Synthesis and Antitumor Evaluation of α-Methylene-γ-bu-tyrolactone-Linked to 5- Substituted Uracil Nucleic Acid Bases

Kim, Seon-Hee,Kim, Si-Hwan,Choi, Soon-Kyu,Kim, Ji-A,Park, Jin-Il,Kim, Jack C.,Park, Won-Woo 東亞大學校附設基礎科學硏究所 1997 基礎科學硏究論文集 Vol.14 No.1

Six, heretofore undescribed, 5¹-Methyl-5¹-(5-Substituted uracil-1-ylmethyl) -2¹-oxo-3¹-methylenetetrahydrofurans (F, Cl, Br, I, CH₃, H) (6a-f) were synthesized and evaluated against three cell lines (FM-3A, P-388 and U-937). For the preparation of α-methylene-γ-butyrolactone bearing 5-substituted uracils (6a-f), the efficient Reformatsky type reaction was employed which involves the treatment of ethyl α-(bromomethyl) acrylate and zinc with the respective 5-substituted uracil-1-ylacetones (5a-f). The acetone derivatives (5a-f) were directly obtained by the respective alkylation reaction of 5-substituted uracils with chloroacetone in the presence of K₂CO₃(or NaH). These lactone compounds 6a-f exhibited moderate to significant activity in all of the three cell lines, and 6b, 6c and 6e showed significant antitumor activities (inhibitory concentrations (IC??) ranged from 1.3-3.8 ㎍/ml).

Potential Antitumor ${\alpha}$-methylene-${\gamma}$-butyrolactone-bearing nucleic acid bases. 2. synthesis of $5^I-Methyl-5^I$-[2-(5-substituted uracil-1-yl)ethyl]-$2^I-oxo-3^I$-methylenetetrahydrofurans

Kim, Jack-C.,Kim, Ji-A,Park, Jin-Il,Kim, Si-Hwan,Kim, Seon-Hee,Choi, Soon-Kyu,Park, Won-Woo The Pharmaceutical Society of Korea 1997 Archives of Pharmacal Research Vol.20 No.3

Ten, heretofore unreported, $ 5^I-methyl-5^I-[2-(5-substituted uracil-1-yl)ethyl)]-2^I-oxo-3^I$-methylenetetrahydrofurans (H, F, Cl, Br, I, $ CH_3$,$CF_3$,$CH_2CH_3$,$ CH=CH2$, SePh) (7a-j) were synthesized and evaluated against four cell lines (K-562, FM-3A, P-388 and U-937). For the preparation of ${\alpha}$-methylene-${\gamma}$-butyrolactone-linked to 5-substituted uracils (7a-j), the convenient Reformasky type reaction was employed which involves the treatment of ethyl ${\alpha}$-(bromomethyl)acrylate and zinc with the respective 1-(5-substituted uracil-1-yl)-3-butanone (6a-j). The 5-substituted uracil ketones (6a-j) were directly obtained by the respective Michael type reaction of vinyl methyl ketone with the $K_2CO_3$(or NaH)-treated 5-substituted uracils (5a-j) in the presence of acetic acid in the DMF solvent. The .alpha.-methylene-.gamma.-butyrolactone compounds showing the most significant antitumor activity are 7e, 7f, 7h and 7j (inhibitory concentration $(IC_50)$ ranging from 0.69 to $2.9 {\mu}g/ml$), while 7b, 7g and 7i have shown moderate to significant activity. The compounds 7a, 7c and 7d were found to be inactive. The synthetic intermediate compounds 6a-j were also screened and found marginal to moderate activity where compounds 6b and 6g showed significant activity $(IC_50:0.4~2.8 {\mu}g/ml)$.

