Hirokazu Annoura

A novel class of antagonists for metabotropic glutamate receptors, 7-(Hydroxyimino)cyclopropa[b]chromen-1a-carboxylates

7-(Hydroxyimino)cyclopropa[b]chromen-la-carboxylates (4a-c), highly potent antagonists for a phospholipase C-linked metabotropic glutamate receptor, mGluR1, were synthesized through cyclopropanation onto 4-oxo-4H-1-benzopyran-2-carboxylates (5a-c) utilizing dimethyloxosulfonium methylid followed by treatment with hydroxylamine.

Total syntheses of hymenialdisine and debromohymenialdisine: Stereospecific construction of the 2-amino-4-oxo-2-imidazolin-5(Z)-disubstituted y ylidene ring system

Abstract The first total synthesis of hymenialdisine ( 1a ) and debromohymenialdisine ( 1b ) was achieved via a novel stereospecific construction of the 2-amino-4-oxo-2-imidazoline-5(Z)-disubstituted ylidene ring system.

Asymmetric synthesis of anthracyclinones using chiral acetal: synthesis of a new chiral AB-synthon, ()-2-bromo-6-ethynyl-6-hydroxy-5, 6, 7, 8-tetrahydro-1, 4-naphthoquinone, and its application for ()-7-deoxydaunomycinone

Abstract A synthesis of a new chiral AB-synthon ( 4 ) for preparing the optically active anthracyclinones was attained through a stereospecific nucleophilic addition of trimethylsilylethynylmagnesium chloride to the chiral 2-tetralone-1-acetal ( 2 ). Synthesis of ( )-7- deoxydaunomycinone ( 1c ) was achieved by a regiospecific cycloaddition of 4 to 4-acetoxy-8-methoxyhomophthalic anhydride ( 5 ).

Diastereoselective nucleophilic addition to chiral open-chain α-ketoacetals: Synthesis of (R)- and (S)-mevalolactone

Abstract Highly stereoselective addition of Grignard reagents to chiral open-chain α,-ketoacetals ( 3a , 3b ) has been attained. Application of the reaction to syntheses of the key intermediates ( 6 , 8 ) for (R)- and (S)-mevalolactone is also described.

Synthesis and biological evaluation of new 4-arylpiperidines and 4-aryl-4-piperidinols: dual Na+ and Ca2+ channel blockers with reduced affinity for dopamine D2 receptors

Abstract A series of novel 4-arylpiperidines and 4-aryl-4-piperidinols ( 2a – f , 3a – f and 4a – f ) was synthesized and evaluated for blocking effects on both neuronal Na + and T-type Ca 2+ channels and binding affinity for dopamine D 2 receptors. Most of the compounds blockaded both ion channels with potency greater than or equal to flunarizine 1a which was adopted as a reference standard. In addition, these compounds had significantly reduced affinity for dopamine D 2 receptors which is common in this class of structure. Compounds 2a – f , 3a – f and 4a – f exhibited potent anticonvulsant effects following systemic (ip) administration on audiogenic seizures in DBA/2 mice, indicating their excellent brain permeability. The neuroprotective activity of 2a , 3a and 4a was also assessed in a transient middle cerebral artery occlusion (MCAO) model. These compounds significantly reduced neuronal damage without affecting ischemic hyperthemia, while flunarizine 1a produced only minor reductions. In particular, 4a had 1.7-fold the potency in this MCAO model but only 1/20 the affinity for dopamine D 2 receptors of 1a . The superposition of 2a , 3a and 4a on the basis of analyses of systematic conformation and similar structure has revealed that the cinnamyl, phenacyl and phenoxypropanol groups are likely to be structurally and biologically equivalent. Moreover, the superposition of 2a and 2f shows that diphenyl ether and biphenyl groups occupy a similar space, suggesting that both groups act as a bioisostere for the blockade of ion channels; however, this is not the case for dopamine D 2 receptors since only biphenyl compounds such as 2f had high affinity similar to flunarizine 1a . Compound 4a (SUN N5030) has a good pharmacological profile and may be useful in the alleviation and treatment of ischemic diseases.

Diastereoselective addition of grignard reagents to chiral α-ketoacetals

Abstract High diastereoface—differenciating addition occurred in the reaction of chiral cyclic α-ketoacetals 1a and 1b with Grignard reagents

A novel class of Na+ and Ca2+ channel dual blockers with highly potent anti-ischemic effects

A series of novel arylpiperidines (4a-d) which have highly potent blocking effects for both neuronal Na+ and T-type Ca2+ channels with extremely low affinity for dopamine D2 receptors were synthesized. Among these compounds, 1-(2-hydroxy-3-phenoxy)propyl-4-(4-phenoxyphenyl)-piperidine hydrochloride (4c; SUN N5030) exhibited remarkable neuroprotective activity in a transient middle cerebral artery occlusion (MCAO) model.

Highly stereoselective reduction of chiral α-keto-β,γ-unsaturated acetals: synthesis of both epimeric allyl alcohols by proper choice of additive

Abstract Highly stereoselective reduction of chiral α-keto-β, γ-unsaturated acetals ( 1a - 3a ) into each two epimeric optically active allyl alcohols ( 1b - 3b and 1c - 3c ) was attained by LiAlH 4 using additive (LiBr, MgBr 2 ).

Synthesis and biological evaluation of truncated α-galactosylceramide derivatives focusing on cytokine induction profile

A series of truncated analogs of α-galactosylceramide with altered ceramide moiety was prepared, and evaluated for Th2-biased response in the context of IL-4/IFN-γ ratio. Phytosphingosine-modified analogs including cyclic, aromatic and ethereal compounds as well as the C-glycoside analog of OCH (2) with their cytokine inducing profile are disclosed.

2-Aminoalkyl nicotinamide derivatives as pure inverse agonists of the ghrelin receptor

New inverse agonists of the ghrelin receptor (ghrelinR) were obtained through high-throughput screening and subsequent structural modification of 2-aminoalkyl nicotinamide derivatives. The key structural feature to improve in vitro activity was the introduction of a diazabicyclo ring at the 5-position of the pyridine ring. The final product showed potent inverse agonist activity and, despite its low brain permeability, reduced food intake in both normal and obese mice. These results implied that peripheral ghrelinR activity is important for appetite control and that a peripheral ghrelinR inverse agonist could be an anti-obesity drug with reduced risk of central nervous system (CNS)-related side effects.