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

• Published in: Journal of medicinal chemistry 1994-08, Vol.37 (16), p.2513-2519
• Main Authors: Mohan, Prem, Loya, Shoshana, Avidan, Orna, Verma, Sandeep, Dhindsa, Gurnam S, Wong, Man Fai, Huang, Peggy P, Yashiro, Makoto, Baba, Masanori, Hizi, Amnon
• Format: Article
• Language: English
• Subjects: AIDS/HIV; Chemistry; Cholesterol - analogs & derivatives; Cholesterol - chemical synthesis; Cholesterol - pharmacology; Condensed benzenic and aromatic compounds; Exact sciences and technology; HIV Protease Inhibitors - chemical synthesis; HIV Protease Inhibitors - pharmacology; HIV Reverse Transcriptase; HIV-1 - drug effects; human immunodeficiency virus 1; Molecular Structure; Naphthalenesulfonates - chemistry; Nucleic Acid Synthesis Inhibitors; Organic chemistry; Preparations and properties; Reverse Transcriptase Inhibitors; Ribonuclease H - antagonists & inhibitors; RNA Replicase - antagonists & inhibitors; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00042a004

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.