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Synthesis of Benzo[c]phenanthridine Derivatives and their in Vitro Antitumor Activities

Cho, Won-Jea    (College of Pharmacy, Chonnam National University   ); Yoo, Su-Jeong    (College of Pharmacy, Chonnam National University   ); Chung, Byung-Ho    (College of Pharmacy, Chonnam National University   ); Choi, Bo-Gil    (College of Pharmacy, Chonnam National University   ); Cheon, Seung-Hoon    (College of Pharmacy, Chonnam National University   ); Whang, Soon-Ho    (College of Pharmacy, KyungHee University   ); Kim, Sin-Kyu    (College of Pharmacy, KyungHee University   ); Kang, Boo-Hyon    (Screening and Toxicology Research Center, Korea Research Institute of Chemical Technology   ); Lee, Chong-Ock    (Screening and Toxicology Research Center, Korea Research Institute of Chemical Technology  );
  • 초록

    Aiming at the development of anticancer agents by modification of phenolic benzo[c]phenanthridine alkaloid, additional hydroxyl group was put on C10 position of fagaridine (1) by a biomimetic synthetic procedure to afford 10-hydroxyfagaridine (12). All of the synthetic intermediates were also screened in vitro antitumor activities against five different cell lines as well as 12. Among them the representative cytotoxic results are shown as follows; P-quinone (11) $[ED_50;(A549=0.22; {\mu}g/ml)$ , $(HCT;15=0.21 {\mu}g/ml)$ , fagaridine (1) $(HCT;15=0.41 {\mu}g/ml)$ , olefin (6) $(HCT; 15=0.06 {\mu}g/ml)$ , acetal (7) $(SKMEL-2=0.07 {\mu}g/ml)$ , dihydrofagaridne (10) $(A549=0.38 {\mu}g/ml)$ , 10-hydroxyfagaridine (12) $(A 549=0.45{\mu}g/mi)$ . From these observation three main remarks can be drawn; (i) the iminium part of benzo[c]phenanthridine is not essential for showing acitvities, (ii) the additional hydroxyl group did not contribute to enhance the cytotoxicity, (iii) the 3-arylisoquinolin-1(2H)-one derivatives were found to display significant in vitro antitumor activity.


  • 주제어

    Anticancer agents .   Phenolic benzo[c]phenanthridine alkaloids .   Fagaridine .   10-Hy-droxyfagaridine .   3-Arylisoquinolin-1(2H)-ones.  

  • 참고문헌 (15)

    1. Inhibitors of DNA Topoisomerase I Isolated from the Roots of Zanthoxylum nitidum , Fang,S.D.;Wang,L.K.;Hecht,S.M. , J. Org. Chem. / v.58,pp.5025-5027,
    2. Kobayashi,F.;Yokumoto,H.;Suzuki,M.;Tsubaki,M. , Chem. Abstr. / v.118,pp.,
    3. Rubinstein,L.V.;Shoemaker,R.H.;Paul,K.D.;Simon,R.M.;Tosini,S.;Skehan,P.;Scudiero,D.;Monks,A.;Boyd,M.R. , J. Natl. Cancer Inst. / v.82,pp.1113,
    4. Synthesis and Antitumor Activity of Structural Analogues of the Anticancer Benzophenanthridine Alkaloid Fagaronine Chloride , Cushman,M.;Moham,P. , J. Med. Chem. / v.28,pp.1031-1036,
    5. Synthesis and Evaluation of New 6-Amino-substututud Benzo[c]phenanthridine Derivatives , Janain,Y.L.;Croisy,A.;Riou,J.F.;Bisagni,E. , J. Med. Chem. / v.36,pp.3686-3692,
    6. Skehan,P.;Storeng,R.;Scudiero,D.;Monks,A.;McMahon,J.B.;Vistica,D.T.;Warren,J.T.;Bokesch,H.;Kenney,S.;Boyd,M.R. , J. Natl. Cancer Inst. / v.82,pp.1107,
    7. Hanaoka,M.;Mukai,C. , Studies in Natural Products Chemistry / v.14,pp.769-803,
    8. Pharmacological Activity of Benzophenanthridine and Phenanthridine Alkaloids , Simeon,S.;Rios,J.L.;Villar,A. , Pharmazie / v.44,pp.593-597,
    9. Transformation of Protopine and Protoberberine Alkaloid to Benzo[c]phenanthridine Alkaloid , Onda,M.;Yonezawa,K.;Abe,K. , Chem. Pharm. Bull. / v.19,pp.,
    10. Biomimetic Introduction of an Oxy Functionality at the C10 Position in the Benzo[c]phenanthridine Skeleton : Synthesis of 2,3,7,8,10- Pentaoxygenated Benzo[c]phenanthridine Alkaloids, Chelilutine and Sanguilutine , Hanaoka,M.;Cho,W.J.;Yoshida,S.;Mukai,C. , Chem. Pharm. Bull. / v.39,pp.1163-1166,
    11. Utilization of Protopine and Related Alkaloids. XI. , Onda,M.;Yamaguchi,H. , Chem. Pharm. Bull. / v.27,pp.2076-2083,
    12. Synthesis of Fagaridine, A Phenolic Benzo[c]phenanthridine Alkaloids , Hanaoka,M.;Yamagishi,H.;Mukai,C. , Chem. Pharm. Bull. / v.33,pp.1763-1765,
    13. Sufness,M.;Douros,J.;De Vita,V.T.(ed.);Jr.Busch,H.(ed.) , Methods in Cancer Research / v.,pp.474,
    14. A First Synthesis of Isofagaridine : Topoisomerase I Inhibitor , Cho,W.J.;Hanaoka,M. , Arch. Pharm. Res. / v.19,pp.240-242,
         
