Design, Synthesis, and Cytotoxic Activity of Michael Acceptors and Enol Esters in the Benzo[b]acronycine Series

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概要

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• A series of 2-acyl-6-methoxy-3, 3, 14-trimethyl-3, 14-dihydro-7H-benzo[b]pyrano[3, 2-h]acridin-7-ones (4-6) was prepared by treatment of 6-methoxy-3, 3, 14-trimethyl-3, 14-dihydro-7H-benzo[b]pyrano[3, 2-h]acridin-7-one (3) with an excess of an appropriate acyl chloride in the presence of aluminum chloride. Treatment of (±)-cis-1-hydroxy-2-acyloxy-6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-7H-benzo[b]pyrano[3, 2-h]acridin-7-ones (9, 10) or (±)-cis-1, 2-diacyloxy-6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-7H-benzo[b]pyrano[3, 2-h]acridin-7-ones (2, 11) with hydrochloric acid gave the corresponding 2-acyloxy-6-methoxy-3, 3, 14-trimethyl-3, 14-dihydro-7H-benzo[b]pyrano[3, 2-h]acridin-7-ones, exemplified by acetate 7 and butyrate 8. None of the Michael acceptors 4-6 showed significant antiproliferative activity. Enol esters 7 and 8 were markedly cytotoxic toward L1210 leukemia cells, with IC_<50> values within the same range of magnitude as (±)-cis-1, 2-diacetoxy-6-methoxy-3, 3, 14-trimethyl-1, 2, 3, 14-tetrahydro-7H-benzo[b]pyrano[3, 2-h]acridin-7-one (S23906-1), currently under phase I clinical trials. In contrast with S23906-1, enol esters 7 and 8 were not reactive toward purified DNA.

• 公益社団法人日本薬学会の論文
• 2005-08-01

著者

• Koch Michel

  Laboratoire De Pharmacognosie De I'universite Rene Descartes U.m.r. C.n.r.s. N° 8638 Faculte De

• Michel Sylvie

  Laboratoire De Pharmacognosie De I'universite Rene Descartes U.m.r. C.n.r.s. N° 8638 Faculte De

• Leonce S

  Inst. Recherches Servier Croissy Sur Seine Fra

• Doan Thi

  Laboratoire De Pharmacognosie De L'universite Rene Descartes U. M. R. /c. N. R. S. N°8638 Facul

• Koch M

  Univ. Rene Descartes Paris Fra

• Thi Mai

  Laboratoire De Pharmacognosie De L'universite Rene Descartes U.m.r.

• Pfeiffer Bruno

  Institut De Recherches Servier Division Recherche Cancerologie

• TILLEQUIN Francois

  Laboratoire de Pharmacognosie de l'Universite Paris Descartes

• Le´once S

  Institut De Recherches Servier Division Recherche Cancerologie

• PIERRE Alain

  Institut de Recherches Servier, Division Recherche Cancerologie

• GASLONDE Thomas

  C.N.R.S. n°8638, Faculte des Sciences Pharmaceutiques et Biologiques

• KOCH Michel

  C.N.R.S. n°8638, Faculte des Sciences Pharmaceutiques et Biologiques

• BAILLY Christian

  C.N.R.S. n°8638, Faculte des Sciences Pharmaceutiques et Biologiques

• DAVID-CORDONNIER Marie

  Laboratoire de Pharmacognosie de l'Universite Rene Descartes, U.M.R.

• PFEIFFER Bruno

  C.N.R.S. n°8638, Faculte des Sciences Pharmaceutiques et Biologiques

• LEONCE Stephane

  Laboratoire de Pharmacognosie de l'Universite Rene Descartes, U.M.R.

• PIERRE Alain

  C.N.R.S. n°8638, Faculte des Sciences Pharmaceutiques et Biologiques

• Gaslonde Thomas

  Laboratoire De Pharmacognosie De I'universite Rene Descartes U.m.r. C.n.r.s. N° 8638 Faculte De

• Pierre Alain

  Institut De Recherches Servier Division Recherche Cancerologie

• Mitaku S

  Laboratory Of Pharmacognosy Department Of Pharmacy University Of Athens

• Tillequin Francois

  Laboratoire De Pharmacognosie De L'universite Paris Descartes

• Tillequin F

  Laboratoire De Pharmacognoise De 1'universite Rene Descartes Umr/cnrsn ^○8638 Faculte Des Scien

• Mitaku Sofia

  Laboratory Of Pharmacognosy Department Of Pharmacy University Of Athens

• David-cordonnier Marie

  Laboratoire De Pharmacognosie De L'universite Rene Descartes U.m.r.

• Bailly Christian

  C.n.r.s. N°8638 Faculte Des Sciences Pharmaceutiques Et Biologiques

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