STRUCTURE-BASED DESIGN OF INHIBITORS OF PURINE NUCLEOSIDE PHOSPHORYLASE .3. 9-ARYLMETHYL DERIVATIVES OF 9-DEAZAGUANINE SUBSTITUTED ON THE METHYLENE GROUP

X-ray crystallography and computer-assisted molecular modeling (CAMM) studies aided in the design of a potent series of mammalian purine nuc leoside phosphorylase (PNP) inhibitors. Enhanced potency was achieved by designing substituted 9-(arymethyl)-9-deazaguanine analogs that int eract favorably with all three of the binding subsites of the PNP acti ve site, namely the purine binding site, the hydrophobic pocket, and t he phosphate binding site. The most potent PNP inhibitor prepared duri ng our investigation, [1-(3-chlorophenyl)-2-carboxyethyl]-9-deazaguani ne (18b), was shown to have an IC50 of 6 nM, whereas the corresponding (R)-isomer was 30-fold less potent.