Synthesis and Antitumor Activity of 9-(Tetrahydro-2-furyl)purine Analogs of Biologically Important Deoxynucleosides¹

Abstract

471250 ml. of saturated ethanolic ammonia was heated in an autoclave a t 135' for 12 hr. The resulting solution was evaporated to dryness and the residue recrystallized from butanol. A final recrystallization from aqueous ethanol afforded an analytically pure product.The structural assignment (see Discussion part) in this group of compounds was further substantiated by paper chromatographic measurements (one spot in each case). Rr values for 2,4-diamino-6-( p-bromoanilino)-5-pyrimidinecarbonitrile: 0.71 (isopropyl alcohol-water, 7 : 3), and 0.80 (butanol saturated with acetic acid); for 2,4-diamino-6-(p-iodoanilino)-5-pyrimidinecarbonitrile: 0.73 and 0.81, respectively.2,4-Diamino-6-( substituted-anilino) -5-pyrimidinecarboxamide (Table I). General Procedure.-With good stirring, 2,4-diamino-6-(substituted-anilino)-5-pyrimidinecarbonitrile (0.05 mole) was added slowly to 50 ml. of concentrated sulfuric acid a t 30-35". The solution was stirred a t this temperature for 12 hr. and then added, with stirring, to 500 g. of flaked ice. The precipitated product was separated by filtration and washed well with icewater. The crude product was dissolved in hot, dilute sulfuric acid, treated with charcoal, and filtered. The filtrate was adjusted to pH 8 with aqueous ammonia and the product filtered while hot, washed with water, and dried at 100'. Repeated reprecipitation afforded product of analytical purity. 4,6-Dichloro-2-methylaminopyrimidine.-In a flask equipped with two modified Friedrichs condensers designed to retain low boiling liquids was added 23 g. (0.23 mole) of triethylamine and 7 g. (0.23 mole) of methylamine diluted with 200 ml. of ethyl acetate. To this solution was added 30 g. (0.154 mole) of 4,6dichloro-2-( methyl~ulfony1)pyrimidine~~ dissolved in 200 ml. of ethyl acetate.The temperature was kept below 35" during the entire reaction. After 2 hr. of stirring the reaction mixture was evaporated and the pale yellow residue recrystallized from ethanol to give 13 g. (77%) of white crystals, m.p. 162-163". The product was found to be identical with that reported by Winkelmann'4* and B 0 0 n . l~~ 4-Amino-6-chloro-2-methylaminopyrimidine.-A mixture of 4,6-dichloro-2-methylaminopyrimidine ( 10.8 g.) and ethanolic ammonia wm heated a t 80' for 8 hr. in a sealed vessel. Evaporation of the reaction mixture and purification of the product from methanol afforded 7 g. (657,) of white crystals, m.p. 193-194". Anal. Calcd. for CsH7ClN4.H20: N, 31.8. Found: N, 31.9. General Preparations of 4-(Substituted-anilino)-5-nitrosopyrimidines (V).A.-A mixture of the appropriate 4chloropyrimidine, an equivalent amount (plus a 10% excess) of the substituted aniline, and several milliliters of concentrated hydrochloric acid was heated in an oil bath. A clear, dark colored melt was observed around 150" followed by an exothermic reaction that caused the temperature to rise to ca. 200". The reaction mixture was held at this temperature for several minutes. It was then cooled, dissolved in boiling ethanol, treated with charcoal, and filt...

Purification and Characterization of West Nile Virus Nucleoside Triphosphatase (NTPase)/Helicase: Evidence for Dissociation of the NTPase and Helicase Activities of the Enzyme

“…6B) was prepared from 6-chloro-2-aminopurine (Fig. 6A) by the method of Bowles et al (9). N-alkylation of O 6 -benzylguanine gave a mixture of N 7 -and N…”

Depletion of mammalian O6-alkylguanine-DNA alkyltransferase activity by O6-benzylguanine provides a means to evaluate the role of this protein in protection against carcinogenic and therapeutic alkylating agents.

“…06_ Benzylguanine (37,38), 06-(p-chlorobenzyl)guanine, and 06-(p-methylbenzyl)guanine were prepared by treating 2-amino-6-chloropurine (0.018 mol) with 2.2 equivalents of sodium benzyloxide, sodium 4-chlorobenzyloxide, or sodium 4-methylbenzyloxide in 30 g of benzyl, 4-chlorobenzyl, or 4-methylbenzyl alcohol, respectively, at 130°C for 6 hr. The resulting suspensions were cooled to room temperature, treated with 2.5 ml of glacial acetic acid with stirring, and then poured into 1 liter of diethyl ether with vigorous stirring.…”

Synthesis of Some Biologically Active Halogenopurines

“…[4][5][6] Moreover, some halogenopurines displayed a wide range of biological activities themselves such as fungicide, antitumour, immunosuppressant and anticonvulsant, etc. 7,8 2-Amino-6-halogenopurines are usually prepared by chlorine/halogen exchange reactions between potassium halide (KX) and 2-amino-6-chloropurine, and a variety of catalysts have been developed for such halogen exchanges, such as ammonium salts, 9-11 metal carbonyls, 12-14 chromium oxide on alumina, [15][16][17] etc. [18][19][20][21] Unfortunately, many of these procedures are associated with one or more disadvantages such as high cost, low selectivity, use of stoichiometric and even excess amounts of catalysts, complicate the separation of the products, and drastic reaction conditions.…”