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Chemical Compound Review:

SureCN313652 2-amino-9-[(2R,4R,5R)-3,3- difluoro-4...

Synonyms: AC1L3UEE, KB-228160, LY-223592, AKOS016008753, AK110611, ...

Smid, K. et al., Zhu, C. et al., Solaroli, N. et al., Gandhi, V. et al.

Solaroli, Johansson, Balzarini, Karlsson,

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High impact information on LY-223592

The cytotoxic anti-cancer purine nucleoside analogs 2-chloro-2'-deoxyadenosine (CdA), 9-beta-D-arabinofuranosylguanine (araG), and 2',2'-difluorodeoxyguanosine (dFdG) are phosphorylated by human mitochondrial deoxyguanosine kinase (dGK) in vitro [1].
These engineered enzymes showed a relative increase in phosphorylation of purine nucleoside analogs such as ganciclovir, 9-beta-D-arabinofuranosylguanine and 2',2'-difluorodeoxyguanosine compared to the wild-type enzyme [2].
Based on the structure-activity relationship studies of catabolism and anabolism, 2',2'-difluorodeoxyguanosine (dFdG) emerged as a lead candidate among the difluoropurine analogs [3].
In cell culture, moderate cross-resistance (about 2-fold) was observed to 1-ss-D-arabinofuranosylcytosine (ara-C), 2-chloro-2'deoxyadenosine (CdA), LY231514 (ALIMTA), and cisplatin (CDDP), and pronounced cross-resistance (>23-fold) to 2',2'-difluorodeoxyuridine (dFdU) and 2',2'-difluorodeoxyguanosine (dFdG) [4].

References

Enhanced cytotoxicity of nucleoside analogs by overexpression of mitochondrial deoxyguanosine kinase in cancer cell lines. Zhu, C., Johansson, M., Permert, J., Karlsson, A. J. Biol. Chem. (1998) [Pubmed]
Enhanced toxicity of purine nucleoside analogs in cells expressing Drosophila melanogaster nucleoside kinase mutants. Solaroli, N., Johansson, M., Balzarini, J., Karlsson, A. Gene Ther. (2007) [Pubmed]
Difluorodeoxyguanosine: cytotoxicity, metabolism, and actions on DNA synthesis in human leukemia cells. Gandhi, V., Mineishi, S., Huang, P., Yang, Y., Chubb, S., Chapman, A.J., Nowak, B.J., Hertel, L.W., Plunkett, W. Semin. Oncol. (1995) [Pubmed]
Micro-array analysis of resistance for gemcitabine results in increased expression of ribonucleotide reductase subunits. Smid, K., Bergman, A.M., Eijk, P.P., Veerman, G., Ruiz van Haperen, V.W., van den Ijssel, P., Ylstra, B., Peters, G.J. Nucleosides Nucleotides Nucleic Acids (2006) [Pubmed]

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