Oxime and dithiolane derivatives of 5-formyl-2'-deoxyuridine and their 5'-phosphates: antivirial effects and thymidylate synthetase inhibition

Abstract

5-Formyl-2'-deoxyuridine (2a), an effective inhibitor of herpes simplex virus type 1 or 2 (HSV-1, HSV-2) and vaccinia virus, was converted to the oxime (3a) and dithiolane (4a) derivatives. The oxime (3a) was equally as potent as the formyl compound against HSV-1, but one-fifth as active against HSV-2, 100 times less effective against vaccinia, and 25 times less toxic for the host cells. In addition, compound 3a was about 10 times less active than 2a in inhibiting thymidylate synthetase in vivo (as reflected by a differential inhibition of dThd and dUrd incorporation into host cell DNA). The dithiolane (4a) did not exert an appreciable effect on either virus multiplication or dThd or dUrd incorporation, nor was it cytotoxic. All these compounds as their 5'-phosphate derivatives were potent in vitro inhibitors of thymidylate synthetase (Lactobacillus casei). The inhibition was competitive with substrate with Ki/Km ratios of 0.05 for the formyl 2b, 0.5 for the oxime 3b, and 0.2 for the dithiolane 4b. Thus, 3b was 10 times less active than 2b as an in vitro inhibitor of thymidylate synthetase, which appears to corroborate the in vivo findings.

5-Substituted-2′-deoxyuridines as anti-HSV-1 Agents: Synthesis and Structure Activity Relationship

“…-p----Substituent -CH=CH 2 (De Clercq et al, 1979a) -CH=CH-CI -CH=CH-Br (De Clercq et al, 1979a) -CH=CH-I (De Clercq et al, 1979a) -CH=CH-CF 3 (Bergstrom et al, 1984) -CH=CH-F (Reefschliiger et al, 1984 -CH=CH-CH 3 (Bergstrom et al, 1984) -CH=CF2 (Bobek et al, 1987a) -CF=CF 2 (Herdewijn et al, 1992) -CF=CFCI (Coe et al, 1982) -CH=CH-COOCH 3 (Griengl et el., 1985) -CCI=CH2 (De Clercq et al, 1979a) -CH=CH-CH2-CH3 (Goodchild et al, 1983) -CH 2-CH=CH-CH3 (Goodchild et al, 1983) HSV-1 activity' (De Clercq at al., 1979a) -CH='"C-CH3 -C='"C-CH2-CH3 -C='"C-CH2-O-CH3 -C='"C-C(CH3la -C='"C-CH2-CH 2-CH 3 -C='"C-CH=CH2 -CH=O (Park et al, 1980) -CH=N-OH (Park et al, 1980) -CH=CBr2 (Goodchild et al, 1983) -CH=CH-S-CH3 (Goodchild et al, 1983) -C(CH 3)=CH-Br (Goodchild et aI., 1983) -CH =C(Br)-CH3 (Goodchild et al, 1983) HSV-1 activity'…”

A pyrimidine–pyrazolone nucleoside chimera with potent in vitro anti-orthopoxvirus activity

“…23 Entry to such chimeric structures centered on the 5-position of pyrimidine nucleosides can be gained most readily through the intermediacy of the previously described 5-formyl-2 0 -deoxyuridine. [24][25][26][27] The aldehyde precursor, 3 0 ,5 0 -di-O-acetyl-5-formyl-2 0 -deoxyuridine (3, Scheme 1), was prepared through the oxidation of 3 0 ,5 0 -di-O-acetylthymidine (2, Scheme 1) with potassium peroxysulfate (K 2 S 2 O 8 ) in the presence of CuSO 4 AE5H 2 O and 2,6-lutidine in aqueous acetonitrile. The corresponding deacetylated counterpart, 5-formyl-2 0 -deoxyuridine (8, Scheme 2), was prepared by first protecting the aldehyde group of 3 as the dimethyl acetal (7), followed by sequential treatment with NaOMe/MeOH and AcOH/H 2 O to give 8.…”

Thymidylate synthetase‐positive and ‐negative murine mammary FM3A carcinoma cells as a useful system for detecting thymidylate synthetase inhibitors

“…The sources of the compounds were as follows: 5-fluoro-dUrd (Aldrich, Milwaukee, WI); 5-trifluoromethyl-dUrd (P.-L. Biochemicals, Milwaukee, WI); 5-nitro-dUrd (provided by M.J. Robins, Edmonton, Canada); 5-ethynyl-dUrd [25,26], 5-formyl-dUrd [27], 5-hydroxymethyl-dUrd (Calbiochem-Behring, Lucerne), 5-vinyl-dUrd [26], Q-5-(2-iodovinyl)-dUrd [26], (Q-5-(2-bromovinyl)-dUrd [26,28], 5-ethyl-dUrd [29,30], 5-azido2methyl-dUrd [3 1,321, 5-cyano-dUrd [33], Q-5-(Zchlorovinyl)-dUrd [26], 5-methylthiomethyldUrd [32,34], 5-(1,3-dithiolan-2-yl)-dUrd [27], 5-propyl-dUrd [35], 5-methylsulfinylmethyl-dUrd [34], 5-hydroxy-dUrd (Sefochem, Emek Hayarden, Israel), 5-propynyloxy-dUrd [36], dUrd (Sigma, MO), dThd (Sigma).…”