Synthesis and antitumor evaluation of $\alphamethylene-\gamma-butyrolactone-linked$ to 5-substituted uracil nucleic acid bases

Kim, Jack-C.,Kim, Ji-A,Kim, Si-Hwan,Park, Jin-Il,Kim, Seon-Hee,Park, Soon-Kyu,Park, Won-Woo The Pharmaceutical Society of Korea 1996 Archives of Pharmacal Research Vol.19 No.3

Six, heretofore undescribed, $5^I-Methyl-5^I-(5-Substituted uracil-1-ylmethyl)-2^I-oxo-3^I-methylenetetrahydrofurans(F, Cl, Br, l, CH_3, H)(6a-f)$were synthesized and evaluated against three cell lines (FM-3A, P-388 and U-937). For the preparation of .alpha.-methylene-.gamma.-butyrolactone bearing 5-substituted uracils (6a-f), the effcient Reformatsky type reaction was employed which involves the treatment of ethyl .alpha.(bromomethyl) acrylate and zinc with the respective 5-substituted uracil-1-ylacetones (5a-f). The acetone derivatives (5a-f) were directly obtained by the respective alkylation reaction of 5-substituted uracils with chloroacetone in the presence of $K_{2}$$CO_{3}$(or NaH). These lactone compounds 6a-f exhibited moderate to significant activity in all of the three cell lines, and 6b, 6c and 6e showed significant antitumor activities (inhibitory concentrations ($IC_{50}$) ranged from 1.3-3.8 .mu.g/ml.

Potential Antitumor α-Methylene-γ-butyrolactone- Bearing Nucleic Acid Bases. 2. Synthesis of 5¹-Methyl-5¹-[2-(5-substituted uracil-1-yl)ethyl]-2¹-oxo-3¹-methyleneterahydrofurans

Kim, Seon-Hee,Park, Jin lI,Choi, Soon-Kyu,Kim, Ji-A,Kim, Si-Hwan,Kim, Jack C.,Park, Won-Woo ]東亞大學校附設基礎科學硏究所 1998 基礎科學硏究論文集 Vol.15 No.1

Ten, heretofore unreported, 5¹-methyl-5¹-[2-(5-substituted uracil-1-yl)ethyl)]-2¹-oxo-3¹-methylenetetrahydrofurans (H, F, Cl, Br, I, CH₃, CF₃, CH₂CH₃, CH=CH₂, SePh) (7a-j) were synthesized and evaluated against four cell lines (K-562, FM-3A, P-388 and U-937). For the preparation of α-methylene-γ-butyrolactone-linked to 5-substituted uracils (7a-j), the convenient Reformasky type reaction was employed which involves the treatment of ethyl α-(bromomethyl)acrylate and zinc with the respective 1-(5-substituted uracil-1-yl)-3-butanone (6a-j). The 5-substituted uracil ketones (6a-j) were directly obtained by the respective Michael type reaction of vinyl methyl ketone with the K₂CO₃(or NaH)-treated 5-substituted uracils (5a-j) in the presence of acetic acid in the DMF solvent. The α-methylene-γ-butyrolactone compounds showing the most significant antitumor activity are 7e, 7f, 7h and 7j (inhibitory concentration (IC) ranging from 0.69 to 2.9 ㎍/ml), while 7b, 7g and 7i have shown moderate to significant activity. The compounds 7a, 7c and 7d were found to be inactive. The synthetic intermediate compounds 6a-j were also screened and found marginal to moderate activity where compounds 6b and 6g showed significant activity (IC:0.4∼2.8 ㎍/ml).

Potential Antitumor $\alpha$-Methylene-$\gamma$-butyrolactone-Bearing Nucleic Acid Base. 3. Synthesis of $5^1$-Methyl-$5^1$-[(6-substituted-9H-purin-9-yl)methyl]-$2^1$-oxo-$3^1$-methylenetetrahydrofurans

Kim, Jack-C.,Kim, Si-Hwan,Kim, Ji-A,Choi, Soon-Kyu,Park, Won-Woo The Pharmaceutical Society of Korea 1998 Archives of Pharmacal Research Vol.21 No.4

