Shigetada Kozai

Synthesis and antiviral activity of 1,3-disubstituted uracils against HIV-1 and HCMV.

The development of new non-nucleoside reverse transcriptase inhibitors (NNRTIs) is an efficient strategy for finding new therapeutic agents against human immunodeficiency virus (HIV). A large number of 6-substituted uracil derivatives have been prepared in order to explore new NNRTIs. However, there are few approaches to anti-HIV agents from 1,3-disubstituted uracil derivatives. Therefore, we tried to prepare several 1,3-disubstituted uracils, which were easily obtainable from uracil by preparation under alkali and Mitsunobu conditions, and examined their antiviral activity against HIV-1 and human cytomegalovirus (HCMV). We found that 1-benzyl-3-(3,5-dimethylbenzyl)uracil and 1-cyanomethyl-3-(3,5-dimethylbenzyl)-4-thiouracil showed powerful inhibition against HCMV and HIV-1, respectively.

Method for the Synthesis of Uric Acid Derivatives

Abstract A general procedure to obtain tetra-substituted uric acid by stepwise N-alkylation is described. 2,6-Dichloropurine (1) was condensed with 1-propanol by Mitsunobu reaction to give 9-propyl congener (2). Treatment of 2 with ammonia gave adenine derivative (4a), which was converted to the 8-oxoadenine (5b) in 3 steps. Methylation of 5b proceeded site-specifically to give 6-amino-2-chloro-7,8-dihydro-7-methyl-9-propylpurin-8-one (6) as a sole product. Compound 6 was successively treated with NaNO2 and iodomethane to give 2-chloro-1,6,7,8-tetrahydro-1,7-dimethyl-9-propylpurin-6,8-dione (9) accompanied by the O 6-methyl product (8) in 75% and 6.9%, respectively. After nucleophilic substitution of 9 with NaOAc, the product (11) was reacted with iodomethane to give the uric acid (12) and the 2-methoxy product (13) in 46% and 15.5%, respectively. However, the reaction of 11 with the benzylating agents gave only O-benzyl products (14a,b).

Reaction of 7-(2-Mesyloxy-2-phenylethyl)theophylline with Amines: Synthesis of 1,2,3,6-Tetrahydro-6-imino-2-oxo-7 H -purine Derivatives

Abstract Theophylline was converted to 7-(2-phenyl-2-methanesulfonyloxy)ethyl congener and the product was treated with ammonia or primary amines in a mixture solution of water and organic solvents. Two products were proven to be the styrene analogue and 7-(2-amino-2-phenylethyl)theophylline. The structure of the third product was elucidated as the 1,2,3,6-tetrahydro-6-imino-2-oxo-7H-purine derivatives by spectroscopic analysis including HMBC correlation and X-ray crystallography.

Synthesis of N-Aryl Uracils and Hypoxanthines and Their Biological Properties

Abstract 1-Benzyluracils 2a,b were treated with iodobenzene in the presence of cuprous oxide in 2,4,6-trimethylpyridine at 180°C to give the N 1-phenyl derivatives 3a and 3b in 47% and 55%, respectively. Similar reaction of 2a with 2-bromopyridine at 120°C gave the 3-(2-pyridinyl)uracil 4a in 42% yield. However, unusual product 5 as well as 3-(2-pyridinyl) derivative 4b were obtained in the case of 2b. The structure of 5 was identified as 1-(2,6-difluorobenzyl)-3-[(2,4-dimethyl-2-pyridinyl)methyl]uracil from spectroscopic data. Reaction of the hypoxanthines 7a,b with 2-bromopyridine gave the 1-(2-pyridinyl)hypoxanthines 8a,b in low yields. But N-phenylation of 7a,b were unsuccessful.

Antiviral Activity of 3-(3,5-Dimethylbenzyl)Uracil Derivatives Against Hiv-1 and HCMV

Antiviral activity of 1,3-disubstituted uracil derivatives was evaluated against HIV-1 and HCMV. It appears that the nitrogen of the 1-cyanomethyl group is important for anti-HIV-1 activity, suggesting interaction with the amino acid residues of HIV-1 reverse transcriptase. 1-Arylmethyl derivatives also exhibited good anti-HIV-1 activity; and that of the 2- and 4-picolyl derivatives was particularly excellent.

Reaction of N3-benzyluracil and N-hydroxymethylphthalimide with the Mitsunobu reagent: synthesis of hydrazylmethyluracils

Abstract N3-Benzyluracil was treated with N-hydroxymethylphthalimide in the presence of the Mitsunobu reagent to give an unusual product bearing a hydrazylmethyl group ( 2 ) and/or the condensate ( 3 ).

A NEW METHOD FOR THE SYNTHESIS OF N 2-ALKYLGUANOSINES USING MITSUNOBU REACTION AS A KEY STEP

Peracetylated guanosine was reacted with POCl3 to give an 2-acetamido-6-chloro-9H-purine derivative, which was condensed with primary or secondary alcohols to give N 2-alkylated analogues. The products were treated with mercaptoethanol in the presence of sodium methoxide to afford N 2-alkylguanosines.

SYNTHESIS OF N 2-ALKYLGUANOSINE USING MITSUNOBU REACTION AS A KEY STEP

Peracetylated guanosine was reacted with POCl3 to give an 2-acetamido-6- chloro-9H-purine derivative, which was condensed with primary or secondary alcohols to give N 2-alkylated analogues. The products were treated with mercaptoethanol in the presence of sodium methoxide to afford N 2-alkylguanosines.

Introduction of a benzoyl group onto riboside in aqueous solution: One-step synthesis of 6-chloropurine 2′,3′-di-O-benzoylriboside

Abstract A benzoyl group was introduced onto the 3′-hydroxyl group of 6-chloropurine riboside by treatment with benzoylating agents in the presence of an organic or inorganic base in aqueous solution, in which further reaction gave 6-chloropurine 2′,3′-di- O -benzoylriboside.

Synthesis of 8-Substituted Analogues of 2′-Deoxy-2′-Fluoroadenosine

Abstract After 3′, 5′-di-O-protection of 8-bromoadenosine, the product was converted to the arabinoside, which was successively treated with diethylaminosulfur trifluoride (DAST) and acid to afford 8-bromo-2′-deoxy-2′-fluoroadenosine. However, the formation of an 8, 2′-anhydro compound was noted by treatment of the arabinoside with alkali. Finally, the 8-oxo analog was obtained from the 8-bromo congener.