Structure-activity relationship studies with symmetric naphthalenesulfonic acid derivatives. Synthesis and influence of spacer and naphthalenesulfonic acid moiety on anti-HIV-1 activity

Mohan, P. Maruthi; Wong, Man Fai; Verma, Sandeep; Huang, Peggy; Wickramasinghe, Anura; Baba, Masanori

doi:10.1021/jm00066a008

Cited by 9 publications

(2 citation statements)

References 13 publications

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“…Parniak and co-workers have shown that indiscriminate inhibition of both activities by N-(4-tert-butylbenzoyl)-2-hydroxy-1naphthaldehyde hydrazone (BBNH) also occurs (IC 50 $4.0 mM) (15). Certain analogues of naphthalene sulfonic acid exhibit non-selective inhibition of both DNA polymerase and RNase H catalytic functions of HIV-1 RT, with IC 50 values in the 15-28 mM range for the most potent compounds (16).…”

Section: Introductionmentioning

confidence: 99%

Diversity-oriented solid-phase synthesis and biological evaluation of oligonucleotide hairpins as HIV-1 RT RNase H inhibitors

Hannoush

Min

Damha

2004

Nucleic Acids Research

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The inhibitory potencies of several hairpins comprising DNA, RNA and 2',5'-linked RNA segments were assessed against the RNase H activity of the human immunodeficiency virus reverse transcriptase (HIV-1 RT), an indispensable enzyme for HIV genomic replication. The hairpin library was constructed via diversity-oriented nucleic-acid synthesis (DONAS), an approach inspired from traditional split-pool synthesis. DONAS provided access to an array of oligonucleotide hairpins possessing distinct conformational, structural and biological properties. The inhibitory potency of these compounds was highly specific towards HIV-1 RT RNase H and strongly depended on the structure of both the stem and tetraloop. Hairpins that have an overall A-type geometry are better inhibitors of RNase H activity than hairpins with 'intermediate' or B-type conformations, although interestingly, the inhibitory activity is quite sensitive to the nucleotide sequence in both the stem and loop regions of the hairpin. The most potent hairpins bear a 3',5'-linked rather than 2',5'-linked RNA loop, but the latter is necessary for activity of hairpins consisting of DNA stems. Inhibitory activity was essentially independent of hairpin thermal stability. The potent hairpins also demonstrated high nuclease resistance in biological media, particularly those bearing a 2',5'-linked tetraloop. These studies collectively bring into light a new class of nucleic acid aptamers that act exclusively upon the retroviral RNase H domain in vitro, and thus represent novel lead compounds for the development of specific and potent HIV-1 RT inhibitors.

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Section: Introductionmentioning

confidence: 99%

Diversity-oriented solid-phase synthesis and biological evaluation of oligonucleotide hairpins as HIV-1 RT RNase H inhibitors

Hannoush

Min

Damha

2004

Nucleic Acids Research

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“…These have included the inhibition of HIV-1 cytopathogenicity using both a laboratory strain and a clinical isolate, inhibition of HIV-1 induced syncytia formation, and both HIV-1 and HIV-2 RT inhibition. [5][6][7][8] In the present study, we report the synthesis and evaluation of the inhibitory effects of over 25 naphthalenesulfonic acid derivatives on the different catalytic functions of HIV-1 RT.…”

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confidence: 99%

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

Mohan¹,

Loya²,

Avidan³

et al. 1994

J. Med. Chem.

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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.

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Binding of Multivalent Anionic Porphyrins to V3 Loop Fragments of an HIV‐1 Envelope and Their Antiviral Activity

Watanabe

Negi

Kiriyama

et al. 2010

Chemistry An Asian Journal

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Interactions of multivalent anionic porphyrins and their iron(III) complexes with cationic peptides, V3(Ba-L) and V3(IIIB), which correspond to those of the V3 loop regions of the gp120 envelope proteins of the HIV-1(Ba-L) and HIV-1(IIIB) strains, respectively, are studied by UV/Vis, circular dichroism, (1)H NMR, and EPR spectroscopy, a microcalorimetric titration method, and anti-HIV assays. Tetrakis(3,5-dicarboxylatophenyl)porphyrin (P1), tetrakis[4-(3,5-dicarboxylatophenylmethoxy)phenyl]porphyrin (P2), and their ferric complexes (Fe(III)P1 and Fe(III)P2) were used as the multivalent anionic porphyrins. P1 and Fe(III)P1 formed stable complexes with both V3 peptides (binding constant K>10(6) M(-1)) through combined electrostatic and van der Waals interactions. Coordination of the His residues in V3(Ba-L) to the iron center of Fe(III)P1 also played an important role in the complex stabilization. As P2 and Fe(III)P2 form self-aggregates in aqueous solution even at low concentrations, detailed analysis of their interactions with the V3 peptides could not be performed. To ascertain whether the results obtained in the model system are applicable to a real biological system, anti-HIV-1(BA-L) and HIV-1(IIIB) activity of the porphyrins is examined by multiple nuclear activation of a galactosidase indicator (MAGI) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. There is little correlation between chemical analysis and actual anti-HIV activity, and the size rather than the number of the anionic groups of the porphyrin is important for anti-HIV activity. All the porphyrins show high selectivity, low cytotoxicity, and high viral activity. Fe(III)P1 and Fe(III)P2 are used for the pharmacokinetic study. Half-lives of these iron porphyrins in serum of male Wistar rats are around 4 to 6 h owing to strong interaction of these porphyrins with serum albumin.

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Structure-activity relationship studies with symmetric naphthalenesulfonic acid derivatives. Synthesis and influence of spacer and naphthalenesulfonic acid moiety on anti-HIV-1 activity

Cited by 9 publications

References 13 publications

Diversity-oriented solid-phase synthesis and biological evaluation of oligonucleotide hairpins as HIV-1 RT RNase H inhibitors

Diversity-oriented solid-phase synthesis and biological evaluation of oligonucleotide hairpins as HIV-1 RT RNase H inhibitors

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

Binding of Multivalent Anionic Porphyrins to V3 Loop Fragments of an HIV‐1 Envelope and Their Antiviral Activity

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