Influencing epigenetic information with a hydrolytically stable carbocyclic 5-aza-2’-deoxycytidine

Wildenhof, Thomas; Schiffers, Sarah; Traube, Franziska R.; Mayer, Peter and Carell, Thomas (17. June 2019): Influencing epigenetic information with a hydrolytically stable carbocyclic 5-aza-2’-deoxycytidine. In: Angewandte Chemie International Edition, Vol. 58, No. 37: pp. 12719-13160

Abstract

5-Aza-2’-deoxycytidine (AzadC) is an antimetabolite in clinical use, which reduces the level of the epigenetic modification 5-methyl-2’-deoxycytidine (mdC). AzadC is incorporated into the genome of proliferating cells, where it inhibits the DNA methyltransferases (DNMTs) in a suicide process leading to a reduction of mdC. The loss of mdC, which is a transcriptional silencer in promoters, leads to the reactivation of genes including tumor suppressor genes, which elicits a beneficial effect. The problem associated with AzadC is that the compound is hydrolytically unstable. It decomposes during treatment to a variety of poorly characterized hydrolysis products. After its incorporation into the genome, this hydrolytic instability generates abasic sites. It is consequently difficult to dissect if the activity of the compound is caused by DNMT inhibition or more generally by DNA lesion formation. We now discovered that a disarmed version of AzadC, in which the ribose oxygen was replaced by a CH2-group, is surprisingly stable under a variety of pH values while keeping the epigenetic activity against the DNMTs.

• Item Type: Journal article
• EU Funded Grant Agreement Number: 741912
• EU Projects: Horizon 2020 > ERC Grants > ERC Advanced Grant > ERC Grant 741912: EPiR - The Chemical Basis of RNA Epigenetics
• Form of publication: Postprint
• Keywords: epigenetics; 5-methyl-2’-deoxycytidine; DNA methylation; antimetabolite; decitabine
• Faculties: Chemistry and Pharmacy > Department of Chemistry
• Research Centers: Center for Integrated Protein Science Munich (CIPSM)
• Subjects: 500 Science > 540 Chemistry
• Language: English

References

[1] M. Daskalakis, T. T. Nguyen, C. Nguyen, P. Guldberg, G. Kohler, P. Wijermans, P. A. Jones, M. Lubbert, Blood 2002, 100, 2957-2964. [2] H. Kantarjian, J. P. Issa, C. S. Rosenfeld, J. M. Bennett, M. Albitar, J. DiPersio, V. Klimek, J. Slack, C. de Castro, F. Ravandi, R. Helmer, 3rd, L. Shen, S. D. Nimer, R. Leavitt, A. Raza, H. Saba, Cancer 2006, 106, 1794-1803. [3] C. Stresemann, F. Lyko, Int. J. Cancer 2008, 123, 8-13. [4] Y. Koh, Y. A. Kim, K. Kim, J.-A. Sim, S.-S. Yoon, S. M. Park, Y. H. Yun, Blood 2016, 128, 2381-2381. [5] M. Nieto, P. Demolis, E. Béhanzin, A. Moreau, I. Hudson, B. Flores, H. Stemplewski, T. Salmonson, C. Gisselbrecht, D. Bowen, F. Pignatti, Oncologist 2016, 21, 692-700. [6] S. S. Smith, B. E. Kaplan, L. C. Sowers, E. M. Newman, Proc. Natl. Acad. Sci. 1992, 89, 4744-4748. [7] G. G. Wilson, R. J. Roberts, S. Kumar, J. Posfai, M. Sha, S. Klimasauskas, X. Cheng, Nucleic Acids Res. 1994, 22, 1-10. [8] A. Bird, Genes Dev. 2002, 16, 6-21. [9] R. J. Klose, A. P. Bird, Trends Biochem. Sci. 2006, 31, 89-97. [10] R. Jüttermann, E. Li, R. Jaenisch, Proc. Natl. Acad. Sci. 1994, 91, 11797-11801. [11] S. Gabbara, A. S. Bhagwat, Biochem. J. 1995, 307, 87-92. [12] M. Ober, H. Müller, C. Pieck, J. Gierlich, T. Carell, J. Am. Chem. Soc. 2005, 127, 18143-18149. [13] H. Müller, T. Carell, Eur. J. Org. Chem. 2007, 2007, 1438-1445. [14] F. Büsch, J. C. Pieck, M. Ober, J. Gierlich, G. W. Hsu, L. S. Beese, T. Carell, Chem. Eur. J. 2008, 14, 2125-2132. [15] T. H. Gehrke, U. Lischke, K. L. Gasteiger, S. Schneider, S. Arnold, H. C. Müller, D. S. Stephenson, H. Zipse, T. Carell, Nat. Chem. Bio. 2013, 9, 455. [16] Y. Kato, S. Ozawa, C. Miyamoto, Y. Maehata, A. Suzuki, T. Maeda, Y. Baba, Cancer Cell Int. 2013, 13, 89. [17] S. Takahashi, S. Kobayashi, I. Hiratani, Cell. Mol. Life Sci. 2018, 75, 1191-1203. [18] F. R. Traube, S. Schiffers, K. Iwan, S. Kellner, F. Spada, M. Müller, T. Carell, Nat. Protoc. 2019, 14, 283-312. [19] S. Schiffers, T. M. Wildenhof, K. Iwan, M. Stadlmeier, M. Müller, T. Carell, Helv. Chim. Acta 2019, 102, e1800229. [20] M. Tahiliani, K. P. Koh, Y. Shen, W. A. Pastor, H. Bandukwala, Y. Brudno, S. Agarwal, L. M. Iyer, D. R. Liu, L. Aravind, A. Rao, Science 2009, 324, 930-935. [21] S. Ito, L. Shen, Q. Dai, S. C. Wu, L. B. Collins, J. A. Swenberg, C. He, Y. Zhang, Science 2011, 333, 1300-1303. [22] M. Münzel, D. Globisch, T. Carell, Angew. Chem. Int. Ed. Engl. 2011, 50, 6460-6468. [23] A. Unnikrishnan, A. N. Q. Vo, R. Pickford, M. J. Raftery, A. C. Nunez, A. Verma, L. B. Hesson, J. E. Pimanda, Leukemia 2018, 32, 900-910. [24] E. Li, T. H. Bestor, R. Jaenisch, Cell 1992, 69, 915-926. [25] T. Pfaffeneder, B. Hackner, M. Truss, M. Münzel, M. Müller, C. A. Deiml, C. Hagemeier, T. Carell, Angew. Chem. Int. Ed. Engl. 2011, 50, 7008-7012.