Search for a new $\alpha$-methylene-$\gamma$-butyrolactone-bearing 6-substituted purine as a potental antitumor agent has led to synthesize seven, hitherto unreported, $5^1$-Methyl-$5^1$-[(6-substituted-9H-purin-9-yl)methyl]-$2^1$-oxo-$3^1$- methylenetetrahydrofurans (H, Cl, l, $CH_3$, $NH_2$, SH, >C=O) (6a-g). These include $5^1$-Methyl-$5^1$-[(9H-purin-9-yl)methyll-$2^1$-oxo-$3^1$ -methylenetetrahydrofurans (6a), $5^1$-Methyl-$5^1$-[(6-chloro-9H-purin-9-yl)methyl]-$2^1$-oxo-$3^1$-methylenetetrahydr ofurans (6b), $5^1$-Methyl-$5^1$-[(6-chloro-9H-purin-9-yl) methyl]-$2^1$-oxo-$3^1$-methylenetetrahydrofurans (6c), $5^1$-Methyl-$5^1$-[(6-methyl-9H-purin-9-yl) methyl]-$2^1$-oxo-$3^1$-methylenetetrahydrofurans (6d), $5^1$-Methyl-$5^1$-[(9H-adenin-9-yl)methyll-$2^1$-oxo-$3^1$-methylenetetrahydrofurans (6e), $5^1$-Methyl-$5^1$-[(6-mercapto-9H-purin-9-yl) methyl]-$2^1$-oxo-$3^1$-methylenetetrahydrofurans (6f) and $5^1$-Methyl-$5^1$-[(9H-hypoxanthin-9-yl)methyll-$2^1$-oxo-$3^1$-methylenetetrahydrof urans (6g) which were made by the Reformatsky-type reaction of ethyl $\alpha$-(bromomethyl) acrylate with the corresponding (6-substituted-9H-purin-9-yl)-2-propanone intermediates (5a-g). These ketone intermediates 5a-g, 1-(9H-purin-9-yl)-2-propanone (5a), 1-(6-chloro-9H-purin-9-yl)-2-propanone (5b), 1-(6-iodo-9H-purin-9-yi)-2-propanone (5c), 1-(6-methyl-9H-purin-9-yl)-2-propanone (5d), 1-(9H-adenin-9-yl)-2-propanone (Se), 1-(6-mercapto-9H-purin-9-yl)-2-propanone (5f), and 1-(9H-hypoxanthin-9-yl)-2-propanone (5g) were directly obtained by the alkylation of the 6-substituted purine bases with the chloroacetone in the presence of $K_2$$CO_3$ (or NaH) under DMF (or DMSO). The preliminary in vitro cytotoxcity assay for the synthetic .alpha.-methylene-y-butyro-lactone compounds (6a-g) were determined against three cell lines (PM-3A, P-388, and K-562) and showed the moderate antitumor activity ($IC_50$ ranged from 1.4 to 4.3 $\mu\textrm{g}$/ml) with the compound $5^1$-methyl-$5^1$ -[(9H-hypoxanthin-9-yl)methyl]-$2^1$-oxo-$3^1$-methylenetetrahydrofuran (6g) showing the least antitumor activity.

Synthesis of a series of cis-diamminaedichloro-platinum (II) Complexes Linked to Uracil and Uridine as Candidate An-titumor Agents.

Kim, Jack-C.,Kim, Mi-Hyang,Kim, Seon-Hee,Choi, Soon-Kyu The Pharmaceutical Society of Korea 1995 Archives of Pharmacal Research Vol.18 No.6

