Synthesis of 2-Bromomethyl-3-Hydroxy-2-Hydroxymethyl-Propyl Pyrimidine and Theophylline Nucleosides Under Microwave Irradiation. Evaluation of Their Activity Against Hepatitis B Virus

Abstract

Alkylation of 2-methylthiopyrimidin-4(1H)-one (1a) and its 5(6)-alkyl derivatives 1b-d as well as theophylline (7) with 2,2-bis(bromomethyl)-1,3-diacetoxypropane (2) under microwave irradiation gave the corresponding acyclonucleosides 1-[(3-acetoxy-2-acetoxymethyl-2-bromomethyl)prop-1-yl]-2-methyl-thio pyrmidin-4(1H)-ones 3a-d and 7-[(3-acetoxy-2-acetoxymethyl-2-bromomethyl)prop-1-yl]theophylline (8), which upon further irradiation gave the double-headed acyclonucleosides 1,1 '-[(2,2-diacetoxymethyl)-1,3-propylidene]-bis[(2-(methylthio)-pyrimidin-4(1H)-ones] 4a-c, and 7,7 '-[(2,2-diacetoxymethyl)-1,3-propylidene]-bis(theophylline) (9). The deacetylated derivatives were obtained by the action of sodium methoxide. The activity of deacetylated nucleosides against Hepatitis B virus was evaluated. Compound 5b showed moderate inhibition activity against HBV with mild cytotoxicity.

Double-headed nucleosides: Synthesis and applications

“…Four pyrimidine nucleobases 254a–d were treated with methyl iodide in the presence of sodium hydroxide to get methylthio derivatives 255a–d , which were treated with 2,2-bis(bromomethyl)-1,3-diacetoxypropane ( 256 ) in the presence of NaH in DMF to afford the mono-headed acyclic nucleosides 257a–d [ 112 ]. The second nucleobase was introduced in compounds 257a – d by repeating the reaction with the desired nucleobase under otherwise identical conditions (NaH/DMF) giving the acyclic double-headed pyrimidine nucleosides 258a–d .…”

“…The second nucleobase was introduced in compounds 257a – d by repeating the reaction with the desired nucleobase under otherwise identical conditions (NaH/DMF) giving the acyclic double-headed pyrimidine nucleosides 258a–d . Finally, the treatment of compounds 258a – d with NaOMe in methanol produced the unprotected nucleosides 259a–d ( Scheme 67 ) [ 112 ].…”

“…The double-headed nucleoside 261 was obtained by a two-step reaction sequence starting from compound 256 , which was first reacted with theophylline in DMF, to give the acyclic double-headed purine nucleoside 260 followed by treatment with NaOMe in methanol to get the unprotected product 261 . In the sequence, all reactions were carried out under microwave irradiation conditions ( Scheme 68 ) [ 112 ].…”

Repositioning of acefylline as anti-cancer drug: Synthesis, anticancer and computational studies of azomethines derived from acefylline tethered 4-amino-3-mercapto-1,2,4-triazole

“…In addition, theophylline has been diagnosed as an adenosine antagonist to prevent contrast-induced nephropathy (CIN), which is associated with kidney failure and has been shown to be effective in preventing CIN [ 14 ]. Fortunately, some theophylline derivatives, such as theophylline nucleoside derivatives, are also effective against the hepatitis B virus [ 15 ]. Some nitrates of theophylline derivatives were found to have a strong analgesic effect in hypertensive mice [ 16 ].…”

Synthesis, anticancer, anti-HIV-1, and antimicrobial activity of some tricyclic triazino and triazolo[4,3-e]purine derivatives

“…Purines and condensed purines have received much attention over the years for their interesting pharmacological properties as antineoplastic (Peifer et al, 2009;Ito et al, 2007;Lech-Maranda et al, 2006), antileukemic (Ramasamy et al, 1990;Avery et al, 1990;Woo et al, 1992;Steurer et al, 2006;Jeha and Kantarjian, 2007), anti-HIV-1 (McLaren et al, 1991;Johnson et al, 1991;Valiaeva et al, 2006), antiviral (Lee et al, 1999;Li et al, 2005;Kmonickova et al, 2006;ElAshry et al, 2006;Chen et al, 2007) and animicrobial (Zinchenko et al, 1987;KascatanNebioglu et al, 2006) agents.…”