Lipophilic nucleosides

Cai, M. Shi, X. Sidorov, V. Fabris, D. Lam, Y.-F. Davis, J. T. Cation-directed self-assembly of lipophilic nucleosides The cation s central role in the structure and dynamics of a hydrogen-bonded assembly. Tetrahedron 2002, 58, 661-671. 

Here, we present the methods of preparation of liposomes as carriers for lipophilic nucleosides and heterodinucleoside drugs. We do not describe in details the methods used to evaluate the cytotoxic properties of the lipophilic drug formulations. For comprehensive information, we refer to our publications and to the related literature. 

Figure 9 Lipophilic nucleosides G 5 and isoG 6 self-associate in the presence of cations to give hydrogen-bonded G4-quartets or isoG -pentamers. The relative orientation of the nucleoside s hydrogen bond donor and acceptor groups determines assembly size (Adapted from ref 3 with permission).

DELIVERY SYSTEMS FOR PEPTIDES/ OLIGONUCLEOTIDES AND LIPOPHILIC NUCLEOSIDE ANALOGS... 

The formulation of pharmacologically active drug molecules in DDS can improve or abolish these unfavorable properties. However, there are also drawbacks in DDS development, such as system complexity, unwanted biologic effects, stability, costs of development and scale-up, as well as intellectual property issues. In the limited format of this review, it is not possible to cover all methods and references in the field. Hence, we concentrate this review on DDS for the delivery of peptides, DNA, plasmids, oligodeoxynucleotides, siRNA, and lipophilic nucleoside derivatives. Vaccine delivery systems will also be mentioned, and examples will be provided to demonstrate the general development trends. 

Herbert Schott, Institute of Organic Chemistry, University of Tubingen, Tubingen, Germany, Delivery Systems for Peptides/Oligonucleotides and Lipophilic Nucleoside Analogs... 

Montanha, E.A., et al. Properties of lipophilic nucleoside monolayers at the air-water interface. Colloids Surf. B Biointerfaces 77(2), 161-165 (2010)... 

The Zn-N3imide interaction has been used to selectively extract imide-containing nucleosides and nucleotides into lipophilic media (39). Hexadecyl-derivatized Zn2+-cyclen was shown to extract dT from an aqueous solution containing a mixture of C, A, and G nucleobases. The antiviral agent AZT (3 azido-3 deoxythymidine) could also be extracted into CHCI3 from neutral aqueous solutions. Transport across a lipophilic layer was also shown, using acidic conditions, to promote the release of dT and AZT (Fig. 9). 

Lipophilic peptide Multi-Nucleoside reverse transcriptase inhibitor conjugates synthesis to combat HIV resistance... 

S. G. Kerr, T. I. Kalman, Highly Water-Soluble Lipophilic Prodrugs of the Anti-HIV Nucleoside Analogue 2, 3 -Dideoxycytidine and Its 3 -Fluoro Derivative , J. Med. Chem. 1992, 35, 1996 - 2001 S. G. Kerr, T. I. Kalman, V4-(Dialkylaminomelhylcnc Derivatives of 2 -Deoxycytidine and Arabinocytidine Physicochemical Studies for Potential Prodrug Applications , J. Pharm. Sci. 1994, 83, 582 - 586. 

Since the beginning of our work with liposomes that dates back more than 20 years, we chose the approach of the chemical transformation of water-soluble nucleosides of known cytotoxic and antiviral properties into lipophilic drugs or prodrugs (see references summarized in Table 1). 

Ethynylcytidine [l-(3-C-ethynyl-p-D-ribopentafuranosyl)-cytosine] (ETC) is a novel nucleoside that was foimd to be highly cytotoxic (53-55). By combination of ETC with NOAC, we synthesized the new lipophilic derivative NOAC-ETC [3 -C-ethynylcytidylyl-(5 —>5 )-N" -octadecyl-l-p-D-arabinofura-nosylcytosine]. The chemical structure of ETC-NOAC is shown in Fig. 1. 

Schneider and coworkers investigated the capability of the tetraazonia cyclophane 51 to bind nucleosides and nucleotides in water [72]. Its two diphenylmethane units border a lipophilic cavity for the uptake of likewise lipophilic molecules or subunits. As evidenced by HNMR studies of the complexes, only in the case of the purine derived nucleosides and nucleotides (A, G, AXP, GMP) the base moiety is included inside the host cavity but not in the case of the pyrimidine analogues (U, C, UMP, CMP, TMP). Due to their hydrophilic nature, the sugar and phosphate groups remain outside the niche. 

Viswanadhan, V. N., et al., Assessment of Methods Used for Predicting Lipophilicity Application to Nucleosides and Nucleoside Bases. J. Comput. Chem., 1992 14, 1019— 1026. 

Neutral molecules are carried between two organic phases through a water layer by water-soluble receptors containing a lipophilic cavity [6.40, 6.41]. Urea and nucleosides are transported using a metallocarrier [6.42a] and complementary basepairing agents [6.42b], respectively. 

Kerr, S. G. andT. I. Kalman. 1992. Highly water-soluble lipophilic prodrugs of the anti-HIV nucleoside analogue 2/,3/-dideoxycytidine and its 3 uoro derivativeJ. Med. Chem35 1996-2001. 

Shaw has reported the first syntheses of thymidine- and 2 -deoxy-5-fluorouridine - 3, 5 - cyclic boranophosphorothioate (103a,b). These analogues, displaying increased lipophilicity, were prepared from a key intermediate, a cyclic phosphoramidite obtained by heating a thoroughly degassed HMPA solution of the nucleoside. This phosphoramidite was then converted to a cyclic phosphite triester in the presence of 4-nitrophenol and 5-ethylthio-lH-tetrazole, and converted to the boranated complex in situ. The cyclic boranophosphite was then converted to the 3, 5 -cyclic boranophosphorothioate. ... 

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