Correlation of Anti-HIV Activity with Anion Spacing in a Series of Cosalane Analogues with Extended Polycarboxylate Pharmacophores

Santhosh, K. C.; Paul, Gitendra C.; Clercq, Erik De; Pannecouque, Christophe; Witvrouw, Myriam; Loftus, Tracy L; Turpin, Jim A.; Buckheit, Robert W.; Cushman, Mark

doi:10.1021/jm000290u

Cited by 22 publications

(10 citation statements)

References 35 publications

(91 reference statements)

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“…Antiviral activity of the 2,2Ј-bisphenol series (6-9) increased in the order, 6Ͻ7Ͻ8Ͻ9 (see EC 50 values in Table 5). Higher antiviral activity was observed in the 4,4Ј-bisphenol derivative (10) than the 2,2Ј-bisphenol series (6)(7)(8)(9). This most active compound (10) was estimated to have a 50% cytotoxic concentration (CC 50 ) of 25-30 mg/ml by additional experiments.…”

Section: Resultsmentioning

confidence: 99%

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Synthesis of 2,2'-Dihydroxybisphenols and Antiviral Activity of Some Bisphenol Derivatives.

et al. 2002

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Triphenylmethane-type bisphenols have antioxidant activity, 1,2) and some of the derivatives show anticancer activity.3)Recently, we reported a conventional procedure for the preparation of triphenylmethane-type 2,2Ј-dihydroxybisphenols. 4) For the synthetic application of the procedure and biological evaluation of the related compounds, we attempted to synthesize diphenylmethane-type 2,2Ј-dihydroxybisphenol derivatives with some aliphatic aldehydes as starting material. In this paper, we wish to report the syntheses of some 2,2Ј-dihydroxybisphenols for lead compounds and also to communicate significant antiviral activities of some of the related compounds by the plaque reduction assay. 5) Results and DiscussionRegioselective syntheses of 2,2Ј-dihydroxybisphenols (5a-d) with aliphatic aldehydes (2-4) were achieved in good yields according to the procedure described previously.4) The results are summarized in ) and 4,4Ј-dihydroxybisphenol (10) 4) (see Fig. 1) were examined by plaque reduction assay as described by Schinazi et al.5) The results (EC 50 : 50% effective concentration) of six compounds by this assay are summarized in Table 5. Compound 5b having an isobutyl group instead of the substituted aromatic ring had high cytotoxicity. Antiviral activity of the 2,2Ј-bisphenol series (6-9) increased in the order, 6Ͻ7Ͻ8Ͻ9 (see EC 50 values in Table 5). Higher antiviral activity was observed in the 4,4Ј-bisphenol derivative (10) than the 2,2Ј-bisphenol series (6-9). This most active compound (10) was estimated to have a 50% cytotoxic concentration (CC 50 ) of 25-30 mg/ml by additional experiments. The selectivity index (CC 50 /EC 50 ) of 10 was ca. 15.During the past five years, more than a few thousand reports with bisphenol as a key word have appeared, however, to the best of our knowledge, no report has dealt with the an-298 Notes Chem.

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Section: Resultsmentioning

confidence: 99%

“…In this fragment, one can also find 4,4Ј-dihydroxybisphenol moiety. 6) It is noteworthy that these simple bisphenol derivatives showed considerably high antiviral activity. On the basis of our observation, synthetic trials are being made on triphenylmethane-type 4,4Ј-dihydroxybisphenols.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of 2,2'-Dihydroxybisphenols and Antiviral Activity of Some Bisphenol Derivatives.

et al. 2002

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“…2, Compound 1) is an inhibitor of HIV replication, which has activity against both HIV-1 and HIV-2, acting primarily by inhibiting the binding of gp120 to CD4, as well as by hindering a post-binding fusion event [98,99]. This compound was designed by Cushman et al [99] by attaching a dichlorinated disalicylmethane fragment of ATA, aurintricarboxilic acid [100], (a heterogeneous mixture of polymers that forms when salicylic acid is treated with formaldehyde, sulfuric acid, and sodium nitrite and inhibits the cytopathic effect of HIV-1 and HIV-2 in a variety of lymphocyte cell cultures by blocking the attachment of the viral envelope to the cell membrane) to C-3 of cholestane through an alkenyl linker chain [99].…”

