Synthesis and in vitro cytotoxicity of a homologous series of 5-halosubstituted $1,3-Bis(\omega-cyanoalkyl)$uracil analogues

Kim, Jack-C.,Dong, Eun-Soo,Park, Jin-Il,Kim, Young-Hyeun,Choi, Soon-Kyu The Pharmaceutical Society of Korea 1996 Archives of Pharmacal Research Vol.19 No.1

A homologous series of twenty, hitherto unreported, analogues of 5-halosubstituted $1, 3-Bis(\omega-cyanoalkyl)uracil$acyclic nucleosides were synthesized by the series of alkylation reactions of 5-halouracils with the corresponding chloroacetonitrile, chloropropionitrile, chlorobutyronitrile and 5-chlorovaleronitrile $(Cl-(C_ 2)_n-CN: n=l, 2, 3, 4)\; in\; anhydrous\; DMSO\; (or DMF)/K_2CO_3(or NaH)\; under\; 75^{\circ}C$ temperature. Antitumor activities for the synthesized compounds were determined against three cell lines (FM-3A cell, P-388 cell and U-938 cell lines). The compounds that exhibited moderate activity to significant activity, included la-b, 2a-b, 3a-c, and 4a, whose compounds were active against P-388, FM-3A and U-937 cell lines with the compounds la, lb, and 2a, showing significant antitumor activity (inhibitory concentrations $(IC_{50})$ ranged from 2.2 to $7.0\mug/ml$). Their strucrure-activity relationship did not show any activity differences in their effective chain length (methyl, ethyl, propyl, butyl) in 1, 3-bis(.omega.-cyanoalkyl) uracils.

N-Alkyl-N-Nitrosocarbamoyl-3alpha-Amino-와 3beta-Amino-5alpha-Cholestane 유도체들의 합성 및 항암작용 평가

김정균(Jack C. Kim),최순규(Soon Kyu Choi),조인섭(In Seop Cho),유동식(Dong Sik Yu),류성호(Sung Ho Ryu),문경호(Kyung Ho Moon) 대한약학회 1985 약학회지 Vol.29 No.2

The isomeric intermediates, 3alpha- and 3beta-amino-5alpha-cholestane required for the synthesis of N-nitrosoureas, N-(2-chloroethyl)-N-nitrosocarbamoyl-3alpha-amino-5alpha-cholestane (9), N-methyl-N-nitrosocarbamoyl-3alpha-amino-5alpha-cholestane (10), N-(2-chloroethyl)-N-nitrosocarbamoyl-3beta-amino-5alpha-cholestane (7), and N-methyl-N-nitrosocarbamoyl-3beta-amino-5alpha-cholestane (8) were obtained through the LiAlH4 reduction of 5alpha-cholestan-3-one oxime, followed by the chromatographic separation: the assignment of the stereochemistry of both isomers were based on the shape and chemical shift of C3-proton resonances on their NMR spectra and on the elution mobility on the TLC. The urea intermediates, N-(2-chloroethyl)carbamoyl-3alpha-amino-5alpha-cholestane (13), N-methylcarbamoyl-3alpha-amino-5alpha-cholestane (14), N-(2-chloroethyl)carbamoyl-3beta-amino-5alpha-cholestane (11) and N-methyl-3beta-amino-5alpha-cholestane (12) were prepared by the treatment of each isomers (3alpha-amino- and 3beta-amino-5alpha-cholestane) with alkyl isocyanates in anhydrous CHCl3, and the corresponding nitrosoureas, 7~10 were obtained by the nitrosation of the ureas, 11~14, with AcOH (or HCOOH)/NaNO2 in ice-cold condition. The inhibitory activity of the nitrosoureas, 7~10, and their intermediates, 12~14 towards the growth of L1210 murine leukemia cells, were examined. Among them, the compounds 9 and 10 exhibited high activity having ED50 to be 5.5g/ml and 6.1g/ml, respectively.

