Naturally Occurring Quinones as Bioreductive Alkylating Agents

  • Harold W. Moore
  • J. Olle Karlsson
Part of the Recent Advances in Phytochemistry book series (RAPT, volume 20)


Bioreductive alkylation is the term used to describe the effect of those compounds which express their mode of biological action as alkylating agents, but do so subsequent to their reduction in vivo.1 That is, they are pro-drugs which are activated by a bioreduction. Quinones are a class of compounds ideally suited to function as the reducible moiety of bioreductive alkylating agents since their facile reduction in vivo and in vitro to the corresponding hydro-quinones is a well known and extensively studied reaction.2 If the quinone is further substituted with a side-chain bearing a leaving group X at the 1-position of the substituent, then quinonemethide formation can result by an elimination of HX from the hydroquinone.2,3 The reactive quinonemethide is suggested as the discrete alkylating agent and functions as such by a Michael addition of a biologically important nucleophile (Nu-:DNA, protein, carbohydrate, etc.) to the enone of the methide. This postulate is represented by the sequence of reactions outlined in Scheme . i.e., 1234.


Sodium Dithionite Reductive Elimination Carminic Acid Hypoxic Tumor Cell Quinone Methides 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    LIN, A.J., L.A. COSBY, C.W. SHANSKY, A.C. SARTORELLI. 1972. Potential bioreductive alkylating agents. 1. Benzoquinone derivatives. J. Med. Chem. 15: 1247.CrossRefGoogle Scholar
  2. 2.
    PATAI, S., ed. 1974. The Chemistry of the Quinonoid Compounds. Parts 1, 2, J. Wiley and Sons, Inc.Google Scholar
  3. 2a.
    MORTON, R.A. 1965. Biochemistry of Quinones. Academic Press, New York and London.Google Scholar
  4. 3.
    TURNER, A.B. 1964. Quinone methides. Quart. Rev. Chem. (London) 18: 347.CrossRefGoogle Scholar
  5. 4.
    LIN, A.J., R.S. PARDINI, L.A. COSBY, B.J. LILLIS, C.W. SHANSKY, A.C. SARTORELLI. 1973. Potential bioreductive alkylating agents. 2. Antitumor effects and biochemical studies of naphthoquinone derivatives. J. Med. Chem. 16: 1268.CrossRefGoogle Scholar
  6. 4a.
    LIN, A.J., C.W. SHANSKY, A.C. SARTORELLI. 1974. Potential bioreductive alkylating agents. 3. Synthesis and antineoplastic activity of acetoxymethyl and corresponding ethyl carbamate derivatives of benzo-quinones. J. Med. Chem. 17: 558.CrossRefGoogle Scholar
  7. 4b.
    LIN, A.J., B.J. LILLIS, A.C. SARTORELLI. 1975. Potential bioreductive alkylating agents. 5. Antineoplastic activity of quinoline-5,8-dione, naphtha-zarine and naphthoquinones. J. Med. Chem. 18: 917.CrossRefGoogle Scholar
  8. 4c.
    LIN, A.J., A.C. SARTORELLI. 1976. Potential bioreductive alkylating agents. 7. Antitumor effects of phenyl-substituted 2-chloromethyl-3-phenyl-1,4-naphthoquinones. J. Med. Chem. 19: 1336.CrossRefGoogle Scholar
  9. 4d.
    LIN, A.J., A.C. SARTORELLI. 1973. 2,3-Dimethyl-5,6-bis(methylene)-l,4-benzoquinone. The active intermediate of bioreductive alkylating agents. J. Org. Chem. 38: 813.CrossRefGoogle Scholar
  10. 5.
    KENNEDY, K.A., B.A. TEICHER, S. ROCKWELL, A.C. SARTORELLI. 1980. The hypoxic tumor cells: a target for selective cancer chemotherapy. Biochem. Pharmacol. 29: 1CrossRefGoogle Scholar
  11. 6.
    KENNEDY, K.A., S. ROCKWELL, A.C. SARTORELLI. 1980. Preferential activation of mitomycin C to cytotoxic metabolites by hypoxic tumor cells. Cancer Res. 40: 2356.Google Scholar
  12. 7.
