PHENYLSELENENYL-SUBSTITUTED AND PHENYLTHIO-SUBSTITUTED PYRIMIDINES ASINHIBITORS OF DIHYDROURACIL DEHYDROGENASE AND URIDINE PHOSPHORYLASE

Lithiation of 5-bromo-2,4-bis (benzyloxy) pyrimidine (3) with n-BuLi a t -80 degrees C followed by the addition of diphenyl diselenide or dip henyl disulfide as an electrophile furnished the corresponding 5-(phen ylhetera)-2,4-bis(benzyloxy) pyrimidine, which on exposure to trimethy lsilyl iodide in CH2-Cl-2 at room temperature yielded the 5-(phenylhet era)uracils in 70-75% yield. Similarly, the 6-(phenylhetera) uracils w ere prepared from 6-bromo-2,4-bis (benzyloxy) pyrimidine (10). 1-[(2-H ydroxyethoxy)methyl] -5-(phenylselenenyl)uracil (PSAU, 18) and 1-(etho xymethyl)-5- (phenylselenenyl)uracil (17) were synthesized by the elec trophilic addition of benzeneselenenyl chloride to the acyclic uracils under basic conditions. These compounds were evaluated for their abil ity to inhibit dihydrouracil dehydrogenase (DHUDase, E.C. 1.3.1.2), or otate phosphoribosyltransferase (OPRTase, E.C. 2.4.2.10), uridine phos phorylase (UrdPase, E.C. 2.4.2.3), and thymidine phosphorylase (dThdPa se, E.C. 2.4.2.4). 5-(Phenylselenenyl)uracil (PSU, 6) and 5-(phenylthi o)uracil (PTU, 7) inhibited DHUDase with apparent K-i values of 4.8 an d 5.4 mu M, 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 ap parent K-i value of 3.8 mu M. 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 infec ted primary human lymphocytes.