도시와 농촌 비둘기 및 인체혈액중의 Vanadium 농도 산정에 관한 연구

문덕환,김준연,김정균 인제대학교 1985 仁濟論叢 Vol.1 No.1

This experiment determined the vanadium concentration in pigeon liver and lung tissues from rural and urban areas and .in bloods of workers (male 20, female 6) by carbon furnace Atomic Absorption spectrometry. The purpose of this experiment was in investigating the status of vanadium pollution in atmosphere. The summarized results were as follows : 1.The mean concentration of vanadium in pigeon liver and lung tissues from rural areas was 36.9±2.04ppb and 58.9±2.94ppb, respectively. 2.The mean concentration of vanadium in pigeon liver and lung tissues from urban areas was 64.0±2.62ppb and 91.7±4.26ppb, respectively. 3.The mean concentration of vanadium in pigeon liver and lung tissues from urban areas was more higher than that of rural (P〈0.05). 4.The mean concentration of vanadium in blood of workers(male 20, female 6) was 23.7±3.48ppb.

N-메틸-N'-치환페닐우레아화합물들의 니트로소화 반응에 있어서 니트로소화 화학종의 반응성 및 위치화학적 영향

김정균,조인섭,최순규,Jack C. Kim,In-Seop Cho,Soon-Kyu Choi 대한화학회 1991 대한화학회지 Vol.35 No.3

비대칭우레아화합물, N-메틸-N'-치환페닐우레아화합물들 ($CH_3NHCONHC_6H_4-G$; G = H, p-$CH_3,\;m-CH_3,\;m-CH_3O$, p-F, m-F, m-Br) 7종 합성하고 이들을 NaN$O_2$와 4종류의 산(d-HCl, HCOOH, C$H_3$COOH, CF$_3$COOH)을 사용하여 니트로소화시킬 때 이 니트로소화 반응의 위치선택성을 조사하였다. 이들 반응 모든 경우에서 두 가지 위치이성질체생성물, N-니트로소-N-메틸-N'-치환페닐우레아생성물(A)들과 N'-니트로소-N-메틸-N'-치환페닐우레아생성물(B)들이 주생성물로 생성되었으며, 이들 생성몰비 B/A를 이들 반응혼합물의 $^1$H-NMR에서의 메틸피이크의 면적을 측정하여 이를 결정하였다. 전자공급체치환기(ㅎ)가 우레아화합물의 페닐기에 치환된 경우 일반적으로 B/A의 비가 증가되었다. 이들 위치이성체 생성물비 B/A로부터 니트로소화 화학종(HONO, HCOONO, CH$_3$ COONO, CF$_3$ COONO)의 페닐치환기에 의한 질소원자 위의 전자밀도변화에 대한 반응민감도를 얻었으며 반응민감도의 상대적 크기는 1.00 : 0.93 : 0.78 : > ∼ 0.7(HONO : HCOONO : CH$_3$ COONO : CF$_3$ COONO)로 나타났다. The regioselectivity in the nitrosation of seven N-methyl-N'-substituted phenylureas ($CH_3NHCONHC_6H_4-G$; G = H, p-CH$_3$, m-CH$_3$, m-CH$_3$O, p-F, m-F, m-Br) was examined using NaNO$_2$ and 4 different acids (diluted HCl, HCOOH, CH$_3$COOH, CF$_3$COOH). In all cases, the two regioisomeric products, N-nitroso-N-methyl-N'-substituted phenylureas (A) and N'-nitroso-N-methyl-N'-substituted phenylureas (B) were observed to be formed as major products and product ratios were determined by the integration of their methyl peaks in $^1$H-NMR. Electron donating substitutent(G) on phenyl of the ureas generally led to increase the ratio of B to A. The data have revealed that the relative sensitivity of the nitrosonium species (HONO, HCOONO, CH$_3$COONO, CF$_3$COONO) toward the change of electron density on nitrogen with phenyl substitutents are 1.00 : 0.93 : 0.78 : > ∼ 0.7.

