chemistry and molecular recognition. Here, we show that 1,3,5-tris(2-benzyl-o-carboran-1-yl)benzene 6 exhibits solvent-dependent conformation in the crystalline state. Recrystallization from dichloromethane-n-pentane gave the anti conformation 6-anti, while recrystallization from methanol-acetone gave the syn conformation 6-syn, in which the three benzyl-o-carboranyl moieties are located to one side of the central benzene ring. Interestingly, one acetone molecule is captured in the π-rich space of 6-syn and two complexes facing each other encapsulate two acetone molecules in a π-rich container formed by the eight benzene rings. The inclusion involves several weak interactions, that is, T-shaped C-H···π interactions, and C-H···O and C-H···π interactions. Two C-H···O interactions involving benzylic C-H hydrogens activated by the electron-withdrawing character of the o-carborane cage and the oxygen atom of the acetone seem to be the most important. DFT calculations indicate that the binding energy for entrapment of acetone is 6.6 kcal/mol. Inclusion of acetone is achieved through not only multiple C-H···O interactions but also a number of C-H···π interactions. The third benzyl-o-carborane moiety is fixed in the syn conformation by intramolecular and intermolecular C-H···π interactions.

A new approach to creating noncovalent charge transfer ensembles is described. It is based on two components that are linked through anion-receptor interactions. The first component is sapphyrin, a pentapyrrolic expanded porphyrin, which is capable of carboxylate anion recognition and more importantly can act as a photodonor when irradiated in the presence of a suitable electron acceptor. The second component is the electron acceptor and consists of one of two different C(60) fullerene cores functionalized with multiple carboxylate anion groups arranged in a dendritic fashion. Depending on the specific choice of the fullerene carboxylate anion dendrimer employed in ensemble construction, 1:1 or 1:2 complexes are formed when the C(60) cores are titrated with sapphyrin. The resulting noncovalent arrays undergo sapphyrin-to-fullerene electron transfer when irradiated with 387 nm light. This gives rise to charge separated states with lifetimes of ca. 470 and 600 ps in the case of the 1:1 and 1:2 sapphyrin-fullerene ensembles, respectively.

A novel type of demethylation reaction was designed in the Pd-catalyzed coupling reaction of iodocarboranes with several Grignard reagents, CH3OPhMgBr. 3-Iodo-o-carborane 1 reacted with 2-CH3OPhMgBr to afford the corresponding phenol compound 4b in 78% yield. However, when compound 1 was reacted with the other Grignard reagents, the corresponding methoxyl compounds 5a and 6a were obtained in excellent yields. 2-Iodo-p-carborane 3 reacted with 2-CH3OPhMgBr to afford the corresponding phenol 8b in 50% yield and the methoxyl compound 8a in 41% yield. The carborane C–H geometry, which can form an intramolecular C–H⋯O hydrogen bonding, seems to be an important factor in the demethylation process. To examine the mechanism of the demethylation, compounds 1 and 4a were treated with CH3MgBr and quenched with D2O. While the two C–Hs of compound 1 were completely deuterated, compound 4a showed a replacement of one C–H with C–D. Therefore, we propose a mechanism involving intramolecular C–Mg⋯O interaction instead of intramolecular C–H⋯O interaction, via the generation of 3-iodo-o-carboranyl(MgBr)2, 11. Since it is also possible to replace the C–Hs with various metals other than Mg, new applications of carboranes in coordination and metal catalyst chemistry can be expected.

β-Cyclodextrin formed the most robust complexes with o -carboranols 1b and 1c in aqueous solution, and the association constants estimated from NMR titration studies indicated K a >1 × 10 6 M −1 and K a = 6 × 10 5 M −1 , respectively.

Three series of diesters of 4‐alkoxyphenols containing 12‐vertex p‐carborane (1A[n], n = 1–22), 10‐vertex p‐carborane (1B[n], n = 1–12) or bicyclo[2.2.2]octane (1C[n], n = 1–12) as the central stru...

Four series of mesogenic derivatives of p‐carborane (series A[0] and A[1]) and their benzene analogues (series B[0] and B[1]) with variable linking groups were prepared and investigated for phase b...

2-(2-Hydroxyphenyl)- p -carborane forms an intramolecular hydrogen bonding based on the results of X-ray, IR, and 1 H NMR studies. The hydrogen bonding is released by the addition of acid in solution. Density functional theory (DFT) calculations on the phenol, phenolate and protonated phenol structures indicated two stable conformational state, hydrogen bonding form for phenol and phenolate, and dihydrogen bonding form for protonated phenol.

