• 제목/요약/키워드: Topoisomerase-I

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6-(1-하이드록시 또는 아실옥시알킬)-5,8-디알콕시-1,4-나프토퀴논 유도체의 합성, DNA Topoisomerase-I에 대한 억제, 세포독성 및 항암활성 (6-(1-Hydroxy or Acyloxyalkyl)-5,8-Dialkoxy-1,4-Naphthoquinones: Synthesis, Evaluation of Cytotoxic Activity; Antitumor Activity and Inhibitory effect on DNA Topoisomerase-I)

  • 김용;최수라;명평근;안병준
    • 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.

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DNA topoisomerase I 억제제 β-lapachone에 의한 전립선 암세포의 성장억제 기전연구 (Up-regulation of Bax is associated with DNA topoisomerase I inhibitor β-lapachone-induced apoptosis in human prostate carcinoma cells)

  • 공규리;최병태;최영현
    • 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.

  • https://doi.org/10.5352/JLS.2002.12.4.469 인용 PDF KSCI

Synthesis of Indeno［1.2-c］indenoisoquinoline Derivatives as Potential Topoisomerase I Inhibitors

  • Quynh, Le-Manh;Thanh, Le-Nguyen;Gang, Seong-Gyoung;Chung, Byung-Ho;Cho, Won-Jea
    • 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.

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Design. Synthesis and Antitumor Evaluation of Terpyridine Derivatives Containing Pyridines at 4'- Position

  • Lim, Hyun-Tae;Moon, Yoon-Soo;Zhao, Longxuan;Kim, Eun-Kyung;Kim, Tae-Hyung;Lee, Eung-Seok
    • 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.347.3-347.3
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    • 2002

  • Recent study indicated that terpyridine and its derivatives displayed highly active antitumor properties. In this presentation. derivatives of terpyridines having three pyridine moieties at 2',4',6'-position of central pyridine skeleton were prepared, and evaluated their cytotoxicity against several human cancer cell lines and topoisomerase I inhibitory activities. Most of the prepared compounds showed strong cytotoxicity compared to doxorubicln. In addition. several compounds displayed better cytotoxicity than that of doxorubicin. In addition, several compounds displayed better cytotoxicity than that of doxorubicin. Structure-activity relationship study was perfomed to be indicated that [2.2':6',2']terpyidine skeleton is important to show strong xytotoxicity. Significant topoxicity. Significant topoisomerase I inhibitory activity was not observed for prepared compounds.

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