Synthesis and antitumor and antiviral properties of 5-halo- and 5-(trifluoromethyl)-2'-deoxyuridine 3',5'-cyclic monophosphates and neutral triesters

Abstract

The title diesters (11-15; halo substituents F, C1, Br, I) were prepared by DCC-induced cyclization of the precursor 5'-monophosphate or direct halogenation of the 2'-deoxyuridine 3',5'-cyclic monophosphate. Antitumor activities of 11-15 in cell systems (L1210 and Raji/O) were compared to those of the corresponding nucleosides and 5'-monophosphates. Thus, the 5-F-and 5-CF3-2'-deoxyuridines proved to be highly active derivatives [ID50 values (wg/mL) for L1210,0.002 and 0.06, respectively], with the 5'-monophosphates showing comparable potencies. The corresponding 3',5'-cyclic monophosphate diesters were 20-30 times less potent but nonetheless highly cytostatic.All derivatives including 11-15 had greatly increased IDN values for the thymidine kinase deficient (TK-) L1210and Raji cells. The 3',5'-cyclic diesters (11-15) evidently are not efficient prodrug sources of the nucleoside 5'-monophosphates in TK-cells. They also proved to be 100-to 2000-fold less efficient inhibitors of L1210 thymidylate synthetase than were the 5'-monophosphates. The 5-substituted 2'-deoxyuridines and their 5'-monophosphates were potent inhibitors of herpes simplex virus (MICN mostly 0.07-10 pg/mL) and vaccinia virus (MICN 0.07-0.2 wg/mL), with antiviral activity decreasing in the order 5-I,5Br > 5-CF3 > 5-C1> 5-F. The 3',5'-cyclic monophosphates (11-15) were for the most part 10-to 40-fold less active than the 5'-monophosphates in the virus assay systems (e.g., MICm for the 5-Br and 5-1 derivatives ranged 1-20 wg/mL). By contrast 11-15 were considerably more potent inhibitors of vaccinia virus growth (MI& 0.4-2 pg/mL). As the neutral 3',5'-cyclic methyl phosphate triesters (16-18), the 5-1 and 5-Br compounds were less potent in antiviral and cytostatic agents than the 3',5'-cyclic diesters, while the 5-iodo benzyl triester was in several cases as active as the 3',5'-cyclic diester. The title compounds (11-15) appear to require extracellular hydrolysis to the nucleoside before functioning as antitumor or antiviral agents.

Synthesis and structure-activity relationships of 2-substituted-6-(dimethylamino)-9-(4-methylbenzyl)-9H-purines with antirhinovirus activity

“…The ether solution was evaporated, and the residue was recrystallized from ethanol to give 0.171 g (24%) of 6: mp 238. 1.9-Dihydro-2-methyl-9-(4-methylbenzyl)-6H-puriu-6-one (8) . Ethanol (50 mL) was added dropwise, through a water-cooled condenser, to stirred, pentane-washed sodium hydride (60.2% in mineral oil) (2.61 g, 65.5 mmol).…”

“…The solid was collected and recrystallized from cyclohexane to give 0.102 g (47%) of 11 (mp 133-133.5 °C), which was identical by TLC and mixture melting point with 11 prepared by an unambiguous route. 8 6-Chloro-2-methyl-9-(4-methylbenzyl)-9fl'-purine (12). A solution prepared from dimethylformamide (0.365 g) and thionyl chloride (0.40 mL) was added to a refluxing solution of 8 (0.500 g, 1.97 mmol), dimethylformamide (7 mL), and chloroform (10 mL).…”

“…That 4 was the correct isomer was confirmed by condensation of 4 with ethyl formate6 to give the 6-oxopurine 7, which had an ultraviolet spectrum similar to that of inosine.7 Chlorination of 7 gave 6-chloropurine 11, which was identical with the sample prepared by an unequivocal route. 8 The 2-methyl- (8) and 2-ethylpurines (9) were isolated when 4 was heated with ethyl acetate or ethyl propionate, respectively. However, when 4 was reacted with trifluoroacetic anhydride in trifluoracetic acid, the intermediate amide 5 was isolated.…”

Nucleotide Prodrugs for HCV Therapy

“…3′,5′-Cyclic phosphate nucleotide prodrugs The use of a 3′,5′-cyclic phosphate prodrug construct for delivering a nucleoside 5′-monophosphate into cells is a relatively uncommon prodrug motif [95–97]. Its application has only recently been selectively applied in the development of nucleotide inhibitors for HCV polymerase.…”