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 language | English |
|---|---|
| Pages (from-to) | 603-609 |
| Number of pages | 7 |
| Journal | Molecular Pharmacology |
| Volume | 50 |
| Issue number | 3 |
| Publication status | Published - Sep 1996 |
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ASJC Scopus subject areas
- Pharmacology
Cite this
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 journal › Article
}
TY - JOUR
T1 - Biochemical and pharmacological activity of novel 8- fluoroanthracyclines
T2 - Influence of stereochemistry and conformation
AU - Animati, Fabio
AU - Arcamone, Federico
AU - Bigioni, Mario
AU - Capranico, Giovanni
AU - Caserini, Claudia
AU - De Cesare, Michelandrea
AU - Lombardi, Paolo
AU - Pratesi, Graziella
AU - Salvatore, Carmela
AU - Supino, Rosanna
AU - Zunino, Franco
PY - 1996/9
Y1 - 1996/9
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=9544232513&partnerID=8YFLogxK
M3 - Article
C2 - 8794900
AN - SCOPUS:9544232513
VL - 50
SP - 603
EP - 609
JO - Molecular Pharmacology
JF - Molecular Pharmacology
SN - 0026-895X
IS - 3
ER -