Abstract
Adenosine, the adenine nucleoside, has demonstrated various pharmacological properties related to the treatment of relevant clinical diseases. With respect to this, one of the most fascinating biological activities of adenosine is its capacity for reversing hepatic fibrosis, which has been established in several in vitro and in vivo studies. Although adenosine seems to be a privileged compound, it lacks of metabolic stability to be considered as a drug candidate. For this reason, in this preliminary study, six prodrugs were developed in order to enhance the plasma half-life of adenosine, in which the esterification at 5′ position of adenosine was considered. According to previous works, the increase in steric hindrance at this position could develop unfavorable interactions inside adenosine deaminase (ADA) catalytic domain, which is reported as the main enzyme implicated in adenosine metabolism. Besides, molecular docking was employed to verify if the hindrance at carbinol group in the prodrugs is enough to diminish its oxidation and also to predict if compounds would be metabolized by a promiscuous esterase. Finally, the in vitro assays corroborated the theoretical findings and also indicated that the compounds are less metabolized than adenosine by ADA; in the case of compounds containing proline and thioproline progroups (4d and 4e, respectively), the reduction was more than three-fold of decrease.
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References
Bencharit S, Morton CL, Hyatt JL, Kuhn P, Danks MK, Potter PM, Redinbo MR (2003) Crystal structure of human carboxylesterase 1 complexed with the Alzheimer’s drug tacrine: from binding promiscuity to selective inhibition. Chem Biol 10:341–349
Ciuffreda P, Loseto A, Allessandrini L, Terraneo G, Santaniello E (2003) Adenylate deaminase (5′-adenylic acid deaminase, AMPDA)-catalyzed deamination of 5′-deoxy-5′-substituted and 5′-protected adenosines: a comparison with the catalytic activity of adenosine deaminase (ADA). Eur J Org Chem 24:4748–4751
Ciuffreda P, Buzzi B, Alessandrini L, Santaniello E (2004) Activity of adenosine deaminase (ADA) and adenylate deaminase (AMPDA) towards 6-chloropurine nucleosides modified in the ribose moiety. Eur J Org Chem 21:4405–4409
Cronstein BN, Kramer SB, Weissmann G, Hirschorn R (1983) Adenosine: a physiological modulator of superoxide anion generation by human neutrophils. J Exp Med 158:1160–1177
Curtis MA, Varkhedkar V, Pragnacharyulu PVP, Abushanab E (1998) Adenosine deaminase inhibitors. Synthesis and biological evaluation of aralkyladenines (ARADS). Bioorg Med Chem Lett 8:1639–1642
Gulizar A (2004) Antioxidant effects of sulfur-containing amino acids. Yonsei Med J 45:776–788
Haskó G, Németh ZH, Vizi ES, Salzman AL, Szabó C (1998) An agonist of adenosine A3 receptors decreases interleukin-12 and interferon-gamma production and prevents lethality in endotoxemic mice. Eur J Pharmacol 358:261–268
Hernandez-Munoz R, Diaz-Munoz M, Lopez V, Lopez-Barrera F, Yanez L, Vidrio S, Aranda-Frausto A, Chagoya de Sánchez V (1997) Balance between oxidative damage and proliferative potential in an experimental rat model of CCl4-induced cirrhosis: protective role of adenosine administration. Hepatology 26:1100–1110
Hernández-Muñoz R, Díaz-Muñoz M, Suárez J, Chagoya de Sánchez V (1990) Adenosine partially prevents cirrhosis induced by carbon tetrachloride in rats. Hepatology 12:242–248
Hernández-Muñoz R, Díaz-Muñoz M, Suárez-Cuenca JA, Trejo-Solís C, López V, Sánchez-Sevilla L, Yañez L, de Sánchez VC (2001) Adenosine reverses a preestablished CCl4-induced micronodular cirrhosis through collagenolytic activity and stimulating hepatocyte cell proliferation in rats. Hepatology 34:667–687
Huey R, Morris GM, Olson AJ, Goodsell DA (2007) A semiempirical free energy force field with charge-based desolvation. J Comput Chem 28:1145–1152
