Yoshiyuki Taoda

Boron Cluster-based Development of Potent Nonsecosteroidal Vitamin D Receptor Ligands: Direct Observation of Hydrophobic Interaction between Protein Surface and Carborane

We report here the design and synthesis of a novel vitamin D receptor (VDR) agonist whose hydrophobic core structure is p-carborane (1,12-dicarba-closo-dodecaborane, an icosahedral carbon-containing boron cluster having remarkable thermal and chemical stability and a characteristically hydrophobic B-H surface). This carborane-based VDR ligand exhibited moderate vitamin D activity, comparable to that of the natural hormone, despite its simple and flexible structure. X-ray structure analysis provided direct evidence that the carborane cage binds to the hydrophobic surface of the ligand-binding pocket of the receptor, promoting transition to the active conformation. These results indicate that the spherical B-H surface of carborane can function efficiently as a hydrophobic anchor in binding to the receptor surface, thereby allowing induced fitting of the three essential hydroxyl groups on the alkyl chains to the appropriate positions for interaction with the VDR binding site, despite the entropic disadvantage of the flexible structure. We suggest that carborane structure is a promising option in the design of novel drug candidates.

Electronic effects of icosahedral carboranes: kinetic evidence for interaction between boron atom and nucleophile in the solvolysis of (o-carboranyl)benzyl tosylates

Abstract Solvolysis of ( o -, m - and p -carboranyl)benzyl toluene- p -sulfonates substituted at the second carbon atom with a phenyl group bearing a range of substituents at the para position has been performed. The rates of hydrolysis of m - and p -carboranyl derivatives measured linearly with increasing electron-releasing character of the substituent group ( ρ =−0.23, ρ =−0.35), which indicates that these carboranes transmit electronic effects, and the substituents affect the stability of the neighboring carbocation. In contrast, the rate of hydrolysis of o -carboranyl derivatives showed a linear decrease with increasing electron-releasing character of the substituent ( ρ =+1.12), which indicates that the interaction between the B(3) atom of the o -carborane cage and the nucleophile controls this particular reaction.

Electronic effects of icosahedral carboranes. Friedel-Crafts acylation of 1-phenyl-1,2-, 1,7-, and 1,12-dicarba-closo-dodecaboranes

Abstract Friedel-Crafts acylation of the benzene nucleus of 1-phenyl-1,2-, 1,7- and 1,12-dicarba- closo -dodecaboranes (phenylcarboranes) proceeded in the presence of trifluoromethanesulfonic acid. In spite of the strong electron-withdrawing effect of the carborane skeleton, para -acylated products predominated. However, substitution of a methyl group at the 2-position of 1-phenyl-1,2-carborane resulted in a change of isomer distribution.

Novel vitamin D receptor ligands bearing a spherical hydrophobic core structure—Comparison of bicyclic hydrocarbon derivatives with boron cluster derivatives

Vitamin D receptor (VDR) is a nuclear receptor for 1α,25-dihydroxyvitamin D(3) (1α,25(OH)(2)D(3)), and is an attractive target for multiple clinical applications. We recently developed novel non-secosteroidal VDR ligands bearing a hydrophobic p-carborane cage, thereby establishing the utility of this spherical hydrophobic core structure for development of VDR ligands. Here, we synthesized two series of novel non-secosteroidal VDR ligands with different spherical hydrophobic cores, that is, bicyclo[2.2.2]octane derivatives and p-carborane derivatives, and compared their biological activities in order to examine the difference between the interactions of the C-H hydrocarbon surface and the B-H carborane surface with the receptor. Carborane derivatives exhibited more potent differentiation-inducing activity toward HL-60 cells than did the corresponding bicyclo[2.2.2]octane derivatives. These results suggest that the hydrophobic carborane cage may interact more efficiently than the hydrocarbons with the hydrophobic surface of VDR. This finding further supports the view that carborane structure is a promising option for drug development.

Synthesis and structure–activity relationship of p-carborane-based non-secosteroidal vitamin D analogs

1α,25-Dihydroxyvitamin D3 [1α,25(OH)₂D₃: 1] is a specific modulator of nuclear vitamin D receptor (VDR), and novel vitamin D analogs are therapeutic candidates for multiple clinical applications. We recently developed non-secosteroidal VDR agonists bearing a p-carborane cage (a carbon-containing boron cluster) as a hydrophobic core structure. These carborane derivatives are structurally quite different from classical secosteroidal vitamin D analogs. Here, we report systematic synthesis and activity evaluation of carborane-based non-secosteroidal vitamin D analogs. The structure-activity relationships of carborane derivatives are different from those of secosteroidal vitamin D derivatives, and in particular, the length and the substituent position of the dihydroxylated side chain are rather flexible in carborane derivatives. The structure-activity relationships presented here should be helpful in development of non-secosteroidal vitamin D analogs for clinical applications.

Discovery of novel 5-hydroxy-4-pyridone-3-carboxy acids as potent inhibitors of influenza Cap-dependent endonuclease

We report the discovery of a novel series of influenza Cap-dependent EndoNuclease (CEN) inhibitors based on the 4-pyridone-carboxylic acid (PYXA) scaffold, which were found from our chelate library. Our SAR research revealed the lipophilic domain to be the key to CEN inhibition. In particular, the position between the chelate and the lipophilic domain in the derivatives was essential for enhancing the potency. Our study, based on virtual modeling, led to the identification of 2y as a potent CEN inhibitor with an IC50 of 5.12nM.