Abstract
5′-Methylthioadenosine (MTA) is a natural substrate of MTA phosphorylase (MTAP) and is converted to adenine via a salvage pathway for AMP production in normal healthy cells. The lack of MTAP expression in many solid tumors and hematologic malignancies compared to normal healthy cells has been explored in a potential therapeutic strategy to selectively target tumor cells using antimetabolites such as 5-fluorouracil (5-FU) and 6-thioguanine (6-TG) while protecting normal healthy cells with MTA. Herein, a series of carbamate prodrugs, namely the N-(alkyloxy)carbonyl-MTA derivatives 2a-f, was designed, synthesized, and evaluated as potential prodrugs of MTA. All carbamate prodrugs were stable in phosphate buffer, pH 7.4 at 37 °C. In the presence of mouse liver microsomes, the prodrugs were converted to MTA at varying rates with the hexyl and butyl carbamates 2a and 2b most readily activated (t1/2 of 1.2 and 9.4 h, respectively). The activation was shown to be mediated by carboxyesterases present in mouse liver microsomes.
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Abbreviations
- AMP:
-
adenosine monophosphate
- APRT:
-
adenine phosphoribosyltransferase
- BNPP:
-
bis(4-nitrophenyl)-phosphate
- 5-FU:
-
5-fluorouracil
- HLM:
-
human liver microsome
- HPLC:
-
high performance liquid chromatography
- IC 50 :
-
concentration required to produce 50% inhibition
- LC-MS:
-
liquid chromatography-mass spectrometry
- MLM:
-
mouse liver microsome
- MTA:
-
5′-methylthioadenosine
- MTAP:
-
MTA phosphorylase
- NADPH:
-
nicotinamide adenine dinucleotide phosphate
- PRPP:
-
phosphoribosyl-1-pyrophosphate
- 6-TG:
-
6-thioguanine
- TLC:
-
thin layer chromatography
References
Casero RA Jr, Marton LJ. Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases. Nat Rev Drug Disco. 2007;6:373–90. https://doi.org/10.1038/nrd2243.
Avila MAA, Garcı́a-Trevijano ER, Lu SC, Corrales FJ, Mato JM. Methylthioadenosine. Int J Biochem Cell Biol. 2004;36:2125–30. https://doi.org/10.1016/j.biocel.2003.11.016.
Lubin M, Lubin A. Selective Killing of Tumors Deficient in Methylthioadenosine Phosphorylase: a Novel Strategy. PLoS ONE. 2009;4:e5735. https://doi.org/10.1371/journal.pone.0005735.
Tang B, Testa JR, Kruger WD. Increasing the therapeutic index of 5-fluorouracil and 6-thioguanine by targeting loss of MTAP in tumor cells. Cancer Biol Ther. 2012;13:1082–90. https://doi.org/10.4161/cbt.21115.
Bertino JR, Waud WR, Parker WB, Lubin M. Targeting tumors that lack methylthioadenosine phosphorylase (MTAP) activity: current strategies. Cancer Biol Ther. 2011;11:627–32. https://doi.org/10.4161/cbt.11.7.14948.
Kung P-P, Zehnder LR, Meng JJ, Kupchinsky SW, Skalitzky DJ, Johnson MC, et al. Design, synthesis, and biological evaluation of novel human 5′-deoxy-5′-methylthioadenosine phosphorylase (MTAP) substrates. Bioorg Med Chem Lett. 2005;15:2829–33. https://doi.org/10.1016/j.bmcl.2005.03.107.
Bloom LA, Boritzki TJ, Ogden R, Skalitzky D, Kung P-P, Zehnder L et al., inventors; Agouron Pharmaceuticals, Inc., assignee. Combination therapies for treating methylthioadenosine phosphorylase deficient cells patent. US20040043959A1. 2004.
Lubin A, Lubin M, inventors; Therapy of tumors and infectious agents deficient in methylthioadenosine phosphorylase patent US 8796241 B2. 2014.
Munshi PN, Lubin M, Bertino JR. 6-Thioguanine: a Drug With Unrealized Potential for Cancer Therapy. Oncologist. 2014;19:760–5. https://doi.org/10.1634/theoncologist.2014-0178.