Imai T (2006) Human carboxylesterase isozymes: catalytic properties and rational drug design. Drug Metab Pharmacokinet 21:173–185
Ishizaki-Koizumi S, Sonaka I, Fujitani S, Nishiguchi S (2002) Mechanism of the protective effect of l-alanine to D-galactosamine-induced hepatocellular injury: comparative studies of l-alanine and pyruvate. Biochem Biophys Res Commun 291:738–743
Jacobson KA, Gao ZG (2006) Adenosine receptors as therapeutics targets. Nat Rev Drug Discov 5:247–264
Jason C, Jaime-Figueroa S, Jiang L, Wagner P (2008) Novel practical deprotection of N-Boc compounds using fluorinated alcohols. Synth Commun 38:3840–3853
Kinoshita T, Nakanishi I, Terasaka T, Kuno M, Seki N, Warizaya M, Matsumura H, Inoue T, Takano K, Adachi H, Mori Y, Fujii T (2005) Structural basis of compound recognition by adenosine deaminase. Biochem 44:10562–10569
Kocic G, Nikolic J, Jevtovic-Stoimenov T, Sokolovic D, Kocic H, Cvetkovic T, Pavlovic D, Cencic A, Stojanovic D (2012) l-Arginine intake effect on adenine nucleotide metabolism in rat parenchymal and reproductive tissues. Sci World J 2012:208–239
Li F, Maag H, Alfredson T (2008) Prodrugs of nucleoside analogues for improved oral absorption and tissue targeting. J Pharm Sci 97:1109–1134
Ligumsky M, Sestieri M, Okon E, Ginsburg I (1995) Antioxidants inhibit ethanol-induced gastric injury in the rat: role of manganese, glycine and carotene. Scand J Gastroenterol 30:854–860
Mendieta-Condado E, Chagoya de Sanchez V, Hernandez-Muñoz R (2007) Adenosine can accelerate the cell cycle during rat liver regeneration induced by partial hepatectomy. J Hepatol 46:S142l-
Michel PP, Marien M, Ruberg M, Colpaert F, Agid Y (1999) Adenosine prevents the death of mesencephalic dopaminergic neurons by a mechanism that involves astrocytes. J Neurochem 72:2074–2082
Morris GM, Goodsell D, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) Automated docking using a Lamarckian genetic algorithm and a empirical binding free energy function. J Comput Chem 19:1639–1662
Mösher GH, Schrader J, Deussen A (1989) Turnover of adenosine in plasma of human and dog blood. Am J Physiol 256:C799–C806
Müller CE, Jacobson KA (2011) Recent developments in adenosine receptor ligands and their potential as novel drugs. Biochim Biophys Acta 1808:1290–1308
Pedersen RC, Berry AJ (1977) Sensitive, optimized assay for serum AMP deaminase. Clin Chem 23:1726–1733
Redinbo MR, Potter PM (2005) Mammalian carboxylesterases: from drug targets to protein therapeutics. Drug Discov Today 10:313–325
Senthilkumar R, Sengottuvelan N, Nalini N (2003) Protective effect of glycine supplementation on the levels of lipid peroxidation and antioxidant enzymes in the erythrocite of rats with alcohol-induced liver injury. Cell Biochem Funct 22:123–128
Suo M, Mukaisho K, Shimomura A, Sugihara H, Hattori T (2006) Thioproline prevents carcinogenesis in the remnant stomach induced by duodenal reflux. Cancer Lett 237:256–262
Willem de Jong J, Kalkman C (1973) Myocardial adenosine kinase: activity and localization determined with rapid radiometric assay. Biochim Biophys Acta 320:388–396
Yang Y, Aloysius H, Inoyama D, Chen Y, Hu L (2011) Enzyme-mediated hydrolytic activation of prodrugs. Acta Pharm Sin B. 1:143–159
Yoo BK, Choi JW, Yoon SY, Ko KH (2005) Protective effect of adenosine and purine nucleos(t)ides against the death by hydrogen peroxide and glucose deprivation in rat primary astrocytes. Neurosci Res 51:39–44
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This work was supported by Grants from CONACyT. The authors thank Dr. Rafael Castillo for lending the software and hardware.
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Hernández-Vázquez, E., Chagoya, V. Potential utility of adenosine 5′-ester prodrugs to enhance its plasma half-life: synthesis and molecular docking studies. Med Chem Res 24, 2325–2335 (2015). https://doi.org/10.1007/s00044-014-1299-z
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DOI: https://doi.org/10.1007/s00044-014-1299-z