    15. A Biomimetic Synthesis of Oxychelerythrine, Dihydrochelerythrine and Chelerythrine from Berberine , Hanaoka,M.;Motonishi,T.;Mukai,C. , J. Chem. Soc. Perkin Trans. / v.1,pp.2253-2256,
  • 이 논문을 인용한 문헌 (1)

    1. 2002. "Two -week Oral Toxicity Study of 1- (4-methylpiperazinyl) -3- phenylisoquinoline (CWJ-a-5) in sprague-Dawley (SD) Rats" Journal of toxicology and public health : an official journal of the Korean Society of Toxicology, 18(1): 47~57     

 저자의 다른 논문

  • Cho, Won-Jea (24)

    1. 1996 "A First Synthesis of Isofagar-idine:Topoisomerase I Inhibitor" Archives of pharmacal research : a publication of the Pharmaceutical Society of Korea 19 (3): 240~242    
    2. 1997 "Synthesis and Structure-Activity Relationship Studies of 2,3-Dihydroimidazo[2,1-a]isoquinoline Analogs as Antitumor Agents" Archives of pharmacal research : a publication of the Pharmaceutical Society of Korea 20 (2): 138~143    
    3. 1997 "Synthesis and Antitumor Activity of 3-Arylisoquinoline Derivatives" Archives of pharmacal research : a publication of the Pharmaceutical Society of Korea 20 (3): 264~268    
    4. 1997 "항진균제 알릴아민류의 합성과 생물학적 평가" 약학회지 = Yakhak hoeji 41 (2): 187~194    
    5. 1997 "항암제 안티네오플라스톤 A10의 동족체합성 및 항암 활성" 약학회지 = Yakhak hoeji 41 (3): 283~293    
    6. 1998 "Synthesis of Antineoplaston A10 Analogs as Potential Antitumor Agents" Archives of pharmacal research : a publication of the Pharmaceutical Society of Korea 21 (2): 157~163    
    7. 1999 "새로운 2-(3-치환)프로피온산 유도체의 합성" 약학회지 = Yakhak hoeji 43 (3): 320~327    
    8. 1999 "Studies on the Synthesis and In Vitro Antitumor Activity of the Isoquinolone Derviatives" Archives of pharmacal research : a publication of the Pharmaceutical Society of Korea 22 (2): 179~183    
    9. 1999 "Synthesis of Sesquiterpene Derivitives as Potential Antitumor Agents; Elemance Derivatives" Archives of pharmacal research : a publication of the Pharmaceutical Society of Korea 22 (6): 575~578    
    10. 2000 "Effects of the Acute and Subacute Administration of 1-(N-methyl) piperazinyl-3-phenyl-isoquinoline on Rat Kidney" Journal of toxicology and public health : an official journal of the Korean Society of Toxicology 16 (1): 47~52    
  • Yoo, Su-Jeong (1)

  • 정병호 (23)

  • Choi, Bo-Gil (25)

  • Cheon, Seung Hoon (25)

  • 황순호 (7)

  • 김신규 (13)

  • 강부현 (29)

  • 이정옥 (47)

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