Synthesis and antiherpetic activity of (S)-, (R)-, and (.+-.)-9-[(2,3-dihydroxy-1-propoxy)methyl]guanine, linear isomers of 2'-nor-2'-deoxyguanosine

Abstract

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.

Synthesis and Antiviral Activity of Novel Acyclic Nucleosides: Discovery of a Cyclopropyl Nucleoside with Potent Inhibitory Activity against Herpesviruses

“…Most of the antiherpetic acyclic nucleosides are phosphorylated by viral TK, and this step is critical for activity and selectivity. To study the phosphorylation of 3 and other compounds, they were incubated with an extract of HSV-1-infected BU25 cells lacking cellular TK and amounts of monophosphates were measured by HPLC analysis . Conversion of each nucleoside to the corresponding monophosphate is summarized in Table .…”

An Alternative Approach to Isoganciclovir: A Prominent Impurity in the Antiviral Drug Ganciclovir

“…were the first to report the anti-herpes properties of (±)-9-[(2,3-dihydroxypropoxy)methyl]guanine 1 ( Fig. 1 ) and its R & S isomers towards HSV type I and type II [ 1 ].…”

“…Since 1 is a prominent impurity of ganciclovir, we were interested in exploring a simple and efficient synthetic route for its preparation. Furthermore, the procedures described earlier have certain disadvantages such as (a) a lengthy work-up procedure involving preparative HPLC for the isolation of the acyclic side chain [ 1 ], (b) usage of the expensive hydrogenation catalysts for deprotection [ 13 – 15 ], and (c) the reaction with highly corrosive and moisture-sensitive chemicals such as trimethylsilyl chloride [ 1 , 12 ]. In our present work, we describe a simple approach towards the preparation of 1 without using any harmful or expensive chemicals.…”

The synthesis of mycobacterial dimycoloyl diarabinoglycerol based on defined synthetic mycolic acids

“…The acceptor fragment 5 was prepared as in Scheme 2. Compound 6 (Reddy et al, 2012;D'Souza et al, 2000) was subjected to a glycosidation reaction with 7 (Ashton et al, 1985) using Niodosuccinimide and silver triflate in dichloromethane at -35 °C to give the α-isomer 8 in 91% yield. The proton NMR of the product showed a downfield signal as a broad doublet at δ 4.98 (J 1.0 Hz), while the 13 C NMR showed a peak at δ 105.6 due to the carbon at position 1, both indicating the α-anomer (Mizutani et al, 1989).…”

“…Molecular sieves 4 Å (5.6 g) were added to a stirred solution of α-D-arabinofuranoside (6) (Reddy et al, 2012;D'Souza et al, 2000) (15.4 g, 0.0255 mol) and 2',3'-di-O-benzyl-L-glycerol (7) (Ashton et al, 1985) (6.9 g, 0.025 mol) in dry CH2Cl2 (25 mL) at rt under nitrogen. The mixture was stirred for 30 min then cooled to -35 °C and N-iodosuccinimide (9.38 g, 0.0383 mol) was added, followed by silver trifluoromethanesulfonate (1.17 g, 0.00460 mol).…”