Anthracyclines fluorinated

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. ... 

Anthracyclines are antitumor quinone containing antibiotics produced by different strains of Streptomyces. Some of them, such as adriamycin doxorubicin), and daunorubicin are broad spectrum antitumor compounds. They act by binding to DNA and interfering with DNA replication and gene transcription. Their limitations for clinical use are cardiac toxicity and drug resistance phenomena. Consequently, intense structure-activity relationship studies have been performed to improve the pharmacological profile as well as to enhance the affinity for DNA. In particular, a number of fluorinated anthracyclines have been prepared with introduction of fluorine atoms into D or A cycles, and into the aglycone side chain linked atC-14. ... 

This chapter aims to offer an updated overview of the efforts made by several research groups in the fleld of fluorinated anthracyclines. We also give, along with the structures, brief descriptions of the syntheses and current status of development. 

Therefore, it is not surprising that the fascination of fluorine entered the field of anthracycline glycoside synthesis. Remarkable chemical interest consequently arose on the introduction of fluorine into the anthracycline molecule with the aim of altering the biorelevance of functional groups, thus providing new compounds whose DNA-drug interaction and antitumor properties could be compared with those exhibited by the clinically used an-thracyclines (1-4) (Fig. 1). 

Generally, fluorinated anthracyclines are obtained via total synthesis of the aglycone or sugar moieties to introduce the fluorine into the specific position. 

We will begin with an overview of fluorinated anthracyclines and go on to describe the compounds reported in the scientific literature and claimed in patents, sketching, at the same time, their total synthesis. Subsequently, we will propose an analysis of the opportunity to introduce the fiuorine atom into this class of antitumor drugs to increase biological activity. 

Anthracyclinones fluorinated on the D-ring were used to obtain the different anthracyclines 9 and also derivatives modified on the sugar moiety, such as morpholinyl-10 [11] or 4 -epi-4 amino-anthracyclines 11 (Fig. 3) [12]. 

In conclusion, fluorine substitution on the A-ring of antitumor anthracyclines was studied. All four possible monosubstitution topologies at positions 8 and 10 were synthesized, showing that the new fluoroanthracyclines retain bioactivity. Nevertheless, the four derivatives show different activity and RI values in different subpanels of tumor cell lines in vitro. 

The hydroxyl group in C-9 is very important for the antitumor activity of anthracyclines, and many derivatives have been synthesized confirming this. The only compound with an interesting activity was amrubicin (SM-5887), a 9-aminoanthracychne that in clinical trials showed almost the same antitumor activity and less cystic irritability as compared to DOXO and EPI [31,32]. When this hydroxyl group was substituted with a fluorine atom, the correspondent derivative showed lower activity as an antitumor agent than the reference compoimds (personal impubhshed data). Therefore, only chemical references are present in the literature on these derivatives. 

The literature reports several examples of substitution of the natural sugar moiety of anthracyclines (daunosamine) with different modified sugars. One of these modifications was the use of a fluorinated sugar. 

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. 

In 1998, Tsuchiya et al. [81] obtained some DOXO- and DAUNO-type anthracyclines 61, bearing a fluorine atom in positions 1 and 3. These deriva-... 

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]. 

Derivatives with both fluorines on C-2 and C-6 (69) (Fig. 10) were claimed [88] where the daunosamine was substituted by a taropyranosyl moiety. These anthracyclines showed low toxicity and higher activity than current carcinostatic agents. 

Disaccharide anthracyclines were synthesized, in which the daunosaraine moiety is separated from the aglycone by either a rhamnose or fucose residue. Fluorine was reported on the fucose moiety (70) [89] and on the aglycone at C-8 (71) [20] (Fig. 11). Both examples indicate two important considerations first, anthracyclines, with an activity comparable to that of DOXO, possess the daunosamine moiety not directly linked to the aglycone second, the fluorine does not lower the activity of these compounds but allows the synthesis of new derivatives with a particularly high activity in inhibiting the growth of cultured human tumor cells. 

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... 

Although many synthesized fluorinated derivatives are able to overcome MDR and reduce cardiotoxicity, two of the main drawbacks of the anthracyclines, no such analogue, to the best of our knowledge, is in an advanced clinical phase and not one has reached the market. 

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