PMEG (antiviral)

PMEG
Names
	IUPAC name 2-(2-Amino-6-oxo-3H-purin-9-yl)ethoxymethylphosphonic acid
	Other names 9-((2-Phosphonylmethoxy)ethyl)guanine
Identifiers
CAS Number	114088-58-3 ;
3D model (JSmol)	Interactive image;
ChemSpider	58514;
ECHA InfoCard	100.208.448
PubChem CID	64989;
UNII	N9YOI96LPP ;
CompTox Dashboard (EPA)	DTXSID90150649 ;
	InChI InChI=1S/C8H12N5O5P/c9-8-11-6-5(7(14)12-8)10-3-13(6)1-2-18-4-19(15,16)17/h3H,1-2,4H2,(H2,15,16,17)(H3,9,11,12,14) Key: NZVORGQIEFTOQZ-UHFFFAOYSA-N;
	SMILES c1nc2c(n1CCOCP(=O)(O)O)[nH]c(nc2=O)N;
Properties
Chemical formula	C8H12N5O5P
Molar mass	289.188 g·mol−1
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
	Infobox references

PMEG (9-[2-(phosphonomethoxy)ethyl] guanine) is an acyclic nucleoside phosphonate. Acyclic nucleoside phosphonates can have significant antiviral, cytostatic and antiproliferative activities.[1] PMEG can inhibit cell proliferation and cause genotoxicity.[2] PMEG is active against leukemia and melanoma in animal tumor models,[3] and also has antiviral activities against herpes viruses in murine models.[4][5]

Successful application of PMEG and PMEG-derivatives analogs may depend on the development analogs with reduced toxicity and enhanced pharmacokinetic properties to tissues. There are no clinical trials using PMEG listed at clinicaltrials.gov. This suggests that the pharmacokinetic properties of PMEG were too toxic to process forward with. There are several different PMEG-derivatives analogs currently being investigated. GS-9191 and GS-9219 prodrugs are just two of the next generation PMEG compounds being evaluated for antiviral and anticancer activities.[6] Both GS-9191 and GS-9219 have made it into clinical trials, but require additional study.

Biology

Acyclic nucleoside phosphonates prodrugs require further phosphorylation in the cell in order to become the active metabolite. Once PMEG is phosphorylated into its triphosphate form, host or viral DNA polymerases can use it a substrate during DNA synthesis. Since it is an acyclic nucleoside, lacking a 3'-OH moiety, to further extension of the DNA strand occurs. Thus this agent uses the classical mechanism of DNA chain terminator. PMEG has often been cited for its antiviral activities.

References

De Clercq E, Holý A (Nov 2005). "Acyclic nucleoside phosphonates: a key class of antiviral drugs". Nat Rev Drug Discov. 4 (11): 928–40. doi:10.1038/nrd1877. PMID 16264436.
Kramata P, Votruba I, Otová B, Holý A (Jun 1996). "Different inhibitory potencies of acyclic phosphonomethoxyalkyl nucleotide analogs toward DNA polymerases alpha, delta and epsilon". Mol Pharmacol. 49 (6): 1005–11. PMID 8649338.
Rose WC, Crosswell AR, Bronson JJ, Martin JC (Mar 1990). "In vivo antitumor activity of 9-[(2-phosphonylmethoxy)ethyl]-guanine and related phosphonate nucleotide analogues". J Natl Cancer Inst. 82 (6): 510–2. doi:10.1093/jnci/82.6.510. PMID 2313724.
Kim, H. T.; Kim, D. K.; Kim, Y. W.; Kim, K. H.; Sugiyama, Y.; Kikuchi, M. (1995-11-01). "Antiviral activity of 9-[[(ethoxyhydroxyphosphinyl)-methoxy]methoxy] guanine against cytomegalovirus and herpes simplex virus". Antiviral Research. 28 (3): 243–251. doi:10.1016/0166-3542(95)00051-m. ISSN 0166-3542. PMID 8629816.
De Clercq, Erik (2013). "Dancing with chemical formulae of antivirals: A personal account". Biochemical Pharmacology. 86 (6): 711–25. doi:10.1016/j.bcp.2013.07.012. PMID 23876344.
Shelton J, Lu X, Hollenbaugh JA, Cho JH, Amblard F, Schinazi RF (Dec 2016). "Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs". Chem Rev. 116 (23): 14379–14455. doi:10.1021/acs.chemrev.6b00209. PMC 7717319. PMID 27960273.

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[De_Clercq_2005-1] De Clercq E, Holý A (Nov 2005). "Acyclic nucleoside phosphonates: a key class of antiviral drugs". Nat Rev Drug Discov. 4 (11): 928–40. doi:10.1038/nrd1877. PMID 16264436.

[Kramata_1996-2] Kramata P, Votruba I, Otová B, Holý A (Jun 1996). "Different inhibitory potencies of acyclic phosphonomethoxyalkyl nucleotide analogs toward DNA polymerases alpha, delta and epsilon". Mol Pharmacol. 49 (6): 1005–11. PMID 8649338.

[Rose_1990-3] Rose WC, Crosswell AR, Bronson JJ, Martin JC (Mar 1990). "In vivo antitumor activity of 9-[(2-phosphonylmethoxy)ethyl]-guanine and related phosphonate nucleotide analogues". J Natl Cancer Inst. 82 (6): 510–2. doi:10.1093/jnci/82.6.510. PMID 2313724.

[4] Kim, H. T.; Kim, D. K.; Kim, Y. W.; Kim, K. H.; Sugiyama, Y.; Kikuchi, M. (1995-11-01). "Antiviral activity of 9-[[(ethoxyhydroxyphosphinyl)-methoxy]methoxy] guanine against cytomegalovirus and herpes simplex virus". Antiviral Research. 28 (3): 243–251. doi:10.1016/0166-3542(95)00051-m. ISSN 0166-3542. PMID 8629816.

[5] De Clercq, Erik (2013). "Dancing with chemical formulae of antivirals: A personal account". Biochemical Pharmacology. 86 (6): 711–25. doi:10.1016/j.bcp.2013.07.012. PMID 23876344.

[Shelton_2016-6] Shelton J, Lu X, Hollenbaugh JA, Cho JH, Amblard F, Schinazi RF (Dec 2016). "Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs". Chem Rev. 116 (23): 14379–14455. doi:10.1021/acs.chemrev.6b00209. PMC 7717319. PMID 27960273.