    IYER, V.N., W. SZYBALSKI. 1964. Mitomycins and porfiromycin-mechanism of activation and cross-linking of deoxyribonucleic acid. Science 145: 55.CrossRefGoogle Scholar
  13. 8.
    MOORE, H.W., R. CZERNIAK. 1981. Naturally occurring quinones as potential bioreductive alkylating agents. Med. Res. Rev. 1: 249.CrossRefGoogle Scholar
  14. 9.
    KELLER, P.J., J.F. KOZLOWSKI, U. HORNEMANN. 1979. Formation of l-ethylxanthyl-2,7-diaminomitosen and 1,10-diethylxanthyl-2,8-diaminodecarbamoylmitosene in aqueous solution upon reduction-reoxidation of mitomycin C in the presence of potassium ethyl-xanthate. J. Am. Chem. Soc. 101: 7121.CrossRefGoogle Scholar
  15. 10.
    HASHIMOTO, Y., K. SHUDO, T. OKAMOTO. 1980. Acylation of 5-guanylic acid by reductively activated mitomycin C. Chem. Pharm. Bull. 28: 1961.CrossRefGoogle Scholar
  16. 11.
    HASHIMOTO, Y., K. SHUDO, T. OKAMOTO. 1983. Modification of deoxyribonucleic acid with reductivity activated mitomycin C. Chem. Pharm. Bull. 31: 861.CrossRefGoogle Scholar
  17. 12.
    PERRY, S. 1974. Summary and general discussion. Cancer, Chemother. Rep. Part 1 58: 117.Google Scholar
  18. 13.
    PIGRAM, W.J., W. FULLER, L.D. HAMILTON. 1972. Stereo-chemistry of intercalation: intercalation of dauno-mycin with DNA. Nature, New Biol. 235: 17.CrossRefGoogle Scholar
  19. 14.
    SINHA, B.K., C.F. CHIGNELL. 1979. Binding mode of chemically activated semiquinone free radicals from quinone anticancer agents to DNA. Chem.-Biol. Interact. 28: 301.CrossRefGoogle Scholar
  20. 15.
    SMITH, T.H., A.N. FUJIWARA, D.W. HENRY, W.W. LEE. 1976. Synthetic approaches to adriamycin. Degradation of daunorubicin of nonasymmetric tetracycline retone and refunctionalization of a ring to adria-mycine. J. Am. Chem. Soc. 98: 1969.CrossRefGoogle Scholar
  21. 16.
    KLEYER, D.L., T.H. KOCH. 1983. Spectroscopic observation of the tautomer of 7-deoxydaunomycinone from elimination of daunosamine from daunomycin hydro-quinone. J. Am. Chem. Soc. 105: 2504.CrossRefGoogle Scholar
  22. 17.
    KLEYER, D.L., T.H. KOCH. 1983. Electrophilic trap-ping of the tautomer of 7-deoxydaunomycinone. A possible mechanism for covalent binding of daunomycin to DNA. J. Am. Chem. Soc. 105: 5154.CrossRefGoogle Scholar
  23. 18.
    RAMAKRISHNAN, K., J. FISHER. 1983. Nucleophilic trapping of 7,11-di-deoxyanthracyclinone quinone methide. J. Am. Chem. Soc. 105: 7187.CrossRefGoogle Scholar
  24. 19.
    KLEYER, D.L., G. GAUDIANO, T.H. KOCH. 1984. Spectro-scopic and kinetic evidence for the tautomer of 7-deoxyaklavinone as an intermediate in the reductive coupling of aclacinomycin A. J. Am. Chem. Soc. 106: 1105.CrossRefGoogle Scholar
  25. 20.
    KARLSSON, J.O., N.V. NGUYEN, L.D. FOLAND, H.W. MOORE. 1985. (2-Alkynylethenyl)ketenes. A new benzoqui-none synthesis. J. Am. Chem. Soc. (in press).Google Scholar
  26. 21.
