Synthesis of Naphthalenesulfonic Acid Small Molecules as Selective Inhibitors of the DNA Polymerase and Ribonuclease H Activities of HIV-1 Reverse Transcriptase

Abstract

Over 25 selected naphthalenesulfonic acid derivatives were evaluated for their inhibitory effect on two different functional domains of the HIV-1 reverse transcriptase (RT), namely the ribonuclease H and DNA polymerase activities. Most of the analogues were found to be either specific toward the DNA polymerase activity or showed nonselective inhibition of both catalytic functions. The most active compounds are either symmetrical derivatives or nonsymmetrical derivatives containing a lipophilic appendage consisting of a palmitoyl or cholesteryl moiety. The six most active compounds in the preliminary screen, derivatives 6, 16, 17, 23, 26, and 27, were subjected to experiments to determine their 50% inhibitory concentration (IC50) values in the assays that measure RNA-dependent DNA polymerase (RDDP), DNA-dependent DNA polymerase (DDDP), and ribonuclease H (RNase H) functions of HIV-1 RT. The most potent derivative was a nonsymmetric cholesterol-linked 4-amino-5-hydroxy-2,7-naphthalenedisulfonic acid analogue, compound 23, which demonstrated an IC50 value of 0.06 microM for inhibiting RDDP activity. Inhibition of DDDP and RNase H activity for this compound was demonstrated at concentrations that were over 100-fold of that for inhibiting RDDP activity. However, the potency of this active compound does not correlate in the whole virus assay, probably due to a lack of cellular entry. The cholesterol derivative, 23, also possesses HIV-1 protease inhibitory activity and belongs to a unique class of multifunctional HIV-1 inhibitors.

HIV-1 RNase H: Recent Progress in an Exciting, yet Little Explored, Drug Target

“…(3), showed IC 50 values of 17 µM and 1 µM, respectively. Unfortunately, both derivatives were not active on virus replication [64]. Differently, a symmetric derivative with an aromatic spacer (10), Fig.…”

“…A first series of naphtalenesulfonic acid derivatives was shown to slightly inhibit the HIV-1 RNase H activity, whereas they were more potent on its RDDP activity [64]. In particular, a N -palmitoylated derivative (8), (Fig.…”

Regional differences in gene expression for calcium activated neutral proteases (calpains) and their endogenous inhibitor calpastatin in mouse brain and spinal cord

“…The action of calpains on these same structural proteins contributes to dendritic pruning (Song et al, 1994), synaptic remodeling (O'Brien et al, 1984), and other regressive events during development and may lead to degeneration in certain neuropathologic states triggered by increased intracellular calcium levels, including ischemia (Rami and Krieglstein, 1993;Arai et al, 1990;Bartus et al, 1994a,b), excitotoxicity (Siman et al, 1989;Siman and Noszek, 1988;Caner et al, 1993;Roberts-Lewis et al, 1993), and several experimental axonopathies (Nixon et al, 1994). In Alzheimer's disease, activated calpain I isoforms are abnormally high in cortical and subcortical brain regions (Saido et al, 1993), calpastatin levels are reduced in brain regions at risk to degenerate (Nixon et al, 1994;Mohan et al, 1994;Nilsson et al, 1990), and calpain-related epitopes become associated with neurofibrillary pathology (Nixon et al, 1994).…”

Inhibition of HIV-1 Ribonuclease H by a Novel Diketo Acid, 4-[5-(Benzoylamino)thien-2-yl]-2,4-dioxobutanoic Acid

“…4). Although there are several published examples of compounds that inhibit RNase H activity in vitro (5)(6)(7)(8)(9)(10)(11), it is still unclear whether their affect on RNase H function is mediated by direct binding to the RNase H domain. In some cases, these inhibitors have been shown to affect both the polymerase and RNase H activities of RT (8,9), which superficially suggests that these compounds may bind at both active sites.…”