Boron clusters for medicinal drug design: Selective estrogen receptor modulators bearing carborane

Abstract

The molecular shape and hydrophobicity of dicarba-closo -dodecaboranes may allow a new medical application as biologically active molecules. Recently, we have developed potent estrogen receptor (ER) agonists bearing carborane cage. The most potent compound (BE120) exhibited activity at least several times greater than that of 17 beta-estradiol in luciferase reporter gene assay and ER alpha binding. We also designed and synthesized estrogen antagonists on the basis of the structure of BE120, and we noticed the characteristic features of compound (BE360) having carborane cage and two phenols. The ER binding affinity of BE360 is comparable to that of estradiol. To examine in vivo estrogenic activity of the compound in bone, ovariectomized (OVX) mice were given BE360 or estradiol subcutaneously for 4 weeks. Treatment with BE360 at 1–30 µg/day dose-dependently restored bone loss in OVX mice to sham level without estrogenic action in uterus. These results suggest its possible application to osteoporosis as a new type of selective ER modulator.

2‐Carbaborane‐3‐phenyl‐1H‐indoles—Synthesis via McMurry Reaction and Cyclooxygenase (COX) Inhibition Activity

“…These properties suggest the use of carbaboranes as phenyl mimetics and their introduction into bioactive structures by replacement of aromatic rings, making them highly interesting targets for the design of novel drugs. [6,10,12] …”

“…Carbaboranes are icosahedral clusters with ten BH and two CH vertices and a volume slightly larger than that of a rotating benzene ring. [1] Besides their use in catalysis and polymer chemistry, [2] carbaborane derivatives were developed for medicinal applications, primarily for use as boron neutron capture therapy (BNCT) agents; [3][4][5] however, their potency as novel pharmacophores in drug development [1,[6][7][8][9][10][11][12][13][14][15] has also been recognized. [16][17][18] In this context, dicarba-closo-dodecaboranes [closo-C 2 B 10 H 12 ] are regarded as promising candidates given their remarkable metabolic stability and low toxicity as well as their high hydrophobicity and three-dimensional aromaticity.…”

Aliphatic Substitution of <i>o</i>-Carboranyl Phenols Enhances Estrogen Receptor Beta Selectivity

“…We have synthesized a range of carboranyl phenol derivatives and have discovered various types of ER modulators, partial agonists, super-agonists, antagonists, and SERMs. [11][12][13][14][15][16][17][18] In addition, our quantitative structure-activity relationship (QSAR) studies of very simple carboranyl phenols showed that the hydrophobicity of the carborane cage is significantly correlated with ERα-binding affinity. 30,31) Although carboraNote * To whom correspondence should be addressed.…”

“…1,9,10) Subsequently, many carboranyl phenol derivatives have been synthesized and their estrogen-related biological activities examined. [11][12][13][14][15][16][17][18] Compounds that either induce or inhibit cellular estrogenic responses are used for estrogen replacement therapy after menopause or the treatment of breast cancer, respectively. [19][20][21] Tissue-selective ligands, which act as agonists for bone metabolism and as antagonists for the female reproductive systems (known as selective estrogen receptor modulators, SERMs) are widely used for the treatment of osteoporosis.…”

Facile Docking and Scoring Studies of Carborane Ligands with Estrogen Receptor

“…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.…”