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

Prem Mohan, Shoshana Loya, Orna Avidan, Sandeep Verma, Gurnam S. Dhindsa, Man Fai Wong, Peggy P. Huang, Makoto Yashiro, Masanori Baba, Amnon Hizi

Research output: Contribution to journalArticlepeer-review

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 μM 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.

Original languageEnglish
Pages (from-to)2513-2519
Number of pages7
JournalJournal of Medicinal Chemistry
Volume37
Issue number16
DOIs
StatePublished - 1 Aug 1994

Fingerprint

Dive into the research topics of 'Synthesis of Naphthalenesulfonic Acid Small Molecules as Selective Inhibitors of the DNA Polymerase and Ribonuclease H Activities of HIV-1 Reverse Transcriptase'. Together they form a unique fingerprint.

Cite this