Synthesis and conformational preference of novel 8-fluoroanthracyclines

• Autorzy: Lombardi P. , Animati F. , Cipollone A. , Giannini G. , Monteagudo E. , Arcamone F.
• Języki publikacji: EN

Abstrakty

EN

Analogues of daunorubicin possessing a fluorine atom at position C(8) of ring A have been synthesized with the aim of comparing their DNA-drug interaction and antitumour properties with those of the clinically useful anthracyclines doxorubicin and idarubicin. The synthesis of (8S)-8-fluoro-4-demethoxydaunorubicin, 1, is reported and molecular mechanics and NMR studies which guided towards the synthesis of the epimeric (8R)-8-fluoro-4-demethoxydaunorubicin, 2, are discussed. Both compounds were prepared by divergent routes starting from the common intermediate, 6, obtained via the Diels-Alder cyclisation between quinizarin diquinone, 3, and 2-(l-hydroxyethyl)-l,3-butadiene, 4. The synthesis of the (8S)-fluoroepimer proceeded via epoxidation of the C(8)-C(9) olefinic bond of 6, oxidation, oxirane cleavage by BF3 • Et20 to give the fluorohydroxyketone, 9, followed by the introduction of the hydroxyl moiety at C(7) and glycosylation. Conversely, the synthesis of the (8R)-fluoroepimer involved the fluorobromination of the C(8)-C(9) olefinic bond of 6, formation of the C(9)-C(13) epoxide, 20 which, after regioselective hydrolysis and oxidation of the resulting fluorodiol to the epimeric fluoro­hydroxyketone, 21, similarly gave the desired fluoroaglycone, 25 and, hence, the corresponding glycoside, 2. The cytotoxic properties of the two 8-fluoroanthracycline analogues, 1 and 2, were markedly affected by the stereochemistry of the fluorine substituent.

Słowa kluczowe

EN

fluorinated drug; chemotherapy; tumour disease; 8-fluoro-4-demethoxydaunorubicin; anthracycline

• Wydawca: -
• Czasopismo: Acta Biochimica Polonica
• Rocznik: 1995
• Tom: 42
• Numer: 4
• Opis fizyczny: p.433-444,fig.

Twórcy

autor

Lombardi P.

• Menarini Ricerche Sud, Via Tito Speri, 10, 00040 Pomezia, Italy

autor

Animati F.

autor

Cipollone A.

autor

Giannini G.

autor

Monteagudo E.

autor

Arcamone F.

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