Structure and conformation of the cyclic phosphate of Ganciclovir, a broad-spectrum antiviral agent.
The title compound, the cyclic phosphate of the antiviral acyclonucleoside Ganciclovir (2'-NDG, DHPG), is itself a potent broad-spectrum antiviral agent, but with a different mechanism of action. The cyclic phosphate, 9-[[[(2-hydroxy-1,3,2-dioxophosphorinan-5-yl)oxy]methyl]-P- oxide]guanine (2'-nor-cGMP,DHPG-cMP), crystallizes in the monoclinic space group P2(1)/n with unit cell dimensions a = 6.612(1) A, b = 11.562(4) A, c = 19.231(5) A and beta = 91.786(2) degrees at -165 degrees C. The N7 of the guanine base is protonated, so that the molecule is in a zwitterionic form, with two water molecules in the asymmetric unit. The principal conformational features of DHPG-cMP in the crystal are as follows: the acyclic chain is partially folded; the six-membered cyclic phosphate ring is in a chair form with C3', O3', C5' and O5' in a plane; P and C4' are displaced in diametrically opposite directions from this plane; the O4' is in the axial orientation with respect to this ring; and the aglycon is in the high syn conformation about the glycosidic bond. The conformation of the cyclic phosphate ring in aqueous medium, determined by means of 1H-NMR spectroscopy, is similar to that in the crystalline form. The conformational features of DHPG-cMP were compared with those of the parent DHPG and other related compounds and, in particular, with those of the second messenger 3':5'-cGMP, of which it is a close structural analogue. Previously reported substrate/inhibitor properties of these compounds in several enzyme systems are examined in relation to the possible mechanism of antiviral activity of DHPG-cMP as a second messenger analogue of cGMP.
Birnbaum
K B
KB
National Research Council of Canada, Ottawa.
Stolarski
R
R
Shugar
D
D
D000998:Antiviral Agents / Q000737:chemistry*; D006152:Cyclic GMP / Q000737:chemistry; D015774:Ganciclovir / Q000737:chemistry*; D006860:Hydrogen Bonding; D008968:Molecular Conformation; D015394:Molecular Structure; D010710:Phosphates / Q000737:chemistry*; D012996:Solutions
D000998:Antiviral Agents; D010710:Phosphates; D012996:Solutions; D006152:Cyclic GMP; D015774:Ganciclovir