Potent estrogen agonists based on carborane as a hydrophobic skeletal structure

Endo, Yasuyuki; Iijima, Toru; Yamakoshi, Yoshiki; Fukasawa, Hiroshi; Miyaura, Chisato; Inada, Masaki; Kubo, Asako; Itai, Akiko

doi:10.1016/s1074-5521(01)00016-3

Cited by 177 publications

(115 citation statements)

References 34 publications

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“…[3][4][5] We have reported applications of carboranes in medicinal drug design as a hydrophobic component of biologically active molecules, 6) targeting nuclear receptors, such as estrogen receptor (ER), 7,8) androgen receptor (AR), 9,10) retinoic acid receptor (RAR) 11,12) and retinoid X receptor (RXR).…”

Section: Notesmentioning

confidence: 99%

“…1,2) Biomedical applications of the carboranes, e.g., in boron neutron capture therapy (BNCT), are of great interest. [3][4][5] We have reported applications of carboranes in medicinal drug design as a hydrophobic component of biologically active molecules, 6) targeting nuclear receptors, such as estrogen receptor (ER), 7,8) androgen receptor (AR), 9,10) retinoic acid receptor (RAR) 11,12) and retinoid X receptor (RXR). 13) It was suggested that the carborane cage works as a hydrophobic group for binding to the hydrophobic cavity of the ligand-binding domain (LBD) on the nuclear receptors, and that hydrophobic van der Waals contacts along the spherical carborane cage produce a stronger interaction than that in the case of the native ligand.…”

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confidence: 99%

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Complexation of .ALPHA.-Cyclodextrin with Carborane Derivatives in Aqueous Solution

Ohta

Konno

Endo

2009

CHEMICAL & PHARMACEUTICAL BULLETIN

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NotesIcosahedral carboranes (dicarba-closo-dodecaboranes) have unique structural and chemical properties, such as high boron content, spherical structure, three isomers (ortho, meta and para), a highly hydrophobic surface, and unexpected thermal and chemical stability (Fig. 1).1,2) Biomedical applications of the carboranes, e.g., in boron neutron capture therapy (BNCT), are of great interest. [3][4][5] We have reported applications of carboranes in medicinal drug design as a hydrophobic component of biologically active molecules, 6) targeting nuclear receptors, such as estrogen receptor (ER), 7,8) androgen receptor (AR), 9,10) retinoic acid receptor (RAR) 11,12) and retinoid X receptor (RXR).13) It was suggested that the carborane cage works as a hydrophobic group for binding to the hydrophobic cavity of the ligand-binding domain (LBD) on the nuclear receptors, and that hydrophobic van der Waals contacts along the spherical carborane cage produce a stronger interaction than that in the case of the native ligand. In the development of carborane-containing estrogen ligands, we have investigated the hydrophobicity of carboranes by measuring the partition coefficients, log P values, and the hydrophobicity parameter p. 14,15) Cyclodextrins (CDs) are widely used as host molecules in a number of areas of chemistry where molecular recognition is required, such as material sciences, supramolecular chemistry, molecular-sensing, and artificial enzymes (Fig. 1). Moreover, CDs are of great utility in the field of medicinal chemistry as solubilizing agents for lipophilic drugs, [16][17][18] as photostabilizers of light-sensitive drugs, [19][20][21] and as sustained-release [16][17][18] and drug delivery systems [22][23][24] for various drugs.Complexes of a-, b-, and g-CD with unsubstituted ocarborane (1a) were isolated, and the stoichiometries of the complexes were determined by elemental analysis and from the ratios of the 1 H-NMR peaks.25) However, the stoichiometric ratio, association constant and complex formation in solution have not been well characterized. Recently, Threadgill and co-workers have reported the formation of a remarkably robust 2 : 1 complex of b-CD with 1-phenyl-o-carborane. 26)An excellent fit of the carborane cage with b-CD was confirmed by a molecular modelling study. This work dealt only with the o-carborane isomer. The attractive properties of mand p-carboranes 27) mean that complexation of these molecules with CDs is also of interest. It is noteworthy that b-CDbonded chiral stationary phases have been used for enantiomeric resolution in the ten-vertex carborane series, 28,29) implying a strong interaction of ten-vertex carborane with b-CD.However, the host-guest complexations of carboranes with CDs are not well understood. Therefore, we have focused on the interaction between the spherical, hydrophobic surface of carboranes and the hydrophobic pocket of CDs. Recently, we reported the complexation of carborane derivatives with b-CD, including association constant values and stoichiometry in aqueous ...

