• Archives of Pharmacal Research
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• v.21 no.5
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• pp.595-598
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• 1998

The rate of the GSH conjugate formation, the inhibition of DNA topoisomerase-I and the cytotoxic activity against L1210 cells of the naphthoquinones showed the same order; 5,8-dimethoxy-1,4-naphthoquinone (DMNQ)>6-(1-hydroxyethyl)-DMNQ>2-(1-hydroxyethyl)-DMNQ; the steric hindrance of the substituents, particularly 2-substutuent, in reacting with cellular nucleophiles must be the main cause for lowering the bioactivities. Acetylation of 2-(1-hydroxyethyl)-DMNQ producing 2-(acetyloxyethyl)-DMNQ potentiated the bioactivities; 2-(-hydroxyethyl)-DMNQ did not react with GSH and the enzyme, and showed $ED_{50}$ of 0.146 mg/ml for the cytotoxcity. Furthermore, the acetylation 2-(1-hydroxyethyl)-DMNQ(T/C, 119%) enhanced the T/C values for the mice bearing S-180 tumor {T/C of 2-(1-acetyloxyethyl)-DMNQ, 276%]. It was assumed that the difference in bioactivities ensued by acetylation was based on the mechanism of the so-called bioreductive alkylation.

• Journal of Physiology & Pathology in Korean Medicine
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• v.16 no.3
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• pp.542-546
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• 2002

The purpose of this study was to investigate the effect of 2-thioDMNQ-S160, shikonin analogue isolated from Uthospermum Erythrorhizon, on the antitumor activity. In the present study, 2-thioDMNQ-S160 exhibited a significant cytotoxicity against L1210, A549, U937, and 816-BL6 cell lines with IC/sub 50/s of 2.4ug/ml, 2,0ugjml. 4ug/ml and 20 ug/ml, respectively. 2-ThioDMNQ-S160 strongly inhibited adhesion of B16-BL6 cells to gelatin and matrigel coated matrices. Also, 2-ThioDMNQ-S160 exhibited anti-invasive effect of B16-BL6 cells. The T/C% was 123 % in 2-ThioDMNQ-S160 treated group in S-180 bearing ICA mice. These results suggested that 2-thioDMNQ-S160 might be a potent candidate of cancer drug.

• YAKHAK HOEJI
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• v.27 no.4
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• pp.309-314
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• 1983

Six hydantoin derivatives, 3-(2-chloroethyl) hydantoin (6a), 3-(2-chloroethyl)-5-isopropylhydantoin (6b), 3-(2-chloroethyl)-5-isobutylhydantoin (6c), 3-(2-chloroetbyl)5-(2-butyl) hydantoin (6d), 3-(2-chloroethyl)-5-benzylhydantoin (6e), 3-(2-chloroethyl)-5-(indolyl-3-methyl) hydantoin (6f), were prepared by the treatment of the corresponding salt of amino acids with 2-chloroethyl isocyanate in cold water, followed by refluxing in concentrated HCl solution. Anticancer activity of the synthesized hydantoin derivatives were examined on murine leukemia L1210 cells growing in Fischer medium. Among them, 3-(2-chloroethy)-5-isobutyl-hydantoin (6c) showed substantially low $ED_{50}$ value of $9.6{\mu}g/ml$.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1997.04a
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• pp.109-109
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• 1997

Inhibitory effect on DNA topoisomerase-I, rate of glutathione conjugation and cytotoxicity of naphthoquinone derivatives were correlated. During 5 min exposure of the derivatives to glutathione (GSH), it was found that 14% of 5,8-dimethoxy-1,4-naphthoquinone(DMNQ) was converted into a GSH-conjugate, whereas 5,8-dihydroxy-1,4-naphthoquinone(DHNQ) did not interact with GSH, implying that DMNQ exerted higher electrophilicity than DHNQ. However, DHNQ (IC$\_$50/, 0.15 ${\mu}$M) showed stronger cytotoxicity in L1210 cells than DMNQ(IC$\_$50/, 0.45 ${\mu}$M). The stronger cytotoxicity of DHNQ, compared to DMNQ, could be ascribed to more rapid redox cycling. Both naphthoquinones (IC$\_$50/, 60-65 ${\mu}$M) exhibiting about the same inhibitory effect on DNA topoisomerase-I were more potent than 1,4-naphthoquinone(1,4-NQ, IC$\_$50/, 134 ${\mu}$M). Thus, 5,8-oxy groups in the structure seem to be important for the inhibition of the enzyme. DMNQ showed a broader dose range while maintaining a good antitumor activity against S-180 fluid tumor. For these reasons, DMNQ was taken as useful pharmacophore for structural modification. Introduction of 1-hydroxyalkyl groups at C-2 of DMNQ lowered all of the activities mentioned above, while acetylation of 1-hydroxyalkyl moiety enhanced the activities by 4-5 times. Introduction of the same side chains at C-6 exhibited stronger activities than 2-substituted ones. Based on these results it was suggested that the quinonoid moiety in 6-substituted DMNQ was more exposed to cellular nucleophiles such as DNA, thiols of enzymes and so on. The synthesis of DHNQ or DMNQ derivatives are going on, and the corelationship between structure-activity will be discussed.

• YAKHAK HOEJI
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• v.34 no.6
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• pp.395-400
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• 1990

The FU-fat conjugates(4a-e) as a prodrug have been synthesized by condensing various fatty acids(1a-e) via isocyanates(2a-e) as carbamoyl group at $N^1-position$ of 5-fluorouracil and their structures characterized. Preliminary testing for their antitumor effect was carried out on leukemia L1210 cells in culture. Most of them(4a-d) like the parent FU exhibited less than 50% inhibition on grouth of the cultrued cells at the concentration of $1\;{\times\;10^{-7}M$. Only a dicarboxylic acid derivative, 4e, showed over 50% inhibition at the same level.

