Nm. Goudgaon et al., PHENYLSELENENYL-SUBSTITUTED AND PHENYLTHIO-SUBSTITUTED PYRIMIDINES ASINHIBITORS OF DIHYDROURACIL DEHYDROGENASE AND URIDINE PHOSPHORYLASE, Journal of medicinal chemistry, 36(26), 1993, pp. 4250-4254
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.