Biochemical and pharmacological activity of novel 8- fluoroanthracyclines: Influence of stereochemistry and conformation

Fabio Animati, Federico Arcamone, Mario Bigioni, Giovanni Capranico, Claudia Caserini, Michelandrea De Cesare, Paolo Lombardi, Graziella Pratesi, Carmela Salvatore, Rosanna Supino, Franco Zunino

Research output: Contribution to journalArticle

Abstract

In an attempt to better understand the role of the cyclohexene ring (ring A) in the biochemical and pharmacological properties of anthracyclines related to doxorubicin and daunorubicin, we investigated the effects of introduction of a fluorine atom at position 8 of idarubicin (4- demethoxydaunorubicin) on drug molecular conformation and biochemical and pharmacological activities. The study showed that the stereochemistry of the substituent at position 8 influenced the 'half-chair' conformation, so that in the (8R)-fluoroepimer the A ring retained the half-chair conformation, which is the most stable for natural compounds (i.e., daunorubicin and doxorubicin), and the (8S)-fluoroepimers preferred the β half-chair conformation. The (8R)-fluoroepimer was more effective than the (8S)- fluoroepimer and idarubicin in stimulating topoisomerase II-mediated DNA cleavage. Similarly, the epimer with the α conformation was markedly more potent than the (8S)-epimer as a cytotoxic agent in a variety of human tumor cell lines and was more effective as an antitumor agent in the treatment of an ovarian carcinoma xenograff. In addition, 8-fluoro derivatives were able to overcome the resistance to doxorubicin in a number of human tumor cell lines expressing different mechanisms of resistance. In conclusion, these findings provide evidence that drug interactions involving the external (nonintercalating) moiety of the anthracycline chromophore play an important role in determining pharmacological properties, including drug ability to induce DNA cleavage, and therefore their antitumor efficacy.

Original languageEnglish
Pages (from-to)603-609
Number of pages7
JournalMolecular Pharmacology
Volume50
Issue number3
Publication statusPublished - Sep 1996

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Idarubicin
Doxorubicin
DNA Cleavage
Daunorubicin
Anthracyclines
Pharmacology
Tumor Cell Line
Molecular Conformation
Type II DNA Topoisomerase
Fluorine
Cytotoxins
Drug Interactions
Pharmaceutical Preparations
Antineoplastic Agents
Carcinoma

ASJC Scopus subject areas

  • Pharmacology

Cite this

Animati, F., Arcamone, F., Bigioni, M., Capranico, G., Caserini, C., De Cesare, M., ... Zunino, F. (1996). Biochemical and pharmacological activity of novel 8- fluoroanthracyclines: Influence of stereochemistry and conformation. Molecular Pharmacology, 50(3), 603-609.

Biochemical and pharmacological activity of novel 8- fluoroanthracyclines : Influence of stereochemistry and conformation. / Animati, Fabio; Arcamone, Federico; Bigioni, Mario; Capranico, Giovanni; Caserini, Claudia; De Cesare, Michelandrea; Lombardi, Paolo; Pratesi, Graziella; Salvatore, Carmela; Supino, Rosanna; Zunino, Franco.

In: Molecular Pharmacology, Vol. 50, No. 3, 09.1996, p. 603-609.

Research output: Contribution to journalArticle

Animati, F, Arcamone, F, Bigioni, M, Capranico, G, Caserini, C, De Cesare, M, Lombardi, P, Pratesi, G, Salvatore, C, Supino, R & Zunino, F 1996, 'Biochemical and pharmacological activity of novel 8- fluoroanthracyclines: Influence of stereochemistry and conformation', Molecular Pharmacology, vol. 50, no. 3, pp. 603-609.
Animati F, Arcamone F, Bigioni M, Capranico G, Caserini C, De Cesare M et al. Biochemical and pharmacological activity of novel 8- fluoroanthracyclines: Influence of stereochemistry and conformation. Molecular Pharmacology. 1996 Sep;50(3):603-609.
Animati, Fabio ; Arcamone, Federico ; Bigioni, Mario ; Capranico, Giovanni ; Caserini, Claudia ; De Cesare, Michelandrea ; Lombardi, Paolo ; Pratesi, Graziella ; Salvatore, Carmela ; Supino, Rosanna ; Zunino, Franco. / Biochemical and pharmacological activity of novel 8- fluoroanthracyclines : Influence of stereochemistry and conformation. In: Molecular Pharmacology. 1996 ; Vol. 50, No. 3. pp. 603-609.
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AU - Caserini, Claudia

AU - De Cesare, Michelandrea

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