Phenylselenenyl- and phenylthio-substituted pyrimidines as inhibitors of dihydrouracil dehydrogenase and uridine phosphorylase

Abstract

Lithiation of 5-bromo-2,4-bis(benzyloxy)pyrimidine (3) with n-BuLi at -80 degrees C followed by the addition of diphenyl diselenide or diphenyl disulfide as an electrophile furnished the corresponding 5-(phenylhetera)-2,4-bis(benzyloxy)pyrimidine, which on exposure to trimethylsilyl iodide in CH2-Cl2 at room temperature yielded the 5-(phenylhetera)uracils in 70-75% yield. Similarly, the 6-(phenylhetera)uracils were prepared from 6-bromo-2,4-bis(benzyloxy)pyrimidine (10). 1-[(2-Hydroxyethoxy)methyl]-5-(phenylselenenyl)uracil (PSAU, 18) and 1-(ethoxymethyl)-5-(phenylselenenyl)uracil (17) were synthesized by the electrophilic addition of benzeneselenenyl chloride to the acyclic uracils under basic conditions. These compounds were evaluated for their ability to inhibit dihydrouracil dehydrogenase (DHUDase, E.C. 1.3.1.2), orotate phosphoribosyltransferase (OPRTase, E.C. 2.4.2.10), uridine phosphorylase (UrdPase, E.C. 2.4.2.3), and thymidine phosphorylase (dThdPase, E.C. 2.4.2.4). 5-(Phenylselenenyl)uracil (PSU, 6) and 5-(phenylthio)uracil (PTU, 7) inhibited DHUDase with apparent K(i) values of 4.8 and 5.4 microM, respectively. The corresponding 6-analogues, compounds 13 and 14, demonstrated inhibitory activity against OPRTase. PTU as well as PSU and its riboside, 2'-deoxyriboside, and acyclonucleosides were inhibitors of UrdPase, with PSAU (18) being the most potent with an apparent K(i) value of 3.8 microM. None of the compounds evaluated had any effect on dThdPase. Interestingly, most of the compounds showed modest selective anti-human-immunodeficiency-virus activity in acutely infected primary human lymphocytes.

Diphenyl diselenide and diphenyl ditelluride differentially affect ?-aminolevulinate dehydratase from liver, kidney, and brain of mice

“…Furthermore, they exhibit thiol peroxidase-like activity, and due to this and other antioxidant properties, a variety of selenide and telluride analogs have been considered for potential use as pharmaceutical antioxidants [51][52][53][54]. Diphenyl diselenide has also been used as an electrophile in the synthesis of a variety of pharmacologically active organic selenium compounds [55,56].…”

Diphenyl Diselenide and Ascorbic Acid Changes Deposition of Selenium and Ascorbic Acid in Liver and Brain of Mice

“…In fact, diphenyl diselenide, (PhSe) 2 , is an important compound used as an electrophilic agent in the synthesis of a range of pharmacologically active organic selenium compounds (Goudgaon et al 1993). Furthermore, diselenides and analogues have glutathione peroxidase-like activity (Wilson et al 1989;Engman et al 1992).…”

Synthesis of Novel 5-Phenylselenenyl-2,4-Disubstituted Pyrimidine Analogs

“…Though several organoselenium compounds are known, they are less explored for their antibacterial properties. Phenylselenenyl substituted pyrimidines were synthesized and evaluated for the inhibition of enzymes involved in pyrimidine metabolism [9][10][11][12][13][14][15][16][17] such as dihydrouracil dehydrogenase (DHUDase), orotate phosphoribosyl transfarase (OPRTase), Thymidine phosphorylase (Thdpase) and uridine phosphorylase (Urdpase). Herein, we report a facile methodology for the synthesis of various 5-phenylselenenyl-4-phenoxy-2-alkylthiopyrimidines starting from 2-thiouracil.…”