Dicarba-closo-dodecaboranes as a Pharmacophore. Retinoidal Antagonists and Potential Agonists.

Iijima, Toru; Endo, Yasuyuki; Tsuji, Motonori; Kawachi, Emiko; Kagechika, Hiroyuki; Shudo, Koichi

doi:10.1248/cpb.47.398

Cited by 64 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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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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Complexation of .ALPHA.-Cyclodextrin with Carborane Derivatives in Aqueous Solution

Ohta

Konno

Endo

2009

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…The required aldehyde 10 was prepared by an unusual partial reduction of known ester 9. 10 The reaction of allyltin reagent 12 and 13 (obtained in two steps from commercially available angelic acid methyl ester and tiglic acid, respectively) 11 with aldehyde 10 in the presence of a stoichiometric amount of BF 3 .Et 2 O provided syn-11 in quantitative yield, as a 2.6:1 and 6.5:1 mixture of diastereomers, respectively. Given literature precedents, the major diastereomer was assumed to be the syn isomer.…”

Section: Synthesis Of the Alkyne Coupling Partnermentioning

confidence: 99%

Ru‐Catalyzed Alkene—Alkyne Coupling. Total Synthesis of Amphidinolide P.

2006

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A coordinatively unsaturated ruthenium complex catalyzed the formation of a carbon-carbon bond between two judiciously chosen alkene and alkyne partners in good yield, and in a chemo-and regioselective fashion, in spite of the significant degree of unsaturation of the substrates. The resulting 1,4-diene forms the backbone of the cytotoxic marine natural product amphidinolide P. The alkene partner was rapidly assembled from (R)-glycidyl tosylate, which served as a linchpin in a one-flask, sequential three-components coupling process using vinyllithium and a vinyl cyanocuprate. The synthesis of the alkyne partner made use of an unusual anti-selective addition under chelation control conditions of an allyltin reagent derived from tiglic acid. In addition, a remarkably E-selective E 2 process using the azodicarboxylate-triphenylphosphine system is featured. Also featured is the first example of the use of a β-lactone as a thermodynamic spring to effect macrolactonization. The oxetanone ring was thus used as a productive protecting group that increased the overall efficiency of this total synthesis. This work was also an opportunity to further probe the scope of the rutheniumcatalyzed alkene-alkyne coupling, in particular using enynes, and studies using various functionalized substrates are described.

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“…Carboranes have high thermal and chemical stability, and exceptionally high hydrophobicity, [26][27][28][29] and we have applied them as hydrophobic core structures of a variety of bioactive compounds, especially ligands for a number of nuclear receptors. [30][31][32][33][34][35] We have reported that p-carborane derivatives rac-5 and 6 (Fig. 2b), bearing a 4-cyanophenyl group on one carbon atom of p-carborane and an alcohol or a ketone group on the other carbon atom, exhibited PR-antagonistic activity at sub-nanomolar concentration.…”

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Novel Non-steroidal Progesterone Receptor Ligands Based on <i>m</i>-Carborane Containing a Secondary Alcohol: Effect of Chirality on Ligand Activity

Mori

Takagaki

Fujii

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

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The progesterone receptor (PR) controls various physiological processes, including the female reproductive system, and nonsteroidal PR ligands are considered to be drug candidates for treatment of various diseases without significant adverse effects. Here, we designed and synthesized m-carborane-based secondary alcohols and investigated their PR-ligand activity. All the synthesized alcohols exhibited PR-antagonistic activity at subnanomolar concentration. Among them, alcohols having a small alkyl side chain and a 4-cyanophenyl group also exhibited PR-agonistic activity in a relatively high concentration range. Optical resolution of secondary alcohols having a methyl side chain was performed, and the PR-ligand activity and PR-binding affinity of the purified enantiomers were examined. The chirality of the secondary alcohol appears to have a more significant influence on PR-agonistic activity than on antagonistic activity.Key words progesterone receptor; antagonist; carborane; chirality; lipase The progesterone receptor (PR) is a member of the nuclear receptor superfamily and plays important roles in many physiological processes, especially in the female reproductive system, via ligand-dependent transcriptional activation of various target genes.1) Progesterone (1, Fig. 1) is an endogenous PR agonist that regulates many physiological processes, [2][3][4][5] including uterine cell proliferation/differentiation, the ovulation cycle, and implantation. In addition, 1 modulates the activities of major physiological systems such as the cardiovascular , 6) immune, 7) and nervous systems. 8) Several synthetic PR agonists and antagonists have been developed for clinical use [9][10][11] in contraception, hormone replacement therapy, treatment of gynecological disorders, and abortion. For example, synthetic PR antagonist mifepristone (2, Fig. 1) is a representative abortifacient.12) It has also been suggested that 2 might be effective in the treatment of endometriosis, 13) uterine leiomyoma, 14) and breast cancer. 15,16) However, all PR ligands currently in clinical use, including 2, are steroid derivatives, and may have significant adverse effects because of their cross-activity toward other steroid hormone receptors. 17) In order to avoid these adverse effects, non-steroidal PR ligands are required, and indeed, several non-steroidal ligands have been developed, such as tanaproget (3) 18) and a sulfonamide derivative (4) 19) (Fig. 1). Results and DiscussionWe have reported non-steroidal PR ligands bearing boroncluster compounds (carborane) as their hydrophobic core structures. [20][21][22] Carboranes, more precisely dicarba-closododecaboranes (C 2 B 10 H 12 ), are carbon-containing boron clusters with icosahedral cage structure; there are three isomers depending upon the position of the two carbon atoms, that is, ortho-, meta-, and para-carborane [23][24][25] (Fig. 2a). Carboranes have high thermal and chemical stability, and exceptionally high hydrophobicity, [26][27][28][29] and we have applied them as hydrophobic core ...

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Dicarba-closo-dodecaboranes as a Pharmacophore. Retinoidal Antagonists and Potential Agonists.

Cited by 64 publications

References 0 publications

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

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

Ru‐Catalyzed Alkene—Alkyne Coupling. Total Synthesis of Amphidinolide P.

Novel Non-steroidal Progesterone Receptor Ligands Based on <i>m</i>-Carborane Containing a Secondary Alcohol: Effect of Chirality on Ligand Activity

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