Section: Cosalane Analoguesmentioning

confidence: 99%

The HIV Entry Inhibitors Revisited

Leonard¹,

Roy

2006

CMC

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The new generation of antiviral drugs intended to counter HIV-1 entry into susceptible cells is emerging swiftly. The antiviral agents that inhibit HIV entry to the target cells (denoted as HIV entry inhibitors) are already in different phases of clinical trials. Operating early in the viral life cycle, they prevent viral entry, and have a novel, highly specific mechanism of action with a low toxicity profile. Entry inhibitors have different toxicity and resistance profiles than the existing reverse transcriptase and protease inhibitors. Some of these compounds demonstrated in vitro synergism with other classes of antivirals, thus offering the rationale for their combination in therapies for HIV-infected individuals. It is worth focusing on recent developments in HIV entry inhibitors, as most of the current drug regimens suffer from the events of developing resistance against existing combination therapies. Recent advances in the understanding of the cellular and molecular mechanisms of HIV-1 entry provide the basis for novel therapeutic strategies that prevent viral penetration of the target cell-membrane, while reducing detrimental virus and treatment effects on cells and prolonging virion exposure to immune defenses. A number of potential sites for therapeutic intervention become accessible during the narrow window between virus attachment and the subsequent fusion of viral envelope with the cell membrane. The HIV-1 coreceptors are particularly attractive from the perspective of identifying new antiviral compounds, since they are seven-transmembrane motif G protein-coupled receptors (GPCRs), a family of proteins that is a well-validated target for drug development. Among the many chemokine receptors that can mediate HIV-1 entry in vitro, only CCR5 and CXCR4 are of frontline pharmacological importance. In particular, CCR5 is essential for viral transmission and replication during the early and clinically latent phase of disease. Several small-molecule antagonists of CCR5 and CXCR4 that block chemokine binding and HIV-1 entry have been identified in recent years. Considerable advances have been made in the last years in the design of derivatives acting as inhibitors of HIV entry. The molecular mechanism involved in viral entry, the structural and functional aspects of entry inhibitors are reviewed here. We have also summarized the recent insights into how small-molecule antagonists interact with CCR5 and CXCR4, focusing on drug development programs that are well documented in the scientific literature. An overview of the entry inhibitors that are in preclinical or early clinical development, and the Quantitative Structure-Activity Relationships (QSAR) studies reported for the coreceptor antagonists are also be presented.

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“…A great variety of polyanionic compounds have been described which act as virus adsorption inhibitors. This class of compounds also comprises the cosalane analogues, containing the polycarboxylate pharmacophore, as well as the sulfated polysaccharides extracted from sea algae (Nakashima et al, 1987a(Nakashima et al, , 1992Santhosh et al, 2001;Witvrouw and De Clercq, 1997). All of these compounds are assumed to exert their anti-HIV activity by shielding the positively charged sites in the V3 loop region of the viral gp120 envelope glycoprotein, and interrupting virus attachment to the negatively charged heparan sulfate proteoglycans on cell surface, and inhibiting the specific binding to the CD4 receptor of CD4 + cells.…”

Section: Introductionmentioning

confidence: 99%

Highly potent anti-HIV-1 activity isolated from fermented Polygonum tinctorium Aiton

et al. 2005

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A water-soluble extract of fermented Polygonum tinctorium Aiton (Polygonaceae) called Sukumo, exhibited a potent inhibitory activity against HIV type 1 in vitro. The extract potently suppressed acute HIV-1 (IIIB) infection in MT-4 cells with EC50 values of 0.5 microg/ml but exhibited low cytotoxicity to MT-4 cells even at a high concentration (CC50 > 1000 microg/ml). It also inhibited giant cell formation in co-cultures of HIV-infected cells and uninfected Molt-4 cells. Sukumo extract was found to interact with both the viral envelope glycoprotein and cellular receptors, thus blocking virus-cell binding and virus-induced syncytium formation. There was a good correlation between the extract's anti-HIV-1 activity and its inhibitory effects on HIV-1 binding. It also suppressed replication of herpes simplex virus type 1 in Vero cells with an EC 50 of 11.56 microg/ml. On the other hand, there was no appreciable activity against influenza A virus, poliovirus or SARS corona virus when tested at concentrations ranging from 3.2-400 microg/ml as shown by microscopic image analysis for cytopathic effect (CPE). Physico-chemical studies revealed that the anti-HIV activity in the extract was essentially maintained after boiling at 100 degrees C in 1N HCl or 1N NaOH, and after treatment with 100 mM NaIO4. The inhibitory activity of the extract was also not reduced after pronase digestion. The active factor in the extract is likely to be a novel compound(s) having a polyanionic substructure and a molecular weight of 10,000-50,000.

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Correlation of Anti-HIV Activity with Anion Spacing in a Series of Cosalane Analogues with Extended Polycarboxylate Pharmacophores

Cited by 22 publications

References 35 publications

Synthesis of 2,2'-Dihydroxybisphenols and Antiviral Activity of Some Bisphenol Derivatives.

Synthesis of 2,2'-Dihydroxybisphenols and Antiviral Activity of Some Bisphenol Derivatives.

The HIV Entry Inhibitors Revisited

Highly potent anti-HIV-1 activity isolated from fermented Polygonum tinctorium Aiton

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