SYNTHESIS AND ANTIVIRAL ACTIVITY OF 2'-SUBSTITUTED 9-[2-(PHOSPHONOMETHOXY)ETHYL]GUANINE ANALOGS

A series of 2'-substituted derivatives of 9-[2-(phosphonomethoxy)ethyl ]guanine (PMEG, 1) have been synthesized and evaluated in vitro for an ti-human immunodeficiency virus (HIV) activity in the XTT assay and fo r anti-herpes activity in the plaque reduction assay. It has been obse rved that the anti-HIV activity of these derivatives depends on the si ze and the nature of the substituent as well as the chirality at the 2 '-position of PMEG. In addition, these compounds generally demonstrate d greater activity against HIV than herpes viruses. The most interesti ng analogues which emerged from these studies are (R)-2'-(azidomethyl) -PMEG [(R)-5] and (R)-2'-vinyl-PMEG [(R)-11]. The former showed anti-H IV activity with an IC50 of 5 muM and a cytotoxicity (CC50) greater th an 1.4 mM in CEM cells. The latter has an IC50 of 13 muM for anti-HIV activity and a CC50 of greater than 1.6 mM. Furthermore, we have demon strated that replacement of the guanine base of these 2'-substituted P MEG analogues with cytosine drastically reduces anti-HIV and anti-herp es activity.