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PubMed2006

Susceptibility of highly pathogenic A(H5N1) avian influenza viruses to the neuraminidase inhibitors and adamantanes.

Since 2003, highly pathogenic A(H5N1) influenza viruses have been the cause of large-scale death in poultry and the subsequent infection and death of over 140 humans. A group of 55 influenza A(H5N1) viruses isolated from various regions of South East Asia between 2004 and 2006 were tested for their susceptibility to the anti-influenza drugs the neuraminidase inhibitors and adamantanes. The majority of strains were found to be fully sensitive to the neuraminidase inhibitors oseltamivir carboxylate, zanamivir and peramivir; however two strains demonstrated increased IC50 values. Sequence analysis of these strains revealed mutations in the normally highly conserved residues 116 and 117 of the N1 neuraminidase. Sequence analysis of the M2 gene showed that all of the A(H5N1) viruses from Vietnam, Malaysia and Cambodia contained mutations (L26I and S31N) associated with resistance to the adamantane drugs (rimantadine and amantadine), while strains from Indonesia were found to be a mix of both adamantane resistant (S31N) and sensitive viruses. None of the A(H5N1) viruses from Myanmar contained mutations known to confer adamantane resistance. These results support the use of neuraminidase inhibitors as the most appropriate class of antiviral drug to prevent or treat human A(H5N1) virus infections.

Acids, Carbocyclic↗
PubMed2005

High-pressure study of adamantane: variable shape simulations up to 26 GPa.

We report simulations of adamantane by carefully combining ab initio and empirical approaches to enable simulations with internal degrees of freedom on crystalline adamantane up to a pressure of 26 GPa. Two sets of simulations, assuming the adamantane molecule as a rigid (RB) and flexible body (FB), have been carried out as a function of pressure up to 26 GPa to understand changes in the crystal structure as well as molecular structure. The flexible body simulations have been performed by including 6 lowest frequency internal modes (obtained from DFT calculations performed with Gaussian98) out of the total of 72. The calculated variation in c/a and V/V(0) from the RB and FB calculations as a function of pressure have been compared with the experimental curve. Other relevant thermodynamic and structural properties reported are the radial distribution functions, deviation in the position of a given type of atom with respect to its position at standard pressure, delta(s), cell parameters, volume, and energy. With an increase in pressure, three additional peaks are seen to develop gradually at three different pressures in the center of mass (com)-com radial distribution function (rdf). We attribute these changes to structural transformations (probably second-order phase transitions) which is consistent with the three phase transitions reported by Vijayakumar et al. for adamantane in the pressure range of 1 atm-15 GPa. Our simulations also show that these additional peaks in the rdf's are associated with the differences between opposite and parallel spin neighbors of Greig and Pawley as well as the crystallographic directional dependence of intermolecular distances in the first three shells of the neighbors. Also, the structural quantities from the RB calculation show considerable deviation from the FB calculation for pressures greater than 5 GPa, which suggests that the rigid body assumption for molecules may not be valid above this pressure.

Journal Article↗
PubMed1983

Identification of hydrophobic regions of the calcium-transport ATPase from sarcoplasmic reticulum after photochemical labeling with adamantane diazirine.

The Ca-ATPase from skeletal muscle sarcoplasmic reticulum was labeled with [3H]adamantane diazirine. Adamantane diazirine is a hydrophobic photoactivated probe that partitions into the cell membrane and can be used to identify regions of proteins that are embedded within the membrane. Digestion of the labeled protein with trypsin and separation of the labeled tryptic fragments by SDS-polyacrylamide-gel electrophoresis indicated that all of the major tryptic fragments were labeled by the probe. The presence of glutathione in the sample buffer during photolysis did not alter the pattern of labeling, indicating that adamantane diazirine labeled the Ca-ATPase from within the lipid bilayer. These results indicate that the Ca-ATPase polypeptide must cross the membrane at least 3 times.

Adamantane↗
PubMed2005

Incidence of adamantane resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern.

