The 2′,3′-dideoxyriboside of 2,6-diaminopurine and its 2′,3′-didehydro derivative inhibit the deamination of 2′,3′-dideoxyadenosine, an inhibitor of human immunodeficiency virus (HIV) replication

Abstract

The 2′,3′-dideoxyriboside of 2,6-diaminopurine (ddDAPR) and its 2′,3′-didehydro derivative (ddeDAPR) are poor substrates for adenosine deaminase (ADA) but potent inhibitors of the enzyme. Their K m values for ADA are of the same order of magnitude as those of the natural adenosine (Ado) and 2′-deoxyadenosine (dAdo), but their V max values are 35-fold (ddDAPR) to 350-fold (ddeDAPR) lower than those of Ado and dAdo. The K i K m values of ADA for ddeDAPR (as inhibitor) and Ado, 2′,3′-dideoxyadenosine (ddAdo) and 9-β- D-ara-binofuranosyladenine (araA) as the substrates are 0.17, 0.05 and 0.06, respectively. ddDAPR is about 3-fold less potent as an inhibitor of ADA than ddeDAPR. The 2,6-diaminopurine derivatives ddeDAPR and ddDAPR [which is also a potent inhibitor of human immunodeficiency virus (HIV)], may hold great promise, from a chemotherapeutic viewpoint, in combination with other adenosine analogues such as ddAdo and araA, which have been recognized and/or being pursued as either anti-retrovirus or anti-herpesvirus agents.