Hideharu Ishihara

Synthesis of 1,3-thiazine derivatives and their evaluation as potential antimycobacterial agents.

A series of eight 5,6-dihydro-4H-1,3-thiazine derivatives was synthesized by the BF3 x Et2O-catalyzed reaction of selected alpha,beta-unsaturated ketones with thiobenzamide at room temperature. The antimycobacterial activities of these compounds were determined against Mycobacterium tuberculosis H37Rv (ATCC 27294) using the Alamar blue susceptibility assay. Three compounds, 5-hydroxy-3-phenyl-4-aza-2-thiabicyclo[3.3.1]none-3-ene 3a, 4-hydroxy-4-methyl-6-pentyl-2-phenyl-5,6-dihydro-4H-1,3-thiazine 3b, and 4-ethyl-4-hydroxy-2-phenyl-5,6-dihydro-4H-1,3-thiazine 3c exhibited inhibitory activities of 97, 77 and 76%, respectively, at a concentration of 6.25 microg/ml. The actual MIC99 for the most active of these compounds, 3a, was also determined to be >6.25 microg/ml. These results, and especially those for 3a, suggest that 1,3-thiazines are potential lead compounds in the search for new antitubercular agents.

Isoselenocyanates: A Powerful Tool for the Synthesis of Selenium-Containing Heterocycles

Selenium-containing heterocyclic compounds have been well recognized, not only because of their remarkable reactivities and chemical properties, but also because of their diverse pharmaceutical applications. In this context, isoselenocyanates have been emerged as a powerful tool for the synthesis of selenium-containing heterocycles, since they are easy to prepare and store and are safe to handle. In this review the recent advances in the development of synthesis methods for selenium-containing heterocycles from isoselenocyanates are presented and discussed.

Novel compounds, '1,3-selenazine derivatives' as specific inhibitors of eukaryotic elongation factor-2 kinase.

The inhibitory activities of 5,6-dihydro-4H-1,3-selenazine derivatives on protein kinases were investigated. In a multiple protein kinase assay using a postnuclear fraction of v-src-transformed NIH3T3 cells, 4-ethyl-4-hydroxy-2-p-tolyl-5, 6-dihydro-4H-1,3-selenazine (TS-2) and 4-hydroxy-6-isopropyl-4-methyl-2-p-tolyl-5,6-dihydro-4H-1, 3-selenazine (TS-4) exhibited selective inhibitory activity against eukaryotic elongation factor-2 kinase (eEF-2K) over protein kinase A (PKA), protein kinase C (PKC) and protein tyrosine kinase (PTK). In further experiments using purified kinases, TS-2 (IC(50)=0.36 microM) and TS-4 (IC(50)=0.31 microM) inhibited eEF-2K about 25-fold more effectively than calmodulin-dependent protein kinase-I (CaMK-I), and about 6-fold (TS-2) or 33-fold (TS-4) more effectively than calmodulin-dependent protein kinase-II (CaMK-II), respectively. TS-2 and TS-4 showed much weaker inhibitory activity toward PKA and PKC, while TS-4, but not TS-2, moderately inhibited immunoprecipitated v-src kinase. TS-2 (10.7-fold) and TS-4 (12.5-fold) demonstrated more potent and more specific eEF-2K inhibitory activity than rottlerin, a previously identified eEF-2K inhibitor. TS-2 inhibited ATP or eEF-2 binding to eEF-2K in a competitive or non-competitive manner, respectively. In cultured v-src-transformed NIH3T3 cells, TS-2 also decreased phospho-eEF-2 protein level (IC(50)=4.7 microM) without changing the total eEF-2 protein level. Taken together, these results suggest that TS-2 and TS-4 are the first identified selective eEF-2K inhibitors and should be useful tools for studying the function of eEF-2K.

1,3-Selenazine derivatives induce cytotoxicity and DNA fragmentation in human HT-1080 fibrosarcoma cells

The inhibitory effects of a series of 5,6-dihydro-4H-1,3-selenazine derivatives, 1,3-selenazole, and 5,6-dihydro-4H-1,3-thiazine derivatives on the proliferation of human HT-1080 fibrosarcoma cells were investigated. The compounds 4-ethyl-4-hydroxy-2-p-tolyl-5, 6-dihydro-4H-1,3-selenazine (TS-2) and 4-hydroxy-4-methyl-6-propyl-2-p-tolyl-5,6-dihydro-4H-1,3-selenazine++ + (TS-6) exhibited the strongest inhibitory effect among 1, 3-selenazine derivatives, and the EC(50) of TS-2 and TS-6 was 7.76 and 8.40 microM, respectively. On the other hand, 1,3-selenazole and 5,6-dihydro-4H-1,3-thiazines had no inhibitory effects. TS-2 and TS-6 inhibited the proliferation of HT-1080 cells time- and dose-dependently. They induced dose-dependent DNA fragmentation in HT-1080 cells, revealing a typical apoptosis characteristics. The present study demonstrated that TS-2 and TS-6 inhibited HT-1080 proliferation through the induction of DNA fragmentation.

Preparation of N,N-unsubstituted selenoureas and thioureas from cyanamides

Abstract Reaction of cyanamides with LiAlHSeH and LiAlHSH in the presence of HCl in diethyl ether provided the corresponding N , N -unsubstituted selenoureas and thioureas in moderate to high yields, respectively.

One-Pot Synthesis of 2-Imino-1,3-selenazolidines by Reaction of Isoselenocyanates with Propargylamine

One-pot synthesis of 2-imino-5-methylene-l,3-selenazolidines has been achieved by reactions of alkylisoselenocyanates with propargylamines in high yields. 1 H NMR and NOESY experiments were used to explain the selenium coupling with hydrogen of carbon-carbon double bond.

THE SYNTHESES OF POTASSIUM SELENOCARBOXYLATES AND THEIR DERIVATIVES

Potassium selenocarboxylates were prepared in good yields on the reaction of diacyl selenides with methanolic potassium hydroxide. They were fairly stable under nitrogen and useful as starting material for the preparation of selenocarboxylic acid derivatives; methyl selenobenzoate, α-(selenobenzoyl)acetophenone, phenyl p-chlorobenzoyl diselenide, O-trimethylsilyl selenobenzoate, bis(selenostearoyl)methane, and dibenzoyl diselenide.

EFFICIENT SYNTHESIS OF SELENOUREAS FROM THE CORRESPONDING CARBODIIMIDES

ABSTRACT Selenoureas were synthesized by the reaction of carbodiimides with LiAlHSeH in the presence of hydrogen chloride.

A Facile Preparation of Aliphatic and Aromatic Primary Selenoamides Using 4-Methylselenobenzoate as a New Selenating Reagent

Aliphatic and aromatic primary selenoamides 2 were isolated by the reaction of the corresponding aliphatic and aromatic nitriles with potassium 4-methylselenobenzoate in the presence of BF3·Et2O in moderate from high yields.

Synthesis of 2-Selenoxoperhydro-1,3-selenazin-4-ones and 2-Selenoxo-1,3-selenazolidin-4-ones via Diselenocarbamate Intermediates

The treatment of substituted acryloyl isoselenocyanates with sodium hydroselenide gave 2-selenoxoperhydro-l,3-selenazin-4-ones. The reaction of diselenocarbamates, generated from alkyl isoselenocyanates and sodium hydroselenide, with bromoacetyl bromide afforded 2-selenoxo-l,3-selenazolidin-4-ones.