BACKGROUND: Adamantanes have been used to treat influenza A virus infections for many years. Studies have shown a low incidence of resistance to these drugs among circulating influenza viruses; however, their use is rising worldwide and drug resistance has been reported among influenza A (H5N1) viruses isolated from poultry and human beings in Asia. We sought to assess adamantane resistance among influenza A viruses isolated during the past decade from countries participating in WHO's global influenza surveillance network. METHODS: We analysed data for influenza field isolates that were obtained worldwide and submitted to the WHO Collaborating Center for Influenza at the US Centers for Disease Control and Prevention between Oct 1, 1994, and Mar 31, 2005. We used pyrosequencing, confirmatory sequence analysis, and phenotypic testing to detect drug resistance among circulating influenza A H3N2 (n=6524), H1N1 (n=589), and H1N2 (n=83) viruses. FINDINGS: More than 7000 influenza A field isolates were screened for specific aminoacid substitutions in the M2 gene known to confer drug resistance. During the decade of surveillance a significant increase in drug resistance was noted, from 0.4% in 1994-1995 to 12.3% in 2003-2004. This increase in the proportion of resistant viruses was weighted heavily by those obtained from Asia with 61% of resistant viruses isolated since 2003 being from people in Asia. INTERPRETATION: Our data raise concerns about the appropriate use of adamantanes and draw attention to the importance of tracking the emergence and spread of drug-resistant influenza A viruses.

Adamantane↗
PubMed1998

How to overcome resistance of influenza A viruses against adamantane derivatives.

We tested two approaches to overcoming resistance of influenza A viruses against adamantane derivatives. First, adamantane derivatives that interfere with the ion channel function of the variant M2 protein of amantadine-resistant viruses may prevent drug resistance, if they are used in mixture with amantadine. Second, amantadine acts on the M2 protein (at low concentrations) and indirectly on the hemagglutinin (at concentrations at least 100 times higher). Identifying and using a drug that reacted with both targets at the same concentration might reduce development of resistance, since, in this case, two mutations, one in each target protein would be necessary at once. Such a double mutation is assumed to be a rare event. We evaluated forty adamantane derivatives and two related compounds to determine whether they interfered with plaque formation by influenza A strains, including A/Singapore/1/57 (H2N2). Variants resistant to drugs that interfered at low concentrations (approximately 1 microg/ml; e.g. amantadine) were cross-resistant with each other, but were sensitive to those agents effective at high concentrations (8 microg/ml; e.g. memantine). The former group of compounds act on the ion channel; the corresponding escape mutants tested had amino acid replacements at positions 27, 30 or 31 of the M2 protein. Hemagglutinin was the indirect target of the latter group of compounds. Variants resistant to these agents lacked amino acid replacements within the ion channel of the M2 protein and the mutants tested had amino acid replacements in the hemagglutinin. Although we failed to identify compounds that interacted with the ion channel of amantadine-resistant variants and inhibited their replication, we were able to construct at least two compounds that interfered with both the ion channel and the hemagglutinin at about the same concentration. After passage in the presence of these compounds, we either failed to obtain any drug-resistant mutants or those obtained had amino acid replacements in the ion channel of the M2 protein and the hemagglutinin.

Adamantane↗
PubMedDate not supplied

Synthesis, hybridization properties, nuclease stability, and cellular uptake of the oligonucleotide--amino-beta-cyclodextrins and adamantane conjugates.

Synthesis of the oligonucleotides conjugated with amino derivatives of beta-cyclodextrin and adamantane, at the 3'-end of host oligonucleotide, has been described. The oligonucleotide conjugates were examined for their nuclease stability, hybridization properties, and cellular uptake. The oligonucleotide conjugates had increased nuclease resistance compared to their parent oligonucleotides. Conjugation of adamantane to the oligonucleotides did not adversely affect the ability of the oligonucleotides to hybridize with their complementary RNA. Conjugation with amino derivatives of beta-cyclodextrin, however, significantly destabilized the duplex formation. In the cellular uptake studies, we found that amino derivatives of beta-cyclodextrin attached at 3'-end of the oligonucleotides did not help to increase the uptake by cells. Cellular uptake of oligonucleotide-adamantane conjugates in association with 2-(hydroxypropyl)-beta-cyclodextrin (HPCD) as a "carrier" was significantly higher than that of control oligonucleotides.

