SYNTHESIS OF NAPHTHALENESULFONIC ACID SMALL MOLECULES AS SELECTIVE INHIBITORS OF THE DNA-POLYMERASE AND RIBONUCLEASE-H ACTIVITIES OF HIV-1 REVERSE-TRANSCRIPTASE

Over 25 selected naphthalenesulfonic acid derivatives were evaluated f or their inhibitory effect on two different functional domains of the HIV-1 reverse transcriptase (RT), namely the ribonuclease H and DNA po lymerase activities. Most of the analogues were found to be either spe cific toward the DNA polymerase activity or showed nonselective inhibi tion of both catalytic functions. The most active compounds are either symmetrical derivatives or nonsymmetrical derivatives containing a li pophilic appendage consisting of a palmitoyl or cholesteryl moiety. Th e six most active compounds in the preliminary screen, derivatives 6, 16, 17, 23, 26, and 27, were subjected to experiments to determine the ir 50% inhibitory concentration (IC50) values in the assays that measu re RNA-dependent DNA polymerase (RDDP), DNA-dependent DNA polymerase ( DDDP), and ribonuclease H (RNase H) functions of HIV-1 RT. The most po tent derivative was a nonsymmetric cholesterol-linked 4-amino-5-hydrox y-2,7-naphthalenedisulfonic acid analogue, compound 23, which demonstr ated an IC50 value of 0.06 mu M for inhibiting RDDP activity. Inhibiti on of DDDP and RNase H activity for this compound was demonstrated at concentrations that were over 100-fold of that for inhibiting RDDP act ivity. However, the potency of this active compound does not correlate in the whole virus assay, probably due to a lack of cellular entry. T he cholesterol derivative, 23, also possesses HIV-1 protease inhibitor y activity and belongs to a unique class of multifunctional HIV-1 inhi bitors.