Simile MM, Banni S, Angioni E, Carta G, De Miglio MR, Muroni MR, et al. 5′-Methylthioadenosine administration prevents lipid peroxidation and fibrogenesis induced in rat liver by carbon-tetrachloride intoxication. J Hepatol. 2001;34:386–94. https://doi.org/10.1016/S0168-8278(00)00078-7.
Wolford RW, Riscoe MK, Johnson L, Ferro AJ, Fitchen JH. Effect of 5’-methylthioadenosine (a naturally occurring nucleoside) on murine hematopoiesis. Exp Hematol. 1984;12:867–71.
Moratti EM, inventor Bioresearch S.P.A., assignee. Pharmaceutical compositions containing 5’-deoxy-5’-methylthioadenosine s-adenosylmethionine and their salts for reducing seborrhea patent. US5753213A. 1998.
Stramentinoli G, Gennari F, inventors; Bioresearch S.r.l., assignee. Adenosine derivatives of anti-inflammatory and analgesic activity, and therapeutic compositions which contain them as their active principle patent. US4454122A. 1984.
Bloom LA, Boritzki TJ, Kung P-P, Ogden RC, Skalitzky DJ, Zehnder LR et al., inventors; Pfizer Inc., assignee. Combination therapies for treating methylthioadenosine phosphorylase deficient cells patent WO 2003074083 A1. 2003.
Miwa M, Ura M, Nishida M, Sawada N, Ishikawa T, Mori K, et al. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer. 1998;34:1274–81. https://doi.org/10.1016/S0959-8049(98)00058-6.
Walko CM, Lindley C. Capecitabine: a review. Clin Ther. 2005;27:23–44. https://doi.org/10.1016/j.clinthera.2005.01.005.
Hu L. Prodrug Approaches to Drug Delivery. In Drug Delivery: Principles and Applications, 2nd Ed., B. Wang, L. Hu, and T. Siahaan, Eds; John Wiley & Sons: Hoboken, New Jersey, 2016; pp 227-271. https://doi.org/10.1002/9781118833322.ch12.
Yang Y, Aloysius H, Inoyama D, Chen Y, Hu L. Enzyme-mediated hydrolytic activation of prodrugs. Acta Pharm Sin B. 2011;1:143–59. https://doi.org/10.1016/j.apsb.2011.08.001.
Desmoulin F, Gilard V, Malet-Martino M, Martino R. Metabolism of capecitabine, an oral fluorouracil prodrug: (19)F NMR studies in animal models and human urine. Drug Metab Dispos. 2002;30:1221–9. https://doi.org/10.1124/dmd.30.11.1221.
Shindoh H, Nakano K, Yoshida T, Ishigai M. Comparison of in vitro metabolic conversion of capecitabine to 5-FU in rats, mice, monkeys and humans - toxicological implications. J Toxicol Sci. 2011;36:411–22. https://doi.org/10.2131/jts.36.411.
Obringer C, Wu S, Troutman J, Karb M, Lester C. Effect of chain length and branching on the in vitro metabolism of a series of parabens in human liver S9, human skin S9, and human plasma. Regul Toxicol Pharm. 2021;122:104918. https://doi.org/10.1016/j.yrtph.2021.104918.
Ozaki H, Sugihara K, Watanabe Y, Fujino C, Uramaru N, Sone T, et al. Comparative study of the hydrolytic metabolism of methyl-, ethyl-, propyl-, butyl-, heptyl- and dodecylparaben by microsomes of various rat and human tissues. Xenobiotica. 2013;43:1064–72. https://doi.org/10.3109/00498254.2013.802059.
Imai T, Taketani M, Shii M, Hosokawa M, Chiba K. Substrate Specificity of Carboxylesterase Isozymes and Their Contribution to Hydrolase Activity in Human Liver and Small Intestine. Drug Metab Dispos. 2006;34:1734–41. https://doi.org/10.1124/dmd.106.009381.
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Dedicated to Professor Gary Grunewald for his more than 50 years of dedicated service on the faculty of the Department of Medicinal Chemistry, University of Kansas School of Pharmacy.
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Ranade, A.S., Bertino, J.R. & Hu, L. Design, synthesis, and evaluation of potential carbamate prodrugs of 5′-methylthioadenosine (MTA). Med Chem Res 30, 1358–1365 (2021). https://doi.org/10.1007/s00044-021-02730-9
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DOI: https://doi.org/10.1007/s00044-021-02730-9