Adamantane↗
PubMedDate not supplied

[Structure and antiviral activity of adamantane-containing polymer preparation].

New water-soluble antiviral chemical agents, containing 10 to 30% of adamantane derivatives (amino-, aminopropyl-adamantane-, aminomethyl- and rimantadine), which were conjugated with polycarboxylic matrixes of the divinyl ether and maleic anhydride copolymers (DIVEMA), were developed. The polymeric drugs exhibited a low cytotoxicity (4 to 10 times less than rimantadine) and a wide spectrum of antiviral activity against influenza viruses, including both the remantadine-resistant strains of A/PR/8/34 (H1N1) and the B/Saint-Petersburg strain/71/77 as well as against herpes viruses of type 1, parainfluenza viruses of types 1 and 3 and RS-virus. A reduction of the viral infection titer in their reproduction in sensitive cells' cultures was more than 2.0 Ig ID50. Complete inhibition of viral-specific syntheses, registered by immune-enzyme assay (IEA) and by hemagglutination test was observed at low infection doses ranging from 1 to 100 ID50. The efficiency of the antiviral effect depends on a drug's molecular weight and a structure of chemical bonds between the adamantane nucleus and the polymeric matrix.

Adamantane↗
PubMed2006

High levels of adamantane resistance among influenza A (H3N2) viruses and interim guidelines for use of antiviral agents--United States, 2005-06 influenza season.

An estimated 200,000 persons are hospitalized each year and 36,000 persons die from complications of influenza in the United States. The cornerstone of influenza prevention is annual vaccination. However, antiviral drugs are an important adjunct to vaccination for influenza prevention and control. Two classes of antiviral medications are available currently: adamantanes or M2 ion channel inhibitors (i.e., amantadine and rimantadine) and neuraminidase inhibitors (i.e., oseltamivir and zanamivir). The adamantanes are active against only influenza A viruses and are used for both treatment and chemoprophylaxis of influenza A, whereas the neuraminidase inhibitors are active against both influenza A and B viruses. Zanamivir is not approved for chemoprophylaxis of influenza in the United States. This report describes new findings regarding the resistance to adamantanes of influenza A viruses currently circulating in the United States and provides interim recommendations that these drugs not be used during the remainder of the 2005-06 influenza season. Amantadine also is used to treat symptoms of Parkinson disease and may continue to be used for this indication.

Adamantane↗
PubMed2003

A theoretical study of reactivity and regioselectivity in the hydroxylation of adamantane by ferrate(VI).

The conversion of adamantane to adamantanols mediated by ferrate (FeO(4)(2)(-)), monoprotonated ferrate (HFeO(4)(-)), and diprotonated ferrate (H(2)FeO(4)) is discussed with the hybrid B3LYP density functional theory (DFT) method. Diprotonated ferrate is the best mediator for the activation of the C-H bonds of adamantane via two reaction pathways, in which 1-adamantanol is formed by the abstraction of a tertiary hydrogen atom (3 degrees ) and 2-adamantanol by the abstraction of a secondary hydrogen atom (2 degrees ). Each reaction pathway is initiated by a C-H bond cleavage via an H-atom abstraction that leads to a radical intermediate, followed by a C-O bond formation via an oxygen rebound step to lead to an adamantanol complex. The activation energies for the C-H cleavage step are 6.9 kcal/mol in the 1-adamantanol pathway and 8.4 kcal/mol in the 2-adamantanol pathway, respectively, at the B3LYP/6-311++G level of theory, whereas those of the second reaction step corresponding to the rebound step are relatively small. Thus, the rate-determining step in the two pathways is the C-H bond dissociation step, which is relevant to the regioselectivity for adamantane hydroxylation. The relative rate constant (3 degrees )/(2 degrees ) for the competing H-atom abstraction reactions is calculated to be 9.30 at 75 degrees C, which is fully consistent with an experimental value of 10.1.