5-Fluorouracil-1-yl-3-butanone의 항암제 내성 극복에 관한 연구

서보정,허경,강치덕,김선희,정병선,김정균 부산대학교 유전공학연구소 1994 분자생물학 연구보 Vol.10 No.-

암화학요법에 대한 암세포의 약제내성을 극복하기 위한 하나의 방법으로 항암제와 그 유사체의 병용에 의한 항종양 활성의 향상이 시도되고 있다. 5-FU는 유암, 자궁암,위암 등에 사용되고 있는 fluorinated pyrimidine계 항암제이나, 암세포의 5-FU에 대한 내성이 치료에 장애가 되고 있다. 5-FU의 항종양 활성의 향상과 내성극복을 위하여 5종의 5-FU 유도체에 대하여 MTT방법으로 5-FU와의 병용에 의하여 5-FU의 활성증강을 시키는 물질을 조사한 바, 신합성물질인 5-Fouirouracil-1-yl-3-butanone(5-FUBO)에 의한 5-FU의 세포독성 증강효과가 5-FU에 감수성인 암세포에서 보다 내성인 암세포에서 병용효과가 높았으며, 5-FU뿐만아니라 임상적으로 사용되고 있는 항암제인 VCR, VBL과의 병용효과를 나타내는 흥미있는 현상을 발견하였다. 이 합성물질에 의한 VCR 내성극복은 항암제 다제내성세포를 사용하여 조사한 바, VCR과 상기의 합성물질인 5-FUBO(o.1㎍/㎖)의 병용에 의한 VCR 내성극복 정도는 다제내성도가 낮은 암세포에서는 2.4배를 나타내었으며 다제내성도가 높은 세포에서는 11배로서 그 효과가 현저히 높은 것으로 확인하였다. 이와 같이 5-FUBO는 5-FU뿐만 아니라 vinca alkaloid계 항암제인 VCR, VBL과의 병용효과를 나타내는 매우 흥미있는 합성물질로서, 이 물질이 항암제 다제내성 변이주에서 발현하는 MDR1 유전자의 발현을 농도의존적으로 억제하였다. The potentiation effect of anticancer agents by their analogues is one of the possible strstergies for overcoming cellular resistance to chemotherapy. 5-Fouirouracil(5-FU)is a fluorinated pyrimidine which has been used in the treatment of gastrointestinal, breast and ovarian cancers. In attempts to improve the efficasy of 5-FU and overcome 5-FU resistance, We enaluated the sensitizing effect om 5-FU-induced cytotoxicity of various newly synthesized 5-FU derivatives by means of a colormetric MTT assay. 5-Fouirouracil-1-yl-3-butanone(5-FUBO), a newly synthesized 5-FU derivative, potentiates the cytotoxicity of 5-FU in 5-FU resistant mutant to a greater extent than drug-sensitive parental cells. Also, it potentiates the cytotoxic activity of clinically useful antitumor agents such as vincristine(VCR) and vinblastine(VBL). Overcoming by VCR resistance by 5-FUBO was investigated by using multidrug resistant (MDR) cells, VCR cytotoxicity was potentiated 2.4 fold in low-grade MDR cells compared with parental cells by 5-FUBO at o.1㎍/㎖ . In MDR P388(P388/M) cells, 5-FUBO gene inhibited the epression of MDR1 gene in dose-dependent manner. It may be noteworthy the cytotoxicity of structurally different anticancer agents were more potentiated drug resistant mutant to a greater extent than the parental cells.

Synthesis and Antitumor Evaluation of cis-(1,2-Diaminoethane) dichloroplatinum (II) Complexes Linked to 5- and 6-Methyleneuracil and -uridine Analogues

Kim, Jack-C.,Lee, Min-Hwa,Choi, Soon-Kyu The Pharmaceutical Society of Korea 1998 Archives of Pharmacal Research Vol.21 No.4

The search for platinum (II)-based compounds with improved therapeutic properties was prompted to design and synthesize a new family of water-soluble, third generation cis-diaminedichloroplatinum (II) complexes linked to uracil and uridine. Six heretofore unreported uracil and uridine-platinum (II) complexes are; [N-(uracil-5-yl-methyl)ethane-1,2-di-amine]dichloroplatinum (II) (3a), [N-(uracil-6-yl-methyl)ethane-1,2-diaminel dichloroplatinum (II) (3b), t[N-($2^1$, $3^1$,$5^1$-tri-O-acetyl)uridine-5-yl-methyl] ethane-1,2-diamineldichloroplatinum (II) (6a), {[N-($2^1$,$3^1$, $5^1$-tri-O-acetyl) uridine-6-yl-methyl]ethane-1,2-diamine)dichloroplatinum (II) (6b),[N-(uridine- 5-yl-methyl)ethane-1,2-diamine]dichloroplatinum (II) (7a), [N-(uridine-6-yl- methyl)ethane-1,2-diamine]dichloroplatinum (II) (7b). These analogues were prepared from the key starting materials, 5-chloromethyluracil (1a) and 6-chloromethyluracil (1b) which were reacted with ethylenediamine to afford the respective 5-[(2-aminoethyl)aminol methyluracil (2a) and 6-[(2-aminoethyl)amino]methyluracil (2b). The cis-platin complexes 3a and 3b were obtained through the reaction of the respective 2a and 2b with potassium tetrachloroplatinate (II). The heterocyclic nucleic acid bases 1a and 1b were efficiently introduced on the .betha.-D-ribose ring via a Vorbruggen-type nucleoside coupling procedure with hexamethyldisilazane, trimethylchlorosilane and stannic chloride under anhydrous acetonitrile to yield the stereospecific .betha.-anomeric 5-chloromethyl- $2^1$,$3^1$,$5^1$-tri-O-acetyluridine (4a) and 6-chloromethyl-$2^1$,$3^1$,$5^1$-tri-O-acetyluridine (4b), respectively. The nucleosides 4a and 4b were coupled with ethylenediamine to provide the respective 5-[(amino-ethyl)aminolmethyl-$2^1$,$3^1$,$5^1$-tri-O-acetyluridine (5a) and 6-[(aminoethyl)amino] methyl-$2^1$,$3^1$,$5^1$-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$_{3}$ONa. The cytotoxic activities were evaluated against three cell lines (FM-3A, P-388 and J-82) and none of the synthesized compounds showed any significant activity.

