14-Fluoroanthracyclines. Novel syntheses and antitumor activity.

Abstract

The 14-fluoroanthracyclines (5-10) carrying L-daunosamine, D-2-deoxyribose, or L-2-deoxyfucose as their glycosidic sugar moieties, were synthesized starting from (-)-7-deoxy-4-demethoxydaunomycinone ((R)-11a) or (-)-7-deoxydaunomycinone ((R)-11b). As key steps, the synthetic route features a novel fluorination reaction in which tetrabutylammonium fluoride is employed in the presence of a half equivalent of p-toluenesulfonic acid, and the previously explored glycosidation reaction in which trimethylsilyl trifluoromethanesulfonate is utilized as an activating reagent. In P388 in vitro tests, 5, 6, 9, and 10 exhibited prominent cytotoxicity comparable with that of adriamycin (1). Notable antitumor activity was also observed for 6 and 9 in P388 in vivo tests.The anthracycline antibiotics, adriamycin (1) and daunorubicin (2), are important anticancer agents which are widely used in the clinic for treating leukemia and solid tumors.2) However, their utility for cancer chemotherapy is seriously restricted by various undesirable side effects, the most well-known and serious of which is dose-related cardiotoxicity.2) Thus, extensive studies on the structure-activity relationships have been carried out to overcome these disadvantages, culminating in the syntheses of various notable congeners of 1 and 2, some of which show superior anticancer activity in the P388 in vivo murine leukemia test system.2,3) Among these congeners of 1 and 2, 4-demethoxyadriamycin (3) and 4-demethoxydaunorubicin (4) are well recognized to exhibit better therapeutic indices than natural 1 and 2.2-5)With the aims of improving the therapeutic properties of pharmacologically active compounds, and moreover, of finding novel pharmacological activities different from those of the parent compounds, a great number of fluorinated derivatives of biologically active compounds have been prepared in the last decade.6,7) In the field of anthracyclines, some derivatives involving fluorinated sugars') or D-rings9) have recently been synthesized. However, syntheses of anthracycline congeners carrying fluorinated C9-side chains have not been reported, probably due to the difficulty which may be encountered in introducing

Fluorinated Anthracyclines: Synthesis and Biological Activity

“…and in vivo antitumor activity (T/C= 0.3-10 mg/Kg) for different derivatives against P388 murine leukemia [63].…”

“…The 14-fluoro-IDA/DAUNO (53) has been obtained after several steps by 7-deoxy-idarubicinone/ daunorubicinone [63][64][65][66][67][68]. The only derivatives with a fluorine atom in this position have been described as trifluoro-ethyl-hydrazones of DOXO and DAUNO.…”