Archives of Pharmacal Research

The Pharmaceutical Society of Korea (대한약학회)
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Synthesis and in vitro Antitumor Activity of lsoazamitosene and lsoiminoazamitosene Derivatives

  • Ahn, Chan-Mug (Department of Basic Sciences, Wonju College of Medicine, Yonsei University) ;
  • Kim, Soo-Kie (Department of Microbiology, Wonju College of Medicine, Yonsei University)
  • Published : 1996.12.01
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Abstract

Seven isoazamitosene derivatives, mitomycin analogues, were synthesized and tested for cytotoxicities against leukemia and gastric cancer cell lines. Preparation of a pyrrolo[1, 2-a]benzimidazole (3) (azamitosene ring system) was completed by utilizing the Lewis acid-catalized cyclization, with .omicron.-chloronitrotoluene as the starting material. Nitration of 3 produced a mixtue of two isomers (5-nitro isomer (4) and 7-nitro isomer (5)) in product ratio of 36 : 52. 4 was directly converted into quinone (7) by reduction and Fremy oxidaton. Finally, quinone derivatives (8, 9, 10, and 11) were synthesized by 1, 4-addition of 7 with cyclic secondary amines. From above-mentioned 5, 8-nitro compound (15) was prepared in 4 steps. At pH 3, Fremy oxidation of 15 produced quinone (16), whereas iminoquinone derivatives (17a and 17b) at pH 7. Isoazamitosene derivatives (8, 9, 10, and 11), containing cyclic amino groups at the 7-position, showed potent cytotoxicity on P388, SNU-1, and KHH tumor cell lines. Among them, 8 had stronger cytotoxicity against SNU-1 cell line than mitomycin and adriamycin. Considering these results, isoazamitosene derivatives may had unique cytotoxicity profiles. However, isoiminoazamitosene derivatives (17a and 17b) revealed very weak cytotoxicity.

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References

  1. J. Am. Chem. Soc. v.108 Electrochemical reductive actication of mitomycin C Andrews,P.A.;Pan,S.;Bachur,N.R.
  2. Cancer Res. v.43 no.2 Cytocidal action of the quinone group and its relationship to antitumor activity Begleiter,J.H.
  3. Cancer Res. v.47 Evaluation of a tetrazolium-based semiautomated colorimetric assay : Assesment of chemosensitivity testing Carmichel,J.;DeGraff,W.G.;Gazdar,A.F.
  4. Cancer Res. v.43 no.2 Effect of anthracycline antibiotics on oxygen radical formation in rat heart Doroshow,J.H.
  5. J. Med. Chem. v.30 Synthesis and antineoplastic activity of 1a-formyl and 1a-thioformyl derivatives of mitomycin C and 2-methylaziridine Fishbein,P.L.
  6. J. Org. Chem. v.55 Synthesis and physical studies of azamitosene and iminoazamitosene reductive alkylating agents. Iminoquinone hydrolytic stability, syn/anti isomerization, and electrochemistry Islam,I.;Skibo,E.B.
  7. J. Med. Chem. v.34 Structure-activity studies of antitumor agents based on pyrrolo[1,2-a] benzimidazoles : new rective alkylating DNA cleaving agents Islam,I.;Skibo,E.B.
  8. J. Med. Chem. v.26 Mitomycin C and porfiromycin analogues with substituted ethylamines at position 7 Iyengar,B.S.;Sami,S.M.;Remers,W.A.;Bradner,W.T.;Schurig,J.E.
  9. Biochem. Pharm. v.29 The hypoxic tumor cell : a target for selective cancer chemotherapy Kennedy,K.A.;Teicher,B.A.;Rockwell,S.;Sartorelli,A.C.
  10. Adv. Enz. Reg. v.23 Chemotherapeutic attack of hypoxic tumor cells by the bioreductive alkylating agent mitomycin C Keyes,S.R.;Heimbrook,D.C.;Fracasso,P.M.;Rockwell,S.;Sligar,S.G.;Sartorelli,A.C.
  11. Adv. Heterocycl. Chem. v.14 Heterocycles by ring closure of ortho-substituted t-anilines(the t-amino effect) Math-Cohn,O.;Suschitzky,H.
  12. Science v.197 Bioactivation as a model for drug design bioreductive alkylation Moore,H.W.
  13. Med. Res. Rev. v.1 Naturally occurring quinones as potential bioreductive alkylating agents Moore,H.W.;Czerniak,P.
  14. Purification of Laboratory Chemicals(2nd ed.) Perrin,D.D.;Armarego,L.F.;Perrin,O.R.
  15. J. Med. Chem. v.27 Mitomycin C analogues with aryl substitutions on the 7-amino group Sami,S.M.;Iyengar,B.S.;Tarnow,S.E.;Remer,W.A.;Bradner,W.T.;Schurig,J.E.
  16. J. Med. Chem. v.36 Pyrrolo[1.2-a]benzimidazole-based aziridinyl quinones, a new class of DNA cleaving agent exhibiting G and A Base specificity Skibo,E.B.;Schulz,W.G.
  17. Biochemistry v.25 Reassignment of the guanine-binding mode of reduced mitomycin C Tomasz,M.;Lipman,R.;Verdine,G.L.;Nakanishi,K.
  18. J. Org. Chem. v.52 Novel mitomycin C amidines : Synthesis and their reactions with amines Vyas,D.M.;Chiang,Y.;Benigni,D.;Doyle,T.W.