Biochemical and pharmacological activity of novel 8-fluoroanthracyclines: influence of stereochemistry and conformation.
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 alpha half-chair conformation, which is the most stable for natural compounds (i.e., daunorubicin and doxorubicin), and the (8S)-fluoroepimers preferred the beta 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 alpha 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 xenograft. 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.
Animati
F
F
Division of Experimental Oncology B, Istituto Nazionale Tumori, Milan, Italy.
Arcamone
F
F
Bigioni
M
M
Capranico
G
G
Caserini
C
C
De Cesare
M
M
Lombardi
P
P
Pratesi
G
G
Salvatore
C
C
Supino
R
R
Zunino
F
F
D000818:Animals; D018943:Anthracyclines / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity*; D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000627:therapeutic use / Q000633:toxicity; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000627:therapeutic use / Q000633:toxicity; D005260:Female; D005461:Fluorine; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D005461:Fluorine; D004317:Doxorubicin; D004250:DNA Topoisomerases, Type II; D003630:Daunorubicin