Duplex drugs

Figure 1 Chemical structures of the 5 —>5 phosphodiester duplex drugs Ara-C-NOAC, mol. wt. 801g/mol, 5-FdU-NOAC, mol. wt. 804g/mol, and ETC-NOAC, mol. wt. 825g/mol. Abbreviations-. Ara-C-NOAC, arabinocytidylyl-(5 —>5 )-lSr -octadecyl-l-P-D-arabinofuranosylcytosine 5-FdU-NOAC, 2 -deoxy-5-fluorouridylyl-(5 5 )-N" -octadecyl-l-P-D-arabinofuranosylcytosine ETC-NOAC, 3 -C-ethynylcytidylyl-(5 5 )-N" -octadecyl-l-P-D-arabinofuranosylcytosine.

Synthesis of Lipophilic Arabinofuranosyl Cytosine N" -Alkyl Derivatives and Heterodinucleoside Phosphate Duplex Drugs... 

In earlier studies, the duplex drugs 5-FdU-NOAC and ara-C-NOAC were found to be strong inhibitors of the cell cycle, mainly arresting tumor cells in the early S-phase (33,46 8). However, with liposome formulations of the duplex drugs cell uptake, intracellular distribution, biodistribution, and metabolism were not yet investigated in details. Due to their similarity to NOAC, it can be assumed that they have comparable pharmacological... 

Figure 2 In vitro cytotoxic activity on B16F1 melanoma cells of the duplex drugs in liposome formulations and of ETC dissolved in phosphate buffered saline. The corresponding IC50 values in mM are shown on the bars. Abbreviations ara-C-NOAC, arabinocytidylyl-N" -octadecyl-l-P-D-arabinofuranosylcytosine 5-FdU-NOAC, 2 -deoxy-5-fluorouridylyl-N" -octadecyl-l -P-D-arabinofuranosylcytosine ETC, ethynylcy-tidine [l-(3-C-ethynyl-P-D-ribopentafuranosyl)-cytosine] NOAC, ISf-octadecyl-ara-C PBS, phosphate buffered saline.

Key words Liposomes, Lipophilic drugs. Lipophilic ara-C drugs, NOAC, Duplex drugs... 

Recently, we further modified NOAC by the synthesis of new duplex drugs by combination of the clinically used cancer drugs ara-C, 5-fluorodeoxyuridine (5-FdU) and the highly active new compound ethynylcytidine (l-(3-C-ethynyl-P-D-ribopentofuranosyl)-cytosine, ETC) with NOAC, yielding the heterodinucleoside phosphates arabinocytidylyl- N -octadecyl-1 -P-D-arabinofuranosyl-cytosine (ara-C-NOAC), 2 -deoxy-5-fluorouridylyl-N -octadecyl-l-P-D-arabinofiiranosylcytosine (5-FdU-NOAC) and ETC-NOAC ( 3 -C-ethynylcytidylyl-(5 5 )- octadecyl-1-p-D-arabinofuranosylcytosine) as shown in Fig. 2 (28-32). 

The cytotoxic activity of such duplex drugs is expected to be more effective as compared to the monomeric nucleosides. Due to the combination of the effects of both active molecules that can be released in the cells as monomers or as the corresponding monophosphates, it can be anticipated that mono-phosphorylated nucleosides are directly formed in the cytoplasm after enzymatic cleavage of the duplex drugs. Thus, mono-phosphorylated molecules would not have to pass the first phosphorlyation step, which is known to be rate limiting. 

A structure-related disadvantage of the duplex drugs is that upon enzymatic cleavage of the phosphodiester bonds, a 1-to-l ratio of nucleoside to nucleotide is obtained (see Figure 7.7-6). Thus, the desired 5 -phosphorylated nucleotide is only formed at maximally 50%. Additionally, one of the two nucleosides has to be transformed into a lipophilic derivative without loss of antitumor or antiviral activity. On the other hand, it was shown that the lipophilic derivatization of nucleosides can result in enhanced activity and modulation of cell specificity [106]. 

Figure 7.7-6. Duplex drugs. Structure of the anticancer amphiphilic heterodinucleosidyl phosphodiester (Duplex-drug) combining the hydrophilic 5-fluoro-deoxyuridine (5-FdU) with the lipophilic N -octadecyiarabino-furanosyicytosine (NOAC). Upon enzymatic hydrolysis of the duplex drugs, different anticancer nucleotides and nucleosides are formed with additive or synergistic activities.

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