• 약학회지
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• 제53권4호
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• pp.228-234
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• 2009

Topoisomerase I (Topo I) participates in the DNA replication, transcription, and repair. Binding of Topo I inhibitor to the Topo I-DNA cleavage complex forms stabilized ternary complex which blocks DNA religation and ultimately causes cell death. Camptothecin (CPT) and its derivatives have been among the most effective anticancer drugs by inhibition of topo I. However, efforts to synthesize non-CPT drugs have been actively going on because the CPT derivatives have several limitations such as poor solubility, short half-life, and side effects. As an indenoisoquinoline, NSC314622 is not as potent as CPT, but its chemical stability and slower reversibility of the cleavage complex made it a good lead compound. Recently, a series of indenoisoquinoline analogues were synthesized with substituted dimethoxy or methylenedioxy on the aromatic ring and alkylamino on the lactam nitrogen. Some of them showed quite good Topo I inhibitory activity. Using the computer docking program, Surflex-Dock, indenoisoquinoline analogues were docked into the human Topo I-DNA cleavable complex. The docking results showed that the compounds with activity better than NSC314622 intercalated between the -1 and +1 base pairs at the cleavage site, but those with little or no activities did not appear to intercalate. These results could be useful to design new Topo I inhibitors improved than CPT.

• 약학회지
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• 제44권2호
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• pp.141-148
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• 2000

A new synthetic method of 6-(1-oxyalkyl)-5,8-dimethoxy-1,4-naphthoquinones was developed, 2-formyl-1,4,5,8-tetramethoxynaphthalene was oxidized to form 6-formyl-5,8-dimethoxy-1,4-naphthoquinone(DMNQ). This was selectively reduced and benzylated to produce 6-formyl-5,8-dimethoxy-1,4-dibenzyloxynaphthalene, to which various alkylmagnesium halide were added, followed by debenzylation and oxidation in sequence, yielding 6-(1-hydroxyalkyl)-DMNQ derivatives. 6-(1-hydroxyalkyl)-5,8-diethoxy-1,4-naphthalene (DENQ) derivatives were synthesized by similar procedure. 1'-OH of the naphthoquinone derivatives was acylated with various alkanoic acids to give 6-(1-acyloxyalkyl)-DMNQ or DENQ derivatives. TOPO-I inhibitory activity and cytotoxicity of DENQs were less potent than that of DMNQs. Among the DMNQ and DENQ analogues, the ones with alkyl group being heptyl were most potent in TOPO-I inhibition $IC_{50}$/; 30.1, 36.4 $\mu$M). DUNQ derivatives with a longer side chain exhibited a weaker cytotoxicity. A correlation between size of the alkyl side chain and cytotoxicity was not observed for DENQ derivatives. Acylation of 1'-hydroxyl group, in general, decreased both TOPO-I inhibitory activity and cytotoxicity T/C (%) values of the DENQ derivatives on S-180 intraperitoneal tumor were larger than those of DMNQ derivatives. Among the compounds synthesized,6-(1-hydroxyheptyl)-DENQ and 6-(1-hex-anoyloxyoctyl)-DMNQ showed the highest T/C values of 183% and 182%, respectively.

• 대한약학회:학술대회논문집
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• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2-2
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• pp.159.1-159.1
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• 2003

Human Topoisomerase I (topo I) helps the control of DNA supercoiling in cells by assisting breaking and religation of DNA strand. It is essential for cellular metabolism and survival, hence, a good target for a novel class of anticancer drugs. As topo I inhibitor binds to the DNA-topo I complex, the religation of DNA strand is suppressed which results in the death of the target cell. Seven compounds of H-Imidazo［4, 5-g］phthalazing-4, 9-dione derivatives with $IC_50$ in the range of 0.001 and 6.27 $\mu$M in 5 different cancer cells and four compounds of 7-chloro-6-quinazoline-5, 8-dione derivatives with positive and negative topo I inhibition activities were studied. (omitted)

