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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.
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)$.
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).
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.
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).
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.
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).
Kim, Jack-C.,Dong, Eun-Soo,Park, Jin-Il,Bae, Sang-Duk,Kim, Seon-Hee The Pharmaceutical Society of Korea 1994 Archives of Pharmacal Research Vol.17 No.6
A number of 5-substituted pyrimidine acyclic nucleosides were synthesized and tested for invitor cytotoxicity against four cell lines (j-82 cell, p-388 cell, FM-3A cell and U-938 cell lines). Synthesis of 1-cyanomethyl-5-substituted pyrimidines (1a-e) and 1-(4-cyanobutyl)-5-substituted pyrimidines (2a-e) was acomplished from the series of alkylation reactions ofl 5-substituted uracils with the corresponding chloacetonitrile and 5-chlorovaleronitile in DMSO under $50^{\circ}C$ temperature. These 5-substituted pyrimidine acylic nucleosides (1a-e and 2a-e) exhibited moderate to significant acitivity aginst four cell lines.
Kim, Jin‐,Soo,Kim, Edward S.,Liu, Diane,Lee, J. Jack,Solis, Luisa,Behrens, Carmen,Lippman, Scott M.,Hong, Waun Ki,Wistuba, Ignacio I.,Lee, Ho‐,Young Wiley Subscription Services, Inc., A Wiley Company 2012 Cancer Vol.118 No.9
<P><B>Abstract</B></P><P><B>BACKGROUND:</B></P><P>The purpose of this study was to characterize insulin receptor (IR) and insulin‐like growth factor‐1 receptor (IGF‐1R) expression in patients with nonsmall cell lung cancer (NSCLC).</P><P><B>METHODS:</B></P><P>A total of 459 patients who underwent curative resection of NSCLC were studied (median follow‐up duration, 4.01 years). Expression of the IR and IGF‐1R protein in tumor specimens was assessed immunohistochemically using tissue microarrays.</P><P><B>RESULTS:</B></P><P>The cytoplasmic IR score was higher in patients with adenocarcinoma (ADC) than in those with squamous cell carcinoma (SCC), whereas cytoplasmic IGF‐1R score was higher in patients with SCC than those with ADC. Neither IR nor IGF‐1R expression was associated with sex, smoking history, or clinical stage. Patients with positive IR or IGF‐1R expression levels had poor recurrence‐free (RFS) (3.8 vs 3.3 years; 3.8 vs 2.0 years, respectively), but similar overall survival (OS). Patients with high expression levels of IR and IGF‐1R had shorter RFS and OS compared with those with low levels of IR and/or IGF‐1R expression. Finally, a multivariate analysis revealed the impact of IR, but not of IGF‐1R, as an independent predictive marker of NSCLC survival: hazard ratio (HR) for OS, 1.005 (95% confidence interval [CI], 1.001‐1.010], HR for RFS, 1.005 (95% CI, 1.001‐1.009), when IR score was tested as a continuous variable.</P><P><B>CONCLUSIONS:</B></P><P>Overexpression of IR predicts a poor survival among patients with NSCLC, especially those with SCC. These results might serve as future guidance to the clinical trials involving IR or IGR‐1R targeting agents. Cancer 2012;. © 2011 American Cancer Society.</P>