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Section: Notesmentioning

confidence: 99%

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confidence: 99%

Complexation of .ALPHA.-Cyclodextrin with Carborane Derivatives in Aqueous Solution

Ohta

Konno

Endo

2009

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…It was reported that the C-and D-rings of E2 play an important role in stabilizing the ligand-receptor complex by the hydrophobic interactions. 22,23) In the case of NPs 6-8, the dimethyl or ethyl branch on the γ-or δ-carbon might play a role in the hydrophobic C and/ or D ring of E2.…”

Section: Relationship Between Estrogenic Activity and Structure Of Nomentioning

confidence: 99%

Estrogenic Activity of Branched 4-Nonylphenol Isomers Examined by Yeast Two-Hybrid Assay

Shioji

Tsunoi

Kobayashi

et al. 2006

JOURNAL OF HEALTH SCIENCE

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Various branched isomers of 4-nonylphenol (NP) and, in addition, the other 4-alkylphenols (APs) were synthesized and their estrogenic activities were assessed using the yeast two-hybrid system. We investigated the relationships between the structure of the nonyl group of NP isomers and their estrogenic activities based on the following five factors: the length of the main alkyl chain, the degree of branching on the α-carbon, the degree of bulkiness, the position of the branch, and the cyclic structure in the nonyl group. An appropriate length of the main alkyl chain was essential for the estrogenic activity. A small effect of the branching on the α-carbon was observed. The importance of the bulkiness and position of the branch in the nonyl group was suggested from the results of the synthesized NP isomers possessing the high estrogenic activities. The bulkiness on the β-carbon was the most important factor for the high estrogenic activity. The investigation of the cyclic structure also indicated the significance of the bulkiness around the β-carbon. The bulkiness on the γ-carbon was also suggested to be an important factor. The metabolic effect of the synthesized APs on the estrogenic activity was also examined using a liver S9. The estrogenic activities of the selected APs were either reduced or lost. In addition, GC-MS analyses of the commercial NP and synthesized NP isomers revealed that the nine synthesized NP isomers were included in the commercial NP.

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“…Indeed, carborane-containing ligands exhibited the enhanced binding affinities to a number of receptors/enzymes proteins (e.g., estrogen receptor, androgen receptor, HIV protease) compared to non-carborane ligands. [5][6][7][8][9][10][11] Despite the utilization of closo-carboranes as hydrophobic scaffolds in drug design and as boron-delivery moieties for BNCT has expanded, in silico molecular modeling of carborane-containing molecules with macromolecules including docking studies, scoring functions and virtual screening have been rarely reported.…”

Section: 4mentioning

confidence: 99%

Facile Docking and Scoring Studies of Carborane Ligands with Estrogen Receptor

Ok¹,

Jung²,

Jee

et al. 2013

Bulletin of the Korean Chemical Society

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Closo-carborane has been considered as an efficient boron-carrier for boron neutron capture therapy (BNCT) and an attractive surrogate of lipophilic phenyl or cyclohexyl ring in drug design. Despite a great number of carborane-containing ligands have been synthesized and evaluated, molecular modeling studies of carborane ligands with macromolecules have been rarely reported. We herein describe a facile docking and scoringfunction strategy of 16 carborane ligands with an estrogen receptor by using the commercial Gaussian, Chem3D Pro and Discovery Studio (DS) computational programs. Docked poses of the carborane ligands in silico exhibited similar binding modes to that of the crystal ligand in the active site of estrogen receptor. Score analysis of the best docked pose for each ligand indicated that the Ligscore1 and the Dockscore have a moderate correlation with in vitro biological activity. This is the first report on the scoring-correlation studies of carborane ligands with macromolecules. The integrated Gaussian-DS approach has a potential application for virtual screening, De novo design, and optimization of carborane ligands in medicinal chemistry.

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Potent estrogen agonists based on carborane as a hydrophobic skeletal structure

Cited by 177 publications

References 34 publications

Complexation of .ALPHA.-Cyclodextrin with Carborane Derivatives in Aqueous Solution

Complexation of .ALPHA.-Cyclodextrin with Carborane Derivatives in Aqueous Solution

Estrogenic Activity of Branched 4-Nonylphenol Isomers Examined by Yeast Two-Hybrid Assay

Facile Docking and Scoring Studies of Carborane Ligands with Estrogen Receptor

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