Kee Dal Nam

Effects of N-adamantyl-4-methylthiazol-2-amine on hyperglycemia, hyperlipidemia and oxidative stress in streptozotocin-induced diabetic rats.

Thiazole derivatives are attractive candidates for drug development because they can be efficiently synthesized and are active against a number of diseases and conditions, including diabetes. In our present study, we investigated the anti-inflammatory and antioxidant properties of N-adamantyl-4-methylthiazol-2-amine (KHG26693), a new thiazole derivative, in a streptozotocin (STZ)-induced model of diabetes mellitus. STZ-induced diabetic rats were intraperitoneally administered KHG26693 (3mg/kg-body weight/day) for 4 weeks. KHG26693 administration significantly decreased blood glucose, triglycerides, and cholesterol and increased insulin. KHG26693 also suppressed several inflammatory responses in STZ-induced diabetic rats, as evidenced by decreased levels of serum tumor necrosis factor-α, interleukin-1β, and nitric oxide. Additionally, KHG26693 significantly modulated hepatic lipid peroxidation, catalase and superoxide dismutase activity, and the nonenzymatic antioxidant status (e.g., vitamins C and E), and reduced the glutathione content. These anti-inflammatory/antioxidative actions occurred as a result of the downregulation of inducible nitric oxide synthase and nuclear factor-kappa B. Taken together, our results suggest that KHG26693 successfully reduces the production of oxidative stress in STZ-induced diabetic rats by regulating the oxidation-reduction system, specifically increasing antioxidant capacity. Furthermore, KHG26693 treatment significantly reverted the key enzymes of glucose metabolism, such as glucokinase, glucose-6-phosphatase, glycogen synthase, glycogen phosphorylase, and fructose-1,6-bisphosphatase, to near-normal levels in liver tissues. These results indicate that KHG26693 normalizes disturbed glucose metabolism by enhancing glucose utilization and decreasing liver glucose production via insulin release, suggesting the possibility of future diabetes treatments.

Quantitative structural-activity relationship (QSAR) study for fungicidal activities of thiazoline derivatives against rice blast.

For the development of new fungicides against rice blast, the quantitative structural-activity relationship (QSAR) analyses for fungicidal activities of thiazoline derivatives were carried out using multiple linear regression (MLR) and neural network (NN). We have studied the substituent effects at para site of R(1) and at three sites (ortho, meta, or para) of R(2) aromatic rings in compounds. The results of MLR and NN analyses in the training set of Set-3 showed good correlations (r(2) values of 0.829 and 0.966, respectively) between the descriptors and the fungicidal activities. Five descriptors including the non-overlap steric volume SV(R2C2)), Connolly surface area SA(R1), hydrophobicity Sigma pi(R2), and Hammett substituent constants (sigma(pR1) and sigma(mR2)) were selected as important factors of fungicidal activities. Although the descriptors of optimum MLR model were used in NN, the results were improved by NN. This means that the descriptors used in MLR model include non-linear relationships.

Rearrangement mechanisms of 1,3-dithiolane sulfoxides.

Oxidation of sulfide 4 gave a mixture of cis and trans monosulfoxides 5 and 6 as major and minor products, respectively, plus a small amount of disulfoxides 7. The structural assignments of cis and trans sulfoxides 5 and 6 were based on 1H NMR spectroscopy and the regiospecific deuterations of the two isomers . Under neutral conditions cis sulfoxides 5 underwent a sigmatropic rearrangement with 2-methylene hydrogens to give sulfenic acids 18, followed by cyclization to dihydro-1,4-dithiins 2. The trans sulfoxides 6 rearranged involving 2-methyl hydrogens to form isomeric dihydrodithiins 3 via sulfenic acids 19. In the reactions of both the sulfoxides, sulfoxides 4 and disulfides 11 were also formed as minor side products. In the presence of acid catalyst cis sulfoxides 5 produced 2 in quantitative yields plus a small amount of 3 , while the trans sulfoxides 6 gave 2 as major product and 3 as minor. The mechanisms of formation of 2, 3, 4 and 11 are discussed.

Exploration of novel 2-alkylimino-1,3-thiazolines: T-type calcium channel inhibitory activity

We have developed combinatorial libraries of new 2-alkylimino-1,3-thiazolines with four diversity points, consisting of more than 500 compounds, in a parallel synthetic fashion. The synthetic strategy was based on the construction of a large library aimed at the discovery of new compounds with T-type calcium channel inhibitory activity through structure modifications of hit compound 2. The syntheses of the compounds of Chemset A with four diversity points were accomplished by the condensation of thioureas 5 with alpha-haloketones 6{1-66} having two diversity points each. A library of phthalimidyl 1,3-thiazolines 24 was synthesized to provide Chemset B, which allowed the introduction of other diversity points through the nucleophilic character of the amino nitrogen. A sublibrary, Chemset C, was constructed from the libraries of Chemset A and Chemset B by functionalization of the C-4 position of the 1,3-thiazoline ring. The products containing ester or acid groups at the C-4 position of the 1,3-thiazoline ring were used in amide synthesis to give a new sublibrary within Chemset C. Deprotection of the phthalimidyl moiety of 24 followed by the reaction with benzoyl chloride gave the corresponding sublibrary in Chemset C. Another sublibrary which includes secondary amino derivatives was obtained by reduction of the amide moiety or reductive amination of 23 with phenyl aldehyde. The selected compounds from the generated libraries were evaluated with respect to inhibition of T-type calcium channels, where some of them have exhibited promising activity.

A derivative of 2‐aminothiazole inhibits melanogenesis in B16 mouse melanoma cells via glycogen synthase kinase 3β phosphorylation

Objectives  We have investigated whether KHG25855 (2‐cyclohexylamino‐1,3‐thiazole hydrochloride) affected melanogenesis in B16 mouse melanoma cells, and the mechanisms involved.