The search for patinum (II)-based compounds with improved therapeutic properties was prompted to design and synthesize a new family of water-soluble, third generation cis-diamminedichlorplatinum (II) complexes linked to uracil and uridine. Six heretofore undescribed uracil and uridine-platinum (II) complexes are ; [N-(2-aminoethyl)uracil-5-carboxamide]dichloroplatinum (II)(3a), [N-2(2-aminoethyl)uracil-6-carboxmide]dichloroplatinum (II) (3b),[5-(2-aminorthyl)carbamoyl-2',3',5',-tri-O-acetyluridine] dichloroplatinum (II) (6b), [5-(2-aminoethyl)-carbamoyl]-2',3',5',-tri-O-acetyluridine] dichloroplatinum (II) (6b), [5-(2-aminoethyl)carbamoylu-ridine]dihloroplatinum (II) (7a), [6-(2-aminoethyl)carbamoyluridine]dichloroplatinum (II) (7b). These analogues were prepared from the key starting materials, 5-carboxyuracil (1a) and 6-carboxyuracil (1b) which were reacted with ethylenediamine to afford the respective N-(2-aminoethyl)uracil-5-carboxmide (2a) land N-(2-aminoethyl)uracil-6-carboxamide (2b). The cisplatin complexes 3a and 3b were obtained through the reaction of the respective 2a and 2b ficiently introduced on the .betha.-D-ribose ring via a Vorbruggen-type nucleoside coupling procedure with hexamethyldisilazane, trimethylchlorosilane and stannicchloride under anhydrous acetonitfile to yield the sterospecific .betha.-anomeric 5-carboxy-2',3',5'-tri-O-acetyluridine (4a) and 6-carboxy-2',3',5'-tri-O-acetyluridine (4b), respective 5-(2-aminoethyl)carbamoyl-2',3',5'-tri-O-acetyluridine (5a) and 6-(2-aminoethyl)carbamoyl-2',3',5'-tri-O-acetyluridine (5b). The diamino-uridines 5a and 5b were reacted with potassium tetrachloroplatinate (II) to give the novel nucleoside complexes, 6a and 6b respectively which were deacetylated into the free nucleosides, 7a and 7b by the treatment with CH/sub 3/ONa. The antitumor activities were evaluated against three cell lines (K-562, FM-3A and P-388).

Synthesis and Antitumor Evaluation of Acyclic 1-[${\omega}$-(N^I-2-chloroethyl-N^I-nitrosoureido)alkyl]thymidine Nucleoside Analogues

Kim, Jack-C.,Kim, Young-Hyun,Park, Jin-Il,Kim, Seon-Hee,Choi, Soon-Kyu The Pharmaceutical Society of Korea 1997 Archives of Pharmacal Research Vol.20 No.3

In the preparation of acyclic thymidine nucleoside analogues, $K_2CO_3$(or NaH) treated thymine in DMSO was alkylated with .omega.-chloroalkyl nitrite (Cl-(CH_2)n-CN; n=1, 2, 3, 4) to provide an isomeric mixture of 1-(${\omega}$-cyanoalkyl)thymine (2a-d) and 1,3-bis(${\omega}$-cyanoalkyl)thymine in approximately 5:1 ratios. Reduction of the cyano function 2a-d with $NaBH_{4}/CoCl_{2}$ center dot$ 6H_{2}O$gave the corresponding 1-(${\omega}$aminoalkyl)thymine (3a-d). The newly formed primary amino function in 3a-d was directly reacted with 2-chloroethylisocyanate to afford the 1-[.omega.($N^{I}$-2-chloroethylureido) alkyl]thymine (4a-d) in good yields. Nitrosation of 1-[5-($ N^{I}-2$-chloroethylureido)pentyl] thymine (4d) with glacial acetic acid and dry $NaNO_{2}$-powder in anhydrous $CH_{2}Cl_{2}$gave two types of regioisomeric nitrosoureas, 1-[5-($N^{I}$--chloroethyl-$N^{I}$--nitrosoureido)pentylithymine (5d) and 1-[5-($N^{I}-2$-chloroethyl-N-nitrosoureido)pentyllthymine in approximately 5 :1 ratios. The in vitro cytotoxicity of the synthesized compounds (2a-d, 3a-d, 4a-d and 5a-d) against three cell lines (K-562, P-388 and FM-3A) are measured as $IC^{50}$ values. Compounds 3b and 4c showed moderate activities against all three cell lines, and all other compounds were found to be not active.