    MARVELL, E.N. 1980. Thermal Electrocyclic Reactions. Academic Press, New York, pp. 124–190.Google Scholar
  27. 21a.
    JACKSON, D.A., M. REY, A.S. DREIDING. 1983. Preparation of 2-vinylcyclobutanones and their conversion to cyclopentenones. Tetrahedron Lett., 4817.Google Scholar
  28. 21b.
    BERGE, J.M., M. REY, A.S. DREIDING. 1982. Addition of vinylketenes to enamines. A method for the preparation of 6,6-dialkylcyclohexa-2,4-dienones and 4,4-dialkylcyclobutenones. Helv. Chim. Acta 65: 2230.CrossRefGoogle Scholar
  29. 21c.
    DANHEISER, R.L., S.K. GEE, H. SARD. 1982. A [4+4] annulation approach to eight-membered carbocyclic compounds. J. Am. Chem. Soc. 104: 7670.CrossRefGoogle Scholar
  30. 21d.
    HUSTON, R., M. REY, A.S. DREIDING. 1982. Vinylketenes as synthons for bicyclo[4.2.1] nonadienones. Helv. Chim. Acta 65: 451.CrossRefGoogle Scholar
  31. 21e.
    DöTZ, K.H., B. TRENKLE, U. SCHUBERT. 1981. Addition to ynamines to vinylketenes. Angew. Chem. 93: 296.CrossRefGoogle Scholar
  32. 21f.
    DANHEISER, R.L., H. SARD. 1980. (Trimethylsilyl) vinylketene. A stable vinylketene and reactive enophile in [42]cycloadditions. J. Org. Chem. 45: 4810.CrossRefGoogle Scholar
  33. 22.
    DANHEISER, R.L., H. GEE. 1984. A regiocontrolled annulation approach to highly substituted aromatic compounds. J. Org. Chem. 49: 1674.CrossRefGoogle Scholar
  34. 23.
    NGUYEN, N.V., K. CHOW, J.O. KARLSSON, H.W. MOORE. 1985. Chemistry of azidoquinones. Conversion of 3-azido-5-alkynyl-1–2-benzoquinones to cyanophenols via (2-alkynylethenyl)ketenes. J. Am. Chem. Soc. (submitted for publication).Google Scholar
  35. 24.
    MOORE, H.W. 1979. Zwittazido cleavage. Acc Chem. Res. 12: 125.CrossRefGoogle Scholar
  36. 25.
    NGUYEN, N.V., H.W. MOORE. 1984. In situ generation and reactions of hexynylcyanoketene. J. Chem. Soc., Chem. Commun., 1066.Google Scholar
  37. 26.
    HAMDAN, A.J., H.W. MOORE. 1985. A novel synthetic route to heterocyclic quinones. J. Org. Chem. (in press).Google Scholar
  38. 27.
    SMITH, L.I., E.W. KAISER. 1940. The reaction between quinones and metallic enolates. XI. Duroquinone and enolates of cyanoacetic ester and β-diketones. J. Am. Chem. Soc. 62: 138.CrossRefGoogle Scholar
  39. 27a.
    JURD, L. 1978. Quinones and quinone methides III. A novel side-chain amination reaction of Z-(l-phenylethyl)-1,4-benzoquinones. Aust. J. Chem. 31: 347.CrossRefGoogle Scholar
  40. 28.
    MOORE, H.W., H.R. SHELDEN. 1968. Rearrangements of azidoquinones. Reaction of thymoquinone and 2,5-dimethyl-1,4-benzoquinone with sodium azide in trichloroacetic acid. J. Org. Chem. 33: 4019.CrossRefGoogle Scholar
  41. 29.
    ODA, K., T. OHMUMA, Y. BAN. 1984. A facile removal of the arenesulfonyl group by electrochemical reduction of sulfonamides in a new cooperative system of anthracene and ascorbic acid: the control of criss-cross annulation. J. Org. Chem. 49: 953.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • Harold W. Moore
    • 1
  • J. Olle Karlsson
    • 1
  1. 1.Department of ChemistryUniversity of CaliforniaIrvineUSA

Personalised recommendations