Journal Article↗
PubMed2003

Novel class of tertiary phosphine ligands based on a phospha-adamantane framework and use in the Suzuki cross-coupling reactions of aryl halides under mild conditions.

[reaction: see text] A new class of sterically hindered phosphines based on a phospha-adamantane framework is described. Arylation or alkylation of the 1,3,5,7-tetramethyl-2,4,8-trioxa-6-phospha-adamantane system allows for the preparation of tertiary phosphines suitable for use in palladium-catalyzed cross-coupling reactions. For example, use of a catalytic system incorporating Pd(2)(dba)(3) and 1,3,5,7-tetramethyl-2,4,8-trioxa-6-phenyl-6-phospha-adamantane is shown to promote the Suzuki cross-coupling of aryl iodides, bromides, and activated chlorides with a variety of aryl boronic acids at room temperature in a few hours with high yields.

Journal Article↗
PubMed1992

[Effect of various adamantane compounds on the reproduction of Sindbis virus. Isolation and properties of a resistant strain].

Rimantadine and its structural analogs, i. e. amide of 1-adamantane carboxylic acid (AACA) and 1-adamantane acetic acid amide, were shown to be able to inhibit reproduction of Sindbis virus in culture Vero cells. AACA had the maximum antiviral activity. Subcultures of the initial sensitive population of Sindbis virus in the presence of AACA led to formation of mutants resistant to AACA as well as to rimantadine, adamantane acetic acid amide and ammonium chloride. The Sindbis virus population was heterogenous in sensitivity to AACA, which was evident from isolation of separate clones with various levels of sensitivity to the above mentioned compounds from the population. It was found that reproduction of the AACA sensitive and resistant strains of Sindbis virus differed: the latent period of the resistant strain was 2 hours longer than that of the sensitive strain. The same effect was observed in the comparative study on synthesis of the virus-specific RNA.

Animals↗
PubMed1998

High-speed magic-angle spinning 13C MAS NMR spectra of adamantane: self-decoupling of the heteronuclear scalar interaction and proton spin diffusion.

We have investigated the carbon line shape of solid adamantane under high-speed magic-angle sample spinning (MAS) acquired without proton decoupling. The CH-group shows a spinning-speed-dependent line broadening while the CH2-group consists of a spinning-speed-independent sharp component and a spinning-speed-dependent broader part. These phenomena can be explained by self-decoupling of the J-interaction due to proton spin diffusion. Such a self-decoupling process can be described by a magnetization exchange process between the multiplet lines. Changing the spin-diffusion rate constant by off-resonance irradiation of the protons allows us to observe the full range from slow exchange to coalescence to fast exchange of the carbon spectra. One of the multiplet components in the CH2-group corresponds to a group spin of the protons of zero and therefore does not couple to the other protons. This gives rise to the sharp central line. The magnetization exchange rate constant between the different multiplet lines can be determined from the spectra and is a measure for the spinning-speed-dependent proton spin-diffusion rate constant. Even at an MAS speed of 30 kHz, proton spin diffusion is still observable despite the relatively weak intermolecular proton dipolar-coupling network in adamantane which results in a static proton line width of only 14 kHz (full width at half height).

Adamantane↗
PubMed2005

Regioselective hydroxylation of adamantane by Streptomyces griseoplanus cells.

Hydroxylation of adamantane using whole cells of bacteria, actinomyces, and molds was examined. The structure of the product was determined using gas chromatography (GC), nuclear magnetic resonance (NMR), and mass spectroscopy (MS). Among 470 strains tested, Streptomyces griseoplanus was highly regioselective to give 1-adamantanol (0.096 mmol) from adamantane (0.3 mmol) in a 32% molar conversion yield after 72-h cultivation in the presence of 3% (v/v) Tween 60. A P450 inhibitor such as 0.5 mM 1-aminobenzotriazole or menadione significantly inhibited the hydroxylation activity. These results suggested that a P450 oxidation system might be involved in this hydroxylation reaction.

