2-Fluoro anthracyclines

Scheme 9 Synthesis of 9-fluoro-Anthracyclines via a fluoro-bromination approach...

For the same purpose as with the 8-fluoro derivatives, the 10-fluoro derivatives were synthesized to obtain molecules with higher affinity for typical anthracycline intercalation sites 5 -(A,T)CG-3 or 5 -(A,T)GC-3 in double stranded DNA. The (101t)-(49) and (lOS)-lO-fluoro anthracyclines (50) were obtained starting from a 9-10 oxirane 48 followed by opening with DAST [27] or with Olah s reagent (HF-Pyr) at room temperature (Scheme 11) [26]. 

Derivatives of MEN10755, an anthracycline analogue currently under evaluation in Phase II clinical trials [90-93], with fluorine on C-8, were synthesized (Scheme 20) and the cytotoxic and antitumor properties of disaccharide 8-fluoro-anthracyclines were markedly affected by the stereochemistry of the... 

Despite all these studies, the first synthesis of a natural anthracycline modified at position 9 with the introduction of a fluoro atom was shown in... 

These esters (p-trifluoromethyl- and p-fluoro-benzoate) are prodrugs of DOXO [52] and have been used in cellular uptake studies. Despite the low cytotoxicity with respect to the parent anthracyclines, these esters may find apphcation for slow release. In fact, this possibility has already been explored. Some 14-(co, CO, -trifluoromethyl)-alkyl-anthracycline derivatives 57 (Fig. 7) with satisfactory carcinostatic properties have also been patented [53]. 

Other 2 -fluoro derivatives have been claimed in different patents [63,79] (Scheme 16). Generally, the cytotoxicity of the carminomycin, (4-hydroxy-IDA), and that of the 2 -fluoro derivative against a number of tumor cell lines are equal in vitro. Both compounds show the same activity in vivo in tests against murine P-388 leukemia. Acute toxicity of the fluorine compounds appears to be lower than carminomycin. Carminomycin is another natural glycoside within the family of the anthracyclines. 

Deoxy-4 -fluoro-DOXO was the object of studies, together with several other derivatives, for determination of the influence of lipophilicity on the cytotoxicity of anthracyclines in LoVo and LoVo/Dx human cell lines. The lipophilic character of selected anthracyclines was measured by means of reverse-phase HPLC, under appropriate experimental conditions. The results obtained in these in vitro models indicate that lipophilicity plays a role in anthracycline activity, influencing drug availability at the site of action. The introduction of a fluorine atom in the sugar moiety structure increases the lipophilicity and cytotoxicity of the drug [84]. 

A variety of anthracyclines fluorinated in ring A have been reported. Glycosy-lation of fluorinated aglycones was used to make 8-fluorocompounds such as 17, whilst 10-fluoro-derivatives were prepared by modification of daunorubicin or idarubicin. Some C-4 epimers were also described. 8-Fluoroanthracyclines have also been the subject of a symposium report. ... 

Most natural anthracyclines contain 2 -deoxyhexoses, a structure that lends susceptibility to acid hydrolysis (190). Tsuchiya and Takagi (190) have synthesized 2 -fluoro derivatives in an effort to stabilize the anthracycline in the presence of acids. Their results indicated that 2 -R configuration was required for biological activity, and that substitutions at 3 caused a dramatic decrease in the activity of the 2 -fluoro derivatives (190). 

Many glycosides have been made in the course of studies of medicinal compounds. In the anthracycline field the 2-fluorodaunosamine glycosylating agent (23) has been coupled to daunomycinone to give 2(S)-2 -fluorodaunorubicin.Other work has involved fluorine substitution in the aglycone, e.g. 2-fluoro- and... 

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