Syntheses of 1,3-Imidazolin-2-Ones and 1,3-Imidazolin-2-Thiones from New Building Blocks, γ-Aminoacetoacetanilides

ReceiVed April 23, 2008 Exploration of new building blocks for the preparation of heterocyclic compound libraries with molecular diversity is an ever-expanding area in combinatorial chemistry. To respond to this demand, new technologies, including multicomponent reactions and click chemistry, have been developed. In our previous paper, we reported that the construction of two different chemical libraries of 1,3imidazolin-2-thione and 2-phenylimino-1,3-thiazoline starting from three building blocks, γ-chloroacetoacetanilides 1, amines, and isothiocyanates. As an expansion of our study for the construction of a new chemical library of heterocyclic compounds, we synthesized new γ-aminoacetoacetanilide derivatives 3 by replacing chlorine in 1 with amino moiety. The γ-aminoacetoacetanilide derivatives 3 would be useful building blocks for preparing new heterocyclic compounds because of their four reactive centers within the molecule. First, the methylene protons are activated by neighboring carbonyl moieties. Second, the amide is an ambient nucleophile by means of the nitrogen and oxygen atoms. Third, the carbonyl of the ketone is susceptive for an addition of nucleophile. Fourth, the primary amine at γ position has good nucleophilic character. In this paper, we report the synthesis of the new building blocks, γ-aminoacetoacetanilide derivatives 3 and the preparations of two different scaffolds, 1,3-imidazolin-2-one 9 and 1,3-imidazolin-2-thione derivatives 10, by the reaction of 3 with isocyanates and isothiocyanates, respectively. 1,3-Imidazolin-2-one and its sulfur analogue, 1,3-imidazolin-2-thione, derivatives have received attention over the past few years because of their interesting biological activities. For example, enoximone and piroximone possess antioxidant, phosphodiesterase, and cardiotonic activities. Others have been shown to exhibit good herbicidal activities, such as imazamethbenz and imazethapyr. There are many known methods for the synthesis of 1,3-imidazolin-2-ones and 1,3-imidazolin-2-thiones, including Marckwald’s method. Recently, the novel synthesis of imidazolin-2thiones was reported by Zeng et al., and their use in organic synthesis was reviewed by Zav’yalov et al. The starting γ-chloroacetoacetanilides 1 were prepared by the same method as previously reported. R-Aminoketones are considerably less well behaved for organic syntheses, as compared to R-aminoesters, because of self-condensation reactions. As shown in Scheme 1, the γ-aminoacetoacetanilides 3 can be prepared easily and efficiently from 1 through a modified procedure of the previously reported method. The reaction of γ-chloroacetoacetanilides 1 with sodium azide in acetonitrile at 40° for 4-6 h gave γ-azidoketone 2 in a quantitative yield. The same reaction at a higher temperature or longer reaction time resulted in low yield of the product. Without purification, treatment of 2 with triphenylphosphine in tetrahydrofuran in the presence of excess amount (3 mol equiv) of p-toluenesulfonic acid monohydrate (p-TSA) at room temperature afforded γ-aminoacetoacetanilides 3 as the p-TSA salts. The structure of 3 was confirmed by the H NMR spectroscopy and the IR spectrometry. For 3a, two singlets at δ 3.71 and 4.08 ppm in the H NMR spectrum and a strong absorption at 3200-3300 cm in the IR spectra were in agreement with the structure. After the supply of 3 was secured, the chemical reactivity and available potentialities for the construction of heterocyclic molecules from 3 were investigated. Because the γ-amino moiety in 3 is a good nucleophile, we decided to react 3 with a good electrophile, such as isocyanate derivatives. The reaction between 3b and o-tolyl isocyanate, which was chosen arbitrarily, proceeded smoothly in the presence of triethylamine at room temperature for 2 h to obtain the desired product 5b (Scheme 2). Acetone was the best solvent of choice for obtaining high yield of 5b. Solvents such as acetonitrile, benzene, methylene chloride, dioxane, dimethylformamide, or ethanol either gave poor yields of 5b or led to the production of side products. Under similar reaction conditions, the γ-aminoacetoacetanilides 3 were subjected to various isocyanate or isothio-

Unexpected formation of pyrrolo[2,1-b]thiazoles by rearrangement of α-hydroxydihydro-1,4-thiazines

A new synthesis of pyrrolo[2,1-b]thiazoles (5) is described. Hydrolysis of acetoxy dihydro-1,4-thiazine (2) prepared by Pummerer reaction of dihydro-1,4-thiazine sulfoxide gave the intermediate α-hydroxy sulfide (4). Dehydration of 4 gave pyrrolo[2,1-b]thiazoles (5). The reaction mechanism for the formation of 5 including the intermediate thiol (6) is discussed.

REARRANGEMENT MECHANISMS OF SOME CYCLIC SULFOXIDES

Abstract Under neutral conditions cis sulfoxides 5 underwent a sigmatropic rearrangement with 2-methylene hydrogens to give sulfenic acids 18, followed by Cyclization to dihydro-1,4-dithiins 2. The trans sulfoxides 6 rearranged involving 2-methyl hydrogens to form isomeric dihydrodithiins 3 via sulfenic acids 19. In the reactions of both the sulfoxides, sulfides 4 and disulfides 11 were also formed as minor side products. In the presence of acid catalyst cis sulfoxides 5 produced 2 in quantitative yields while the trans sulfoxides 6 gave a mixture of 2 and 3. The mechanism of formation of 2,3,4 and 11 are discribed.