Synthesis and antiherpetic activity of (S)-, (R)-, and (+/-)-9-[(2,3-dihydroxy-1-propoxy)methyl]guanine, linear isomers of 2'-nor-2'-deoxyguanosine.
Racemic 9-[(2,3-dihydroxy-1-propoxy)methyl]guanine [(+/-)-iNDG], a new analogue of acyclovir (ACV) and a structural analogue of 2'-nor-2'-deoxyguanosine (2'NDG), was synthesized and found to inhibit the replication of herpes simplex virus types 1 (HSV-1) and 2 (HSV-2). Subsequently, its optical isomers, (R)- and (S)-iNDG, were prepared from chiral intermediates. The chloromethyl ethers of 1,2-di-O-benzyl-D- and -L-glycerol were made and reacted with tris(trimethylsilyl)guanine to give the 9-alkylated guanines, which were deprotected by catalytic hydrogenolysis. Against HSV-1 and HSV-2 in cell culture, (S)-iNDG was approximately 10- to 25-fold more active than the R enantiomer and had an ED50 comparable to those for ACV and 2'NDG. The inferior activity of (R)-iNDG paralleled the poor inhibition of viral DNA polymerase by its phosphorylation products. In mice infected intraperitoneally or orofacially with HSV-1 or intravaginally with HSV-2, (S)-9-[(2,3-dihydroxy-1-propoxy)methyl]guanine [(S)-iNDG] was less efficacious than 2'NDG but comparable to or more active than ACV.
Ashton
W T
WT
Canning
L F
LF
Reynolds
G F
GF
Tolman
R L
RL
Karkas
J D
JD
Liou
R
R
Davies
M E
ME
DeWitt
C M
CM
Perry
H C
HC
Field
A K
AK
D000212:Acyclovir / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D015774:Ganciclovir / Q000031:analogs & derivatives*; D006561:Herpes Simplex / Q000188:drug therapy*; D007536:Isomerism; D051379:Mice; D019384:Nucleic Acid Synthesis Inhibitors; D011817:Rabbits; D018139:Simplexvirus / Q000502:physiology*; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors; D014779:Virus Replication / Q000187:drug effects*
D019384:Nucleic Acid Synthesis Inhibitors; C045895:9-((2,3-dihydroxy-1-propoxy)methyl)guanine; D013937:Thymidine Kinase; D015774:Ganciclovir; D000212:Acyclovir