Adamantane↗
PubMed2006

Increased adamantane resistance in influenza A(H3) viruses in Australia and neighbouring countries in 2005.

The prevention and control of disease caused by seasonal and potential pandemic influenza viruses is currently managed by the use influenza vaccines and antivirals. The adamantanes (amantadine and rimantadine) were the first antivirals licensed for use against influenza A viruses and have been used extensively in some countries. Since the early 2000s increased resistance to these drugs has been reported especially in the A(H3) viruses. In this study we analysed recent human influenza A strains isolated in Australia and regionally for evidence of resistance to adamantanes and found evidence of significant resistant emerging during 2005.

Adamantane↗
PubMed2006

Adamantane 11-beta-HSD-1 inhibitors: Application of an isocyanide multicomponent reaction.

A series of potent and selective adamantane aminoamide 11-beta-HSD-1 inhibitors has been optimized. Chemically these studies were expedited by utilizing readily obtained amino acids as starting materials or an isocyanide multicomponent reaction. Structure-activity relationship studies resulted in the discovery of dual human and mouse 11-beta-HSD-1 potent and selective inhibitors like adamantane 11 and related compounds with high metabolic stability and robust pharmacokinetic profiles.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2005

1H NMR studies on the hydrogen-bonding network in mono-altro-beta-cyclodextrin and its complex with adamantane-1-carboxylic acid.

The hydrogen-bond network in mono-altro-beta-cyclodextrin and in its inclusion complex with adamantane-1-carboxylic acid were investigated by (1)H NMR spectroscopy using the chemical shifts, temperature coefficients and vicinal coupling constants of the exchangeable hydroxy protons. The chemical shifts of the 3-OH signals indicated that the hydrogen-bond network between the 2-OH and 3-OH groups was disturbed not only on each side of the altrose residue, but also along the whole dextrin chain. Upon addition of adamantane-1-carboxylic acid, altrose underwent a conformational change from the (1)C(4) to the (O)S(2) form, allowing a more continuous belt of hydrogen bonding, as evidenced by the downfield shift experienced by the 3-OH proton signals of the glucose residues.

Adamantane↗
PubMed2004

Vibrational frequencies and structural determination of adamantane.

The normal mode frequencies and corresponding vibrational assignments of adamantane in Td symmetry are examined theoretically using the Gaussian 98 set of quantum chemistry codes. All normal modes were successfully assigned to one of eight types of motion predicted by a group theoretical analysis. The vibrational modes of the deuterated form of adamantane were also calculated and compared against experimental data.

Adamantane↗
PubMed1999

Inhibition of HIV-1 replication by newly developed adamantane-containing polyanionic agents.

Newly developed antiviral compounds consisting of an adamantane derivative chemically linked to a water-soluble polyanionic matrix were shown to inhibit HIV-1 infection in lymphoblastoid cells, HeLa CD4+ beta-galactosidase (MAGI) cells and macrophages. The effect of the compounds was recorded by measuring viral reverse transcriptase activity and p24 by ELISA in culture supernatant and by immunoblotting of cell lysates. In this paper we describe the data obtained with one of the most promising compounds, Amant. Amant was not toxic for the host cells at concentrations as high as 1 mg/ml. The inhibition of HIV-1 replication in MT-4 and MAGI cells was observed when Amant was added either before infection or with the virus (0 h of infection), and was expressed even when the compound added at 0 h was removed 1.5 h after infection. Its inhibitory concentration (IC50) against HIV-1 and HIV-2 replication was 2-6 and 93 microg/ml, respectively. The anti-HIV-1 effect of the compound was gradually decreased when it was added 1 and 2 h post infection, and no inhibition was observed when the compound was added 4 h after infection, suggesting that the compound as a membranotropic drug blocks an early step of replication. It completely prevented the transport of Gag proteins into the nuclei. Pretreatment of the virus with Amant did not reduce its infectious activity. The classical adamantane derivatives amantadine and rimantadine hydrochloride did not inhibit HIV replication.

Adamantane↗