Synthesis of some new S-alkylated derivatives of 5-mercapto-2'-deoxyuridine as potential antiviral agents

Abstract

A series of S-alkylated derivatives of 5-mercapto-2'-deoxyuridine have been prepared by alkylation of the preformed nucleoside. Two of these compounds, the S-propargyl and S-allyl derivatives, have shown significant antiviral activity against Herpes simplex type 1 in HeLa TK- cells but appear to be less effective in this assay system than some previously reported 5-substituted 2'-deoxyuridines.

Synthesis and Reaction of Pyrimidine Nucleosides

“…(196) 5-Mercapto-2'-deoxyuridine, prepared by the glycosylation method, was S-alkylated by various alkyl halides containing unsaturations in the alkyl chains. (197) As described in the beginning of this section, the action of bromine with uridine gives the 5-bromo-6-hydroxy-5,6-dihydro intermediate (53). Treatment of (53) with lead oxide, (198) or better with aqueous pyridine, (199) afforded 5-hydroxyuridine (67), In the latter conditions, the replacement of the 5-bromo group of (53) by a hydroxyl group proceeded before dehydration occurs to give the 5,6-dihydroxy intermediate (66), This type of intermediate can be isolated in uridine and 2'-deoxyuridine, although its conversion to the product (67) was not attempted.…”

“…The first example of this type of nucleoside, 2',3'-O-isopropylidene-0 2 ,5'cyclouridine (197), was accidentally formed in an attempt to prepare the 5'-O-acetate derivative from 5' -deoxy-5' -iodo-2',3' -O-isopropylideneuridine by treatment with silver acetate. (477) Compound (197) can be prepared by the treatment of S'-O-tosyl-2',3'-O-isopropylideneuridine with potassium t-butoxide, (472) 4-morpholino-.N,.N'-dicyclohexylcarboxamidine, (478) or 1,5-diazabicyclo-[5.4.0Jundec-5-ene (DBU).…”

“…(477) Compound (197) can be prepared by the treatment of S'-O-tosyl-2',3'-O-isopropylideneuridine with potassium t-butoxide, (472) 4-morpholino-.N,.N'-dicyclohexylcarboxamidine, (478) or 1,5-diazabicyclo-[5.4.0Jundec-5-ene (DBU). (~79) 02,5'-Cyclothymidine was also prepared from the 5'-O-mesylate with I-butoxide or DBU as described.…”

“…(526) 5'-0-Trityl-02,3'-cyclothymidine was treated with potassium phthalimide or potassium thiobenzoate, in the presence of an appropriate acid in dimethylformamide at reflux, followed by deblocking to give 3'-amino-3'-deoxythymidine (230) and the disulfide of 3'-deoxy-3'-mercaptothymidine, respectively. (308) The attack of sodium azide with the 5'-0-trityl derivative of (195) Cleavage of the 02,5'-cyclo bond of (197) with a large excess of liquid hydrogen sulfide in pyridine gave 2',3'-0-isopropylidene-2-thiouridine (236) in high yieldY39) while treatment of (197) with hydrogen sulfide and triethylamine in dimethylformamide gave the 5'-mercapto-5'-deoxyuridine [as a cyclo form, (237)] along with (236). (260.498) Cleavage of (197) with methanolic ammonia gave 2-0-methyluridine derivative first, which was subsequently converted to the isocytidine derivative (238).1477) Treatment of (197) with acetyl chloride lHO ) or benzoyl bromide IS4 !)…”

“…Methanolysis of (197) in the presence of p-toluenesulfonic acid afforded 5'-0-methyluridine (240) in high yield. (542) In this case the protonation of (197) at the N-3 facilitated the substitution at the C-5' position, and by the same principle (197) gave uridine 5'-diphenyl phosphate by treatment with boron trifluoride and diphenyl hydrogen phosphate. An attempted cleavage of (197) with benzylmagnesium bromide resulted in the formation of the 5'-bromo derivative with no C-alkylation being observed.…”