• Natural Product Sciences
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• 제17권3호
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• pp.245-249
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• 2011

Eight compounds, squalene (1), friedelin (2), ${\beta}$-sitosterol (3), ${\beta}$-sitosterol-3-O-glucoside (4), ${\alpha}$-tocopherol (5), betulinic acid (6), trilinolein (7) and 1-O-(9Z,12Z-Octadecadienoyl)-3-nonadecanoyl glycerol (8), were isolated from the barks of Tilia amurensis. Their chemical structures were identified by comparing their physicochemical and spectral data with those published in the literature. These isolated compounds were examined for their inhibitory activities against topoisomerase I and II. Compound 7 showed significant inhibition of DNA topoisomerase I and II activities, with percent decreases in activity of 87 and 95%, respectively at a concentration of $100\;{\mu}M$. Compound 6 exhibited cytotoxicity against the human colon adenocarcinoma cell line (HT-29), the human breast adenocarcinoma cell line (MCF-7) and the human liver hepatoblastoma cell line (HepG-2), with $IC_{50}$ values of 20, 59 and $16\;{\mu}M$, respectively.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1997년도 춘계학술대회
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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.

• Bulletin of the Korean Chemical Society
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• 제29권8호
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• pp.1605-1608
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• 2008

• 대한약학회:학술대회논문집
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• 대한약학회 2002년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2
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• pp.340.3-341
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• 2002

During the research for the development of antitumor agents. we found the 3-arylisoquinoline derivatives exhibited potent cytotoxicity against human tumor cell lines. For extending our study on these compounds. indeno［1.2-c］isoquinolines were chosen as the next research target due to previous studied data of the compounds that showed potent topoisomerase I inhibition activity as well as cytotoxicity against many kinds of tumor cell lines. Retrosynthetic consideration of indeno[1.2-d]isoquinolines indicates that the coupling of o-methyltoluamide with o-hydroxymethylbenxonitrile might afford 3-arylisoquinoline which could be translerred to the aldehtde. Indeno [1.2-c]isoquinolines can be formed by and inframolecular ring cyclization method. Various derlvatives of this compound including 11-alkoxy-6-methyl-6H. 11H-indeno[1.2-c]isoquinolin-5-one and biological activity will be presented with the docking model with topisomerase 1 enzyme.

• Archives of Pharmacal Research
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• 제21권5호
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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.

• 생명과학회지
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• 제12권4호
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• pp.469-476
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• 2002

남미지역에 서식하는 Tabebuia avellanedae의 수피에서 동정된 천연 quinone계 물질인 $\beta$-lapachone은 DNA topoisomerase I 억제제 이외 다양한 약리학적 기능이 있을 것으로 추정되지만 그 기능이 명확하지 않다. $\beta$-lapachone의 생리활성 기전 해석의 일환으로 본 연구에서는 인체 전립선 DU-145 암세포주의 성장에 미치는 $\beta$-lapachone의 영향을 조사하였다. p-lapachone이 함유된 배지에서 자란 암세포들은 $\beta$-lapachone 처리 농도 의존적으로 성장이 억제되었으며, 이는 apoptosis가 유발된 세포에서 특징적으로 관찰되는 chromatin condensation 및 DNA fragmentation 현상을 유발하였고, DNA flow cytometry 분석결과 apoptotic-sub Gl기에 해당하는 세포들의 빈도도 증가되었다. 또한 poly (ADP-ribose) polymerase 및 $\beta$-catenin 단백질의 발현에서도 apoptosis 유발 특이적인 분해 현상을 보여주었으며, DU-145 전립선 암세포에서 $\beta$-lapachone에 의한 이러한 apoptosis의 유발에는 Bax의 발현증가에 따른 Bcl-2 발현의 감소가 중요한 역할을 할 고 있는 것으로 사료된다.

• Archives of Pharmacal Research
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• 제21권5호
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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.