Nitrosation Products of N-Acyl-$N^{\prime}$-Substituted Phenylhydrazines

Jack C. Kim,Sun-Hong Han Korean Chemical Society 1994 Bulletin of the Korean Chemical Society Vol.15 No.2

Synthesis and Antitumor Evaluation of Acyclic 1-[∞-(N¹-2-chloroethyl-N¹-nitrosoureido)alkyl]thymidine Nucleoside Analogues

Kim, Young-Hyun,Kim, Seon-Hee,Park, Jin Il,Kim, Jack C.,Choi, Soon-Kyu 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

In the preparation of acyclic thymidine nucleoside analogues, K₂CO₃(or NaH) treated thymine in DMSO was alkylated with ω-chloroalkyl nitrite ????????? to provide an isomeric mixture of 1-(ω-cyanoalkyl)thymine (2a-d) and 1,3-bis(ω-cyanoalkyl)thymine in approximately 5:1 ratios. Reduction of the cyano function 2a-d with NaBH₄/CoCl₂· 6H₂O gave the corresponding 1-(ω-aminoalkyl)thymine (3a-d). The newly formed primary amino function in 3a-d was directly reacted with 2-chloroethylisocyanate to afford the 1-[ω-(N¹2-chloroethylureido) alkyl]thymine (4a-d) in good yields. Nitrosation of 1-[5-(N¹-2-chloroethylureido)pentyl]thymine (4d) with glacial acetic acid and dry NaNO₂powder in anhydrous CH₂Cl₂gave two types of regioisomeric nitrosoureas, 1-[5-(N¹-2-chloroethyl-N¹-nitrosoureido)pentyl]thymine (5d) and 1-[5-(N¹-2-chloroethyl-N-nitrosoureido)pentyl]thymine 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 ?? 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 Steroidal Cyclophosphamide, 2-Bis(2-chloroethyl)amino-2-oxo-6-(5$\alpha$-cholestanyl)-1,3,2-oxazaphosphorinane

Jack C. Kim,Hyoung Do Paek,Sung Hwan Moon,Si Hwan Kim Korean Chemical Society 1993 Bulletin of the Korean Chemical Society Vol.14 No.3

Study on the Atmospheric NOx Pollution in Busan City

Kim,Jack C.,Lim,Gyong-Teck,Yun,Il,Kang,Shin-Won,Choi,Mun-Hwan,Hong,Seong-Soo 부산대학교 환경문제 연구소 1983 環境硏究報 Vol.1 No.-

NO and NO₂levels were evaluated from the data collected from five auto-monitoring stations in the area of Busan City. Total average of NO was 0.163 ppm(1981). Total average NO level ranges from 0.084 ppm to 0.546 ppm. Average NO₂level ranges from 0.057 ppm to 0.112 ppm. In 1980, NO average was 0.175, and NO₂average was 0.071 ppm. Maximum NO level ranges from 0.83 ppm to 2.878 ppm, and maximum NO₂level ranges from 0.170 ppm to 0.821 ppm. Japanese and U.S.standards were exceeded mainly by the data collected, and plants and material damaging effects are expected to occur within the level determined. Control methods of NO₂were discussed.