• Archives of Pharmacal Research
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• v.21 no.5
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• pp.581-590
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• 1998

We developed a novel water-soluble camptothecin analobue, CKD602, and evaluated the inhibition of topoisomerase I and the antitumor activities against mammalian tumor cells and human tumor xenografts. CKD602 was a nanomolar inhibitor of the topoisomerase I enzyme in the cleavable complex assay. CKD602 was found to be 3 times and slightly more potent than topotecan and camptothecin as inhibitors of topoisomerase, respecitively. In tumor cell cytotoxicity, CKD602 was more potent than topotecan in 14 out of 26 human cancer cell lines tested, while it was comparable to camptothecin. CKD602 was tested for the in vivo antitumor activity against the human tumor xenograft models. CKD602 was able to imduce regression of established HT-29, WIDR and CX-1 colon tumors, LX-1 lung tumor, MX-1 breast tumor and SKOV-3 ovarian tumor as much as 80, 94, 76, 67, 87% and 88%, respectively, with comparable body weight changes to those of topotecan. Also the therapeutic margin (R/Emax: maximum tolerance dose/$ED-{58}$) of CKD602 was significantly higher than that of topotecan by 4 times. Efficacy was determined at the maximal tolerated dose levels using schedule dependent i.p. administration in mice bearing L1210 leukemia. On a Q4dx4 (every 4 day for 4 doses) schedule, the maximum tolerated dose (MTD) was 25 mg/kg per administration, which caused great weight loss and lethality in <5% tumor bearing mouse. this schedule brought significant increase in life span (ILS), 212%, with 33% of long-term survivals. The ex vivo antitumor activity of CKD602 was compared with that of topotecan and the mean antitumor index (ATI) values recorded for CKD602 were significantly higher than that noted for topotecan. From these results, CKD602 warrants further clinical investigations as a potent inhibitor of topoisomerase I.

• Korean Journal of Pharmacognosy
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• v.24 no.4
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• pp.267-281
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• 1993

To find antitumor components from higher fungi, the mycelia of Collybia confluens (Pers. ex Fr.) Kummer were cultured in artificial media. For efficient production of the mycelia, the influences of various modifications of culture conditions were examined. A water-soluble protein-bound polysaccharide fraction, Fr. A, was obtained from the mycelia by hot water extraction. When Fr. A was purified and fractionated by DEAE-cellulose and Sepbadex G-200 gel filtration chromatographies into four fractions which were designated B, C, C-I and C-II. The tumor inhibition ratios of these fractions ranged from 46% to 75% against the solid forms of sarcoma 180 in ICR mice at doses of 20 and 50 mg/kg/day when given intraperitoneally. Especially, Fr. C which was named Collyban(CB) exhibited a marked life-prolonging effect of the mice against ascitic forms of sarcoma 180 at a dose of 50 mg via i.p. administration. To extend spectra of the antitumor activities and eliminate the effects of allograft rejection, the characterization of antitumor effects of CB was performed in syngeneic host-tumor systems. It did not show any antitumor activity against L1210 murine leukemia in $CD_2Fl$ mice but prolonged their life span against ascitic forms of $MM_{46}$ carcinoma in $C_3H/He$ mice. Also it exhibited antitumor activity against human cervical cancer HeLa cells that were xenografted into nude mice having BALB/c genetic backgrounds by the i.p. injection at a dose of 100 mg/kg/day. In order to characterize the antitumor components, CB was examined by chemical analysis. It was acidic protein-bound polysaccharides composed of 31% polysaccharide, 27% protein and 3% hexosamine. CB was fractionated into two fractions, Fr. C-I(M.W.: 500 Kd) and Fr. C-II(M.W.:30 and 8 Kd) by Sephadex G-200 gel filtration chromatography.

• YAKHAK HOEJI
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• v.29 no.2
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• pp.62-69
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• 1985

The isomeric intermediates, $3{\alpha}$and $3{\beta}-amino-5{\alpha}-cholestane required for the synthesis of N-nitrosoureas, N-(2-chloroethyl)-N-nitrosocarbamoyl-$3{\alpha}-amino-5{\alpha}$-cholestane (9), N-methyl-N-nitrosocarbamoyl-3${\alpha}-amino-5{\alpha}-cholestane$ (10), N-(2-chloroethyl)-N-nitrosocarbamoyl-$3{\beta}-amino-5{\alpha}-cholestane$: (7), and N-methyl-N-nitrosocarbamoyl-$3{\beta}-amino-5{\alpha}-cholestane$ (8) were obtained through the $LiAlH_{4}$ reduction of $5{\alpha}$-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 $C_{3}$-proton resonances on their NMR spectra and on the elution mobility on the TLC. The urea intermediates, N-(2-chloroethyl) carbamoyl-3.alpha.-amino-5.alpha.-cholestane (13), N-methylcarbamoyl-$3{\alpha}-amino-5{\alpha}-cholestane$ (14), N-(2-chloroethyl) carbamoyl-$3{\beta}-amino-5{\alpha}-cholestane (11) and N-methyl-$3{\beta}-amino-5{\alpha}$-cholestane (12) were prepared by the treatment of each isomers ($3{\alpha}$-amino-and $3{\beta}-amino-5{\alpha}$-cholestane) with alkyl isocyanates in anhydrous $CHCl_{3}$, and the corresponding nitrosoureas, 7-10 were obtained by the nitrosation of the ureas, 11-14, with AcOH (or HCOOH)/$NaNO_{2}$ 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 $ED_{50}$ to be 5.5g/ml and 6.1g/ml, respectively.