Cytarabine (1-β-d-arabinofuranosylcytosine, Ara-C), a pyrimidine nucleoside analogue, is used for the treatment of both acute and chronic myeloblastic leukemias and non-Hodgkin lymphoma. It has a very short plasma half-life and a very low oral bioavailability. To overcome these disadvantages, much effort has been focused on the design of cytarabine prodrugs. In this study, we have synthesized four different cytarabine prodrugs in order to increase the drug lipophilicity and the affinity of the prodrugs toward the biological membranes, as well as the lipophilic carriers. Differential scanning calorimetry was used to study the interaction of cytarabine and its prodrugs with multilamellar vesicles (MLVs) made of dimyristoylphosphatidylcholine (DMPC) and used as a model of biomembranes as well as a lipophilic carrier. The results showed that the 4-N-acetyl-2′,3′-5′-acetyl derivative and the prodrug with short chain fatty acids do not have a significant affinity with MLVs, whereas the prodrugs with long chain fatty acids have a stronger affinity with the MLVs with respect to cytarabine. The entity of the affinity depends on the fatty acids length. The increased affinity could be due to the fatty acid moieties which allow the molecule to insert among the phospholipid molecules. These results provide information on the interaction of these prodrugs with biomembranes and could be useful to design liposomes as carriers for the prodrugs.
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Drug-Biomembrane Interaction Studies. The application of calorimetric techniques. 1st ed. Cambridge: Woodhead Publishing; 2013.
Nunes C, Brezesinski G, Lopes D, Lima JLFC, Reis S, Lúucio M. Lipid–drug interaction: biophysical effects of tolmetin on membrane mimetic systems of different dimensionality. J Phys Chem B. 2011;115:12615–23.
Gzyl-Malchera B, Handzlik J, Klekowsk E. Temperature dependence of the interaction of prazosin with lipid Langmuir monolayers. Colloids Surf B. 2013;112:171–6.
Tamai N, Inazawa S, Takeuchi S, Goto M, Matsuki H. Phase behavior of binary bilayer membrane of dipalmitoylphosphatidylcholine and stigmasterol. J Therm Anal Calorim. 2019;135:2635–45.
Zhao L, Feng S-S. Effects of lipid chain unsaturation and headgroup type on molecular interactions between paclitaxel and phospholipid within model biomembrane. J Colloid Interface Sci. 2005;285:326–35.
Rouser G, Nelson GJ, Fleischer S, Simon G, Chapman D, editors. Biological membranes. New York: Academic Press; 1968. p. 5–69.
Cevc G. Polymorphism of the bilayer membranes in the ordered phase and the molecular origin of the lipid pretransition and rippled lamellae. Biochim Biophys Acta. 1991;1062:59–69.
Lewis RNAH, McElhancey RN. The mesomorphic phase behavior of lipid bilayers. In: Yeagle P, editor. The structure of biological membranes. London: CRC Press; 1992. p. 73–155.
Shelton J, Lu X, Hollenbaugh JA, Cho JH, Amblard F, Schinazi RF. Metabolism, biochemical actions, and chemical synthesis of anticancer nucleosides, nucleotides, and base analogs. Chem Rev. 2016;116:14379–455.
Chik F, Machnes Z, Szyf M. Synergistic anti-breast cancer effect of a combined treatment with the methyl donors-adenosyl methionine and the DNA methylation inhibitor 5-aza-2′-deoxycytidine. Carcinogenesis. 2014;35:138–44.
Berrío Escobar JF, Pastrana Restrepo MH, Galeano Jaramillo E, Márquez Fernández DM, Márquez Fernández ME, Martínez Martínez A. Synthesis and cytotoxic activity of per-acetylated and halogenated derivatives of nucleosides in breast cancer cells. Ars Pharm. 2017;58:145–54.
Bzowska A, Kulikowska E, Shugar D. Purine nucleoside phophorylases: properties, functions and clinical aspects. Pharmacol Ther. 2000;88:349–425.
Berrío Escobar JF, Arango Carmona VH, Galeano Jaramillo E, Márquez Fernández DM, Márquez Fernández ME, Camargo Guerrero M, Martínez Martínez A. Synthesis and cytotoxic activity of tri-acyl ester derivatives of uridine in breast cancer cells. Ars Pharm. 2016;57:183–91.
Sarpietro MG, Micieli D, Rocco F, Ceruti M, Castelli F. Conjugation of squalene to acyclovir improves the affinity for biomembrane models. Int J Pharm. 2009;382:73–9.
Sarpietro MG, Pitarresi G, Ottimo S, Giuffrida MC, Ognibene MC, Fiorica C, Giammona G, Castelli F. Interaction between drug loaded polyaspartamide-polylactide-polysorbate based micelles and cell membrane models: a calorimetric study. Mol Pharm. 2011;8:642–50.
Librando V, Accolla ML, Minniti Z, Pappalardo M, Castelli F, Cascio O, Sarpietro MG. Calorimetric evidence of interaction of brominated flame retardants with membrane model. Environ Toxicol Pharmacol. 2015;39:1154–60.
Koynova R, Caffrey M. Phases and phase transitions of thephosphatidylcholines. Biochim Biophys Acta. 1998;1376:91–145.
Jain MK, Wu NM. Effect of small molecules on the dipalmitoyl lecithin liposomal bilayer: III. Phase transition in lipid bilayer. J Membr Biol. 1977;34:157–201.
Papahadjopoulos D, Moscarello M, Eylar EH, Isac T. Effects of proteins on thermotropic phase transitions of phospholipid membranes. Biochim Biophys Acta. 1975;401:317–35.
Alvares DS, Wilke N, Neto JR. Effect of N-terminal acetylation on lytic activity and lipid-packing perturbation induced in model membranes by a mastoparan-like peptide. Biochim Biophys Acta Biomembr. 2018;1860:737–48.
Basso LGM, Rodrigues RZ, Naal RMZG, Costa-Filho AJ. Effects of the antimalarial drug primaquine on the dynamic structure of lipid model membranes. Biochim Biophys Acta. 2011;1808:55–64.
Authors thank financing to the University of Antioquia (Project CODI CIQF-155 2012-2014, Strategy of Sustainability 2014-2015).
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Berrio Escobar, J.F., Marquez Fernandez, D.M., Giordani, C. et al. DSC studies on the interaction of lipophilic cytarabine prodrugs with DMPC multilamellar vesicles. J Therm Anal Calorim 138, 2759–2767 (2019). https://doi.org/10.1007/s10973-019-08780-x
- Biological membranes