C-Hydroxylated carboranes, carboranols, have interesting properties resulting from their hydroxyl protons being highly acidic because of the electron-deficient nature of the carborane cage. We described here an efficient synthesis of C-hydroxycarboranes 2 and C,C'-dihydroxycarboranes 3 by the reaction of carboranyl lithium and trimethylborate, followed by oxidation with hydrogen peroxide in the presence of acetic acid, to afford the corresponding o-, m-, and p-hydroxycarboranes 2 and o-, m-, and p-dihydroxycarboranes 3 selectively in high yields through a one-pot procedure. The m- and p-carborane isomers of 2 and 3 were obtained in especially good yields (2b, 85%; 2c, 85%; 3b, 95%; 3c, 96%). DFT calculations were performed on the dihydroxycarboranes 3 to compare the geometrical features of the isomers at the same level of theory and to characterize their electronic and NMR spectroscopic (13C chemical shift) properties.

The icosahedral boron cluster : dicarba-closo-dodecaboranes (carboranes) are chemical building blocks of high boron content, remarkable chemical stability, spherical geometry and hydrophobic molecular surface. These features of carboranes may allow wide variety of application for molecular construction, medicinal chemistry and materials sciences. However, little attention has been paid to the understanding their nature in view of synthetic organic chemistry. We have aimed to understand their electronic property, reactivity and to apply their spherical geometry for design and synthesis of biologically active molecules and three-dimensional structures. In this review, we describe development of synthetic methods on the carborane cage, evaluation of the characteristic electronic effects and steric effects of carborane, molecular construction based on spatial definition by carborane and evaluation and application of the hydrogen-bonding affinity of carboranes.

We designed and synthesized 4,4'-(piperidin-4-ylidenemethylene)bisphenol derivatives as novel tunable estrogen receptor (ER) modulators. The introduction of hydrophobic substituents on the nitrogen atom of the piperidine ring enhanced ERα binding affinity. In addition, the introduction of four methyl groups adjacent to the piperidine ring nitrogen atom remarkably enhanced ERα binding affinity. N-Acetyl-2,2,6,6-tetramethylpiperidine derivative 3b showed high ERα binding affinity, high MCF-7 cell proliferation inducing activity, and high metabolic stability in rat liver S9 fractions.

Monoalkylated bis(4-hydroxyphenyl)methanes (e.g., 1) are reported to show weak binding affinity for estrogen receptor (ER). We hypothesized that introduction of appropriately located hydrophobic substituents in these compounds would increase the binding affinity. Indeed, we found that bis(4-hydroxyphenyl)methane bearing a 3,3-dimethylcyclohexyl group (7) shows potent ERα binding affinity, comparable to that of estradiol. Bulkier substituents could be introduced at the 3,3-position without decreasing the affinity. However, the position of the substituents was critical: the 4,4-dimethylcyclohexyl derivative (2) showed very weak binding affinity. The compounds with high ER-binding affinity showed predominantly agonistic activity, together with weak antagonistic activity at high concentration, in cell proliferation assay with human breast cancer cell line MCF-7. Further structure-function studies of these compounds and their derivatives might lead to the development of more selective and potent estrogen receptor modulators.

We have reported that the carborane compound BE360 is a novel selective estrogen receptor modulator and new therapy option for osteoporosis. The aim of this study was to explore the effects and underlying mechanisms of BE360 on depressive-like behavior and memory impairment in the olfactory bulbectomized (OBX) mice, an experimental animal model of depression and dementia. BE360 was administered subcutaneously to mice using a mini-osmotic pump for 2 weeks. Depressive-like behavior was measured as the reduced intake of a sweet solution in the sucrose preference test. Short-term memory was assessed using the Y-maze test. Cell proliferation was assessed by the analysis of cells expressing 5-bromo-2'-deoxyuridine (BrdU) uptake. The expression of phosphorylated cyclic-AMP response element binding protein (pCREB) and brain-derived neurotrophic factor (BDNF) were measured by immunoblot. The depressive-like behavior and memory impairment in OBX mice were improved by the chronic treatment with BE360. Immunohistochemical analysis showed that the number of BrdU-positive cells in the dentate gyrus of the hippocampus significantly decreased in OBX mice whereas they increased after the chronic treatment with BE360. Immunoblotting studies revealed that pCREB and BDNF were significantly increased in the hippocampus of OBX mice treated with BE360. The present study has shown that BE360 has antidepressant and antidementia effects characterized by hippocampal cell proliferation potentially activated via CREB/BDNF signaling pathways. These results indicate that BE360 may have valuable therapeutic potential against depression and neurodegenerative diseases.

A series of m -carborane derivatives was prepared based upon the structures of antiestrogenic drugs and their activities were evaluated by estrogen receptor alpha (ERα) binding assay and transactivation assay using human breast cancer cell line, MCF-7 cells. The m -carborane bisphenol 5 exhibited about a thousand times more potent ER agonistic activity than the o -carborane bisphenol 11 . The m -carborane bisphenol structure appears to be a favorable hydrophobic pharmacophore for the development of novel selective estrogen receptor modulators (SERMs).