Synthesis of rigid acetylcholine analog intermediates : I. Cyclic α-oximino-ketone from acenaphthequinone and 1-indanone

Jack C. Kim ; Yong Tae Lee ; Won Woo Park ; Si Woo Lee ; Soon Ho Kang ; Li Kyu Youn ; Yoon Bo Shim 부산대학교 1980 論文集: 自然科學篇 Vol.30 No.-

Semi-automatic Atmospheric Sulfur Dioxide Analysis

Kim,Jack C.,Lim,Gyong-Teck,Yun,Il,Shim,Yoon-Bo,Hong,Seong-Soo,Lee,Tah-Yeon 부산대학교 환경문제 연구소 1983 環境硏究報 Vol.1 No.-

Atmospheric SO₂distribution was monitored by semiautomatic SO₂analyzer in Busan area in 1981.Total annual average was 0.062 ppm. It is higher level than Korean Ambient Air Quality Standard and only 33.89% of the days during one year period was below SO₂distribution of 0.05 ppm, whereas the Standard demand is 70%. In other words we have mostly polluted air all year around in Busan area. Commercial areas have higher level than any other areas. Seasonal variation shows high level in winter and low in summer. Acid rain,estimated effects of SO₂,is likely to fall, if we add another SO₂to present level. Metal corrosion is expected in addition to adverse human health effects.

IL-12-STAT4-IFN-${\gamma}$ axis is a key downstream pathway in the development of IL-13-mediated asthma phenotypes in a Th2 type asthma model

Kim, You-Sun,Choi, Seng-Jin,Choi, Jun-Pyo,Jeon, Seong-Gyu,Oh, Sun-Young,Lee, Byung-Jae,Gho, Yong-Song,Lee, Chun-Geun,Zhu, Zhou,Elias, Jack A.,Kim, Yoon-Keun Korean Society for Biochemistry and Molecular Bion 2010 Experimental and molecular medicine Vol.42 No.8

IL-4 and IL-13 are closely related cytokines that are produced by Th2 cells. However, IL-4 and IL-13 have different effects on the development of asthma phenotypes. Here, we evaluated downstream molecular mechanisms involved in the development of Th2 type asthma phenotypes. A murine model of Th2 asthma was used that involved intraperitoneal sensitization with an allergen (ovalbumin) plus alum and then challenge with ovalbumin alone. Asthma phenotypes, including airway- hyperresponsiveness (AHR), lung inflammation, and immunologic parameters were evaluated after allergen challenge in mice deficient in candidate genes. The present study showed that methacholine AHR and lung inflammation developed in allergen-challenged IL-4-deficient mice but not in allergen-challenged IL-13-deficient mice. In addition, the production of OVA-specific IgG2a and IFN-${\gamma}$-inducible protein (IP)-10 was also impaired in the absence of IL-13, but not of IL-4. Lung-targeted IFN-${\gamma}$ over-expression in the airways enhanced methacholine AHR and non-eosinophilic inflammation; in addition, these asthma phenotypes were impaired in allergen-challenged IFN-${\gamma}$-deficient mice. Moreover, AHR, non-eosinophilic inflammation, and IFN-${\gamma}$ expression were impaired in allergen- challenged IL-$12R{\beta}2$- and STAT4-deficient mice; however, AHR and non-eosinophilic inflammation were not impaired in allergen-challenged IL-$4R{\alpha}$-deficient mice, and these phenomena were accompanied by the enhanced expression of IL-12 and IFN-${\gamma}$. The present data suggest that IL-13-mediated asthma phenotypes, such as AHR and non-eosinophilic inflammation, in the Th2 type asthma are dependent on the IL-12-STAT4-IFN-${\gamma}$ axis, and that these asthma phenotypes are independent of IL-4Ralpha-mediated signaling.