Tokuhito Goto

Design and Synthesis of Androgen Receptor Full Antagonists Bearing a p-Carborane Cage: Promising Ligands for Anti-Androgen Withdrawal Syndrome

Pure androgen receptor (AR) full antagonists are candidates to treat anti-androgen refractory prostate cancers. We previously developed a carborane-containing AR antagonist, 3-(12-hydroxymethyl-1,12-dicarba-closo-dodecaborane-1-yl)benzonitrile (BA341), which was more potent than hydroxyflutamide (4) but acted as an agonist toward LNCaP prostate cancer cells expressing T877A AR mutant. Here, we designed and synthesized novel AR full antagonists structurally based upon the clinically used AR full antagonist (R)-bicalutamide (5) to test our hypothesis that the carborane cage is suitable as a hydrophobic pharmacophore for AR ligands. Compounds 7b and 8b showed good biological profiles in AR binding and transactivation assays and dose-dependently inhibited the testosterone-induced proliferation of LNCaP cells, as well as SC-3 cells. The IC(50) values of compounds 7b and 8b were 3.8 x 10(-7) and 4.2 x 10(-7) M, respectively [5, 8.7 x 10(-7) M]. Since compounds 7b and 8b did not show any agonistic activity in functional assays, they seem to be pure AR full antagonists and are therefore candidates for treatment of anti-androgen withdrawal syndrome.

Acidic heterocycles as novel hydrophilic pharmacophore of androgen receptor ligands with a carborane core structure.

A novel series of androgen receptor (AR) ligands bearing an acidic heterocycle with hydrogen-bonding ability as the terminal polar group was developed. Since most non-steroidal AR ligands so far known are structurally limited to nitro- or cyanobenzanilide as the polar pharmacophore, development of alternative hydrogen-bonding components is required to obtain novel AR ligands. Various acidic heterocycles were introduced into a hydrophobic phenylcarborane (1-phenyl-1,12-dicarba-closo-dodecaborane) core structure to provide a moiety that could interact effectively with the critical basic arginine residue of the AR ligand binding domain. The most potent compounds, 1,2,4-oxadiazole-5-thione derivatives 21a and 21b, exhibited higher affinity for hAR than did the well-known anti-androgen hydroxyflutamide. The results suggest that this heterocyclic functionality is potential bioisoster of the nitro and cyano groups forming the polar pharmacophores of known non-steroidal AR ligands.

Design and synthesis of carborane-containing androgen receptor (AR) antagonist bearing a pyridine ring.

We previously developed carborane-containing potent AR antagonists, BA321 and BA341, on the basis of our hypothesis that the carborane cage would be an excellent hydrophobic pharmacophore in place of steroidal C and D rings. As an extension of that work, we designed and synthesized carborane-containing AR antagonist candidates with a pyridine ring. Compound 6b, which has a pyridine ring directly bound to the p-carborane cage at the 3-position, exhibited potent AR-antagonistic activity in transcriptional activation assay using NIH3T3 cells transfected with a hAR-expression plasmid. In addition, it showed more potent antiandrogenic activity than that of the well-known antiandrogen flutamide and comparable activity to that of (R)-bicalutamide in SC-3 cell proliferation assay.

Crystal structure, docking study and structure-activity relationship of carborane-containing androgen receptor antagonist 3-(12-hydroxymethyl-1,12-dicarba-closo-dodecaboran-1-yl)benzonitrile.

A potent androgen receptor (AR) antagonist, 3-(12-hydroxymethyl-1,12 dicarba-closo-dodecaboran-1-yl)benzonitrile (3a, BA341), contains a p-carborane cage as a hydrophobic pharmacophore. We elucidated the structural properties of 3a by means of single-crystal X-ray diffraction analysis and conducted a docking study of 3a with hAR LBD. The cyano group of 3a formed hydrogen bonds with Gln711 and Arg752 and the hydroxymethyl group did so with Asn705 and Thr877 in hAR LBD. The bulky p-carborane cage was accommodated in the hydrophobic pocket of hAR LBD. To understand the structure-activity relationship around the hydroxymethyl group of 3a, we designed, synthesized, and evaluated the biological activities of various novel AR ligands. Since the biological activities of carbonyl compounds 8a, 8b, and 8c were similar to or weaker than those of the parent hydroxyl compounds 3a, 7a, and 7b, it seems to be necessary to have not only a hydrogen bonding acceptor, but also a hydrogen bonding donor adjacent to the hydroxymethyl group of 3a for efficient interaction with hAR LBD.

p-Carborane-based androgen antagonists active in LNCaP cells with a mutated androgen receptor

Development of antagonists for a mutated androgen receptor (AR) is important for treatment of anti-androgen-refractory prostate cancers. We describe here application of the p-carborane cage as a hydrophobic core structure for novel anti-androgens active toward LNCaP human prostate cancer cells with mutated AR. These compounds are expected to be versatile lead compounds not only for development of AR pan-antagonists, but also for discovery of mutant-selective anti-androgens.

Development of androgen receptor ligands by application of ten-vertex para-carborane as a novel hydrophobic core structure

We report here the design, synthesis, androgenic activity and anti-androgenic activity of novel derivatives of hexadecahedral 1,10-dicarba-closo-decaborane, which is generally called ten-vertex para-carborane. The synthesized compounds exhibited very high binding affinity for the androgen receptor and showed anti-androgenic activity toward the androgen-dependent SC-3 cell line. Two compounds also exhibited partial agonistic activity in SC-3 assay. The docking studies of carborane derivatives to AR demonstrate that ten-vertex carborane is useful for development of novel bioactive compounds as well as twelve-vertex carboranes that are well known to be versatile pharmacophores. Ten-vertex carborane, which has not previously been applied in the field of medicinal chemistry, appears to have potential as a hydrophobic pharmacophore with characteristic properties.

Novel androgen receptor full antagonists: Design, synthesis, and a docking study of glycerol and aminoglycerol derivatives that contain p-carborane cages

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.