Dicarba- closo -dodecaborane(12) (carborane) has recently received much attention as a building block for supramolecular assemblies and bioactive compounds. Among carborane isomers, 1,2-dicarba- closo -dodecaborane(12) ( o -carborane) has unique chemical properties, including the ability of the o -carborane C–H hydrogens to form hydrogen bonds. To evaluate intramolecular hydrogen bond formation between the o -carborane C–H hydrogen and various hydrogen bond acceptors in solution, we have designed and synthesized 1-aryl- o -carboranes 2 . Intramolecular hydrogen bonding ability was evaluated by means of 1 H NMR measurement of the o -carborane C–H hydrogen signal of 2 . The 1-(2-methoxyphenyl)- o -carborane derivative 2m appeared to form an intramolecular hydrogen bond between o -carborane C–H hydrogen and the oxygen atom acting as a hydrogen bonding acceptor. In this study, we present evidence for hydrogen bond formation in solution between the o -carborane C–H and hydrogen bond acceptors positioned with appropriate geometry.

A homologous series of carborane‐containing Schiff's bases 1A[n] (n = 1–10) was prepared and compared with the analogous series 1B[n] derived from terephthaldehyde. An exponential fit of the T NI values for both series yielded a quantitative assessment of the effect of ring structure on mesophase stability. This includes the T NI value for n→∞ (86°C for 1A[n] and 209°C for 1B[n]) and steepness of descent (0.135 for 1A[n] and 0.095 for 1B[n]). The difference in behaviour of the two series was attributed, largely, to conformational properties of the central rings A and B. Electronic interactions between the central rings and the π‐substituents were investigated by UV spectroscopy and by quantum‐mechanical calculations. The effect of replacement of O with CH2 in the terminal chain of 1[n] on the namatic phase stability was assessed for n = 5–7.

In the crystal structure of 1,2-bis(o-carboranyl)benzene (2), the benzene ring is remarkably twisted out of planarity, owing to the steric bulkiness of two adjacent carboranyl groups. In the carboracycle (3), the two benzene rings are slantingly stacked owing to spatial control by the carborane cages.

3,6-Diiodo-o-carborane 3, 3,6,9-triiodo-o-carborane 5, 3,9,12-triiodo-o-carborane 6 and 3,6,9,12-tetraiodo-o-carborane 7, which are suitable building blocks for supramolecular assemblies and carboracycles, were regioselectively synthesized by means of electrophilic iodination and introduction of iodine atoms via reconstruction of the o-carborane cage.

Synthesis and structural analysis of 1,2-bis(o-carboranyl)benzene were performed to examine the steric effects of the two extremely bulky o-carborane cages at adjacent positions on the planarity of the benzene ring. X-ray crystallographic analysis supported by DFT calculations revealed that the benzene ring is significantly deformed by the bulky o-carboranyl groups.

Several series of structurally related three-ring esters containing benzene, cyclohexane, bicyclo[2.2.2]octane and p-carborane rings were synthesized and their mesogenic properties investigated using thermal analysis and optical microscopy. Carborane derivatives show only nematic phases, while the richest smectic polymorphism (up to three phases) was observed in the biphenyl series D. The structure–property relationships were studied by comparison of T NI between series. The ring effectiveness in stabilization of nematic phases generally follows the order carborane

The inorganic cage compounds, dicarba-closo-dodecaboranes (carboranes), are chemical building blocks of remarkable thermal and chemical stability, with spherical geometry and exceptional hydrophobic character. We have focused on medicinal drug design using carboranes as a hydrophobic pharmacophore and have developed a potent estrogen agonist, BE120. We also have applied carboranes for structural chemistry, utilizing their specific three-dimensional character to obtain multilayer aromatic structures.

We previously identified o -carborane bisphenol BE360 ( 4 ) as a selective estrogen receptor modulator (SERM), which ameliorated bone loss without inducing estrogenic action in uterus of OVX and ORX mice. Here, we synthesized a fluorinated derivative, B -fluorinated o -carborane bisphenol BE310 ( 5 ) by means of S N Ar reaction. Compound 5 was a partial ER agonist, like 4 , with little change of ERα and ERβ selectivity as compared with 4 . However, its agonistic activity was 40 times weaker than that of 4 . Thus, 5 is a novel SERM candidate with potential for reduced estrogenic side effects, and in vivo evaluation as an anti-osteoporosis agent seems warranted.

Several 2-(arylamino)pyrimidine-5-carboxylic acids were designed as novel retinoid X receptor (RXR) antagonists. Compound 6a or 6b alone did not exhibit differentiation-inducing activity toward HL-60 cells and did not affect the activity of a retinoic acid receptor (RAR) agonist, Am80, but did inhibit the synergistic activity of an RXR agonist, PA024 (3), in the presence of Am80. The activity of 6 was ascribed to selective antagonism at the RXR site of RXR-RAR heterodimers.