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PubMed2006

Discovery of adamantane ethers as inhibitors of 11beta-HSD-1: Synthesis and biological evaluation.

A novel class of adamantane ethers 11beta-hydroxysteroid hydrogenase type I inhibitors has been discovered. These compounds have excellent HSD-1 potency and selectivity against HSD-2. The structure-activity relationships, selectivity, metabolism, PK, ex vivo pharmacodynamic data, and an X-ray crystal structure of one of these inhibitors bound to h-HSD-1 are discussed.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2005

The adamantane-derived bananins are potent inhibitors of the helicase activities and replication of SARS coronavirus.

Bananins are a class of antiviral compounds with a unique structural signature incorporating a trioxa-adamantane moiety covalently bound to a pyridoxal derivative. Six members of this class of compounds: bananin, iodobananin, vanillinbananin, ansabananin, eubananin, and adeninobananin were synthesized and tested as inhibitors of the SARS Coronavirus (SCV) helicase. Bananin, iodobananin, vanillinbananin, and eubananin were effective inhibitors of the ATPase activity of the SCV helicase with IC50 values in the range 0.5-3 microM. A similar trend, though at slightly higher inhibitor concentrations, was observed for inhibition of the helicase activities, using a FRET-based fluorescent assay. In a cell culture system of SCV, bananin exhibited an EC50 of less than 10 microM and a CC50 of over 300 microM. Kinetics of inhibition are consistent with bananin inhibiting an intracellular process or processes involved in SCV replication.

Adamantane↗
PubMed2004

Inhibition of glycolipid biosynthesis by N-(5-adamantane-1-yl-methoxy-pentyl)-deoxynojirimycin protects against the inflammatory response in hapten-induced colitis.

Since glycolipid biosynthesis is potentially involved in immunological and inflammatory responses, we tested the effect of a novel inhibitor of intracellular glycolipid biosynthesis N-(5-adamantane-1-yl-methoxy-pentyl)-deoxynojirimycin (AMP-DNM) in two hapten-induced colitis models: trinitrobenzene sulphonic acid (TNBS)- and oxazolone (4-ethoxymethylene-2phenyl-2oxazoline-5-one; Oxa)-induced colitis. AMP-DNM was given either by intraperitoneal injection or orally via the diet. Mice treated with AMP-DNM had less severe colitis and a more rapid weight recovery, less edema and less wall thickness. Cellular infiltration, goblet cell loss and myeloperoxidase (MPO) activity were reduced in colons of AMP-DNM-treated animals. Intralesional IFN-gamma and IL-18 production were lower in mice of the AMP-DNM-treated groups. Furthermore, AMP-DNM treatment reduced the serum anti-TNBS and anti-Oxa antibody levels. Our findings show that the glycolipid biosynthesis inhibitor AMP-DNM has a strong anti-inflammatory and immune suppressive activity on both TNBS- and Oxa-induced colitis. The data also provide evidence that glycolipid biosynthesis is involved in the inflammatory cascade in these inflammatory bowel disease (IBD) models.

1-Deoxynojirimycin↗
PubMed2006

In vitro biological efficiency of tenocyclidine-TCP and its adamantane derivative TAMORF.

Tenocyclidine-TCP showing a broad spectrum of pharmacological activity including antidotal effect in organophosphorus compounds poisoning, radioprotective and anticancer effects. We investigated in vitro interactions of TCP and its adamantane derivative--TAMORF with human erythrocyte acetylcholinesterase (AChE). Moreover, their genotoxicity and radioprotective activity on human white blood cells were studied using the alkaline comet assay, viability testing and the analysis of the structural chromosome aberrations. The tested compounds were found to be weak inhibitors of AChE, for TCP IC(50)=1 x 10(-5)M and for TAMORF IC(50)>1 x 10(-3)M, without reactivating and protective effects on AChE inhibited by soman. Results suggest that TCP modified by the replacement of the cyclohexyl ring with an adamantly ring and piperidine with morpholine group (TAMORF) have lower toxicity. Both compounds possess low cytotoxicity and radioprotective activity, but TAMORF also shows cell growth inhibitory effects. To clarify differences in their biological efficiency observed in vitro and in vivo, additional analyses are necessary. Since TAMORF was found to significantly inhibit cell growth and proliferation in vitro, it is reasonably to consider it as a source molecule promising for further modifications and development of more potent substances with antitumor properties rather then radioprotector or antidote in organophosphorus poisoning.

Adamantane↗
PubMed1998

Two blocking sites of amino-adamantane derivatives in open N-methyl-D-aspartate channels.

Using whole-cell patch-clamp techniques, we studied the blockade of open N-methyl-D-aspartate (NMDA) channels by amino-adamantane derivatives (AADs) in rat hippocampal neurons acutely isolated by the vibrodissociation method. The rapid concentration-jump technique was used to replace superfusion solutions. A kinetic analysis of the interaction of AAD with open NMDA channels revealed fast and slow components of their blockade and recovery. Mathematical modeling showed that these kinetic components are evidence for two distinct blocking sites of AADs in open NMDA channels. A comparative analysis of different simplest models led us to conclude that these AAD blocking sites can be simultaneously occupied by two blocker molecules. The voltage dependence of the AAD block suggested that both sites were located deep in the channel pore.

Adamantane↗
PubMedDate not supplied

Synthesis and antimicrobial activity of new adamantane derivatives II.

A series of new derivatives of adamantane was synthesised. The new compound 4-(adamant-1-ylethylenoxycarbonyl)phthalanhydride obtained from 1-adamantaneethanol and trimellitic anhydride chloride, as well as 4-(adamant-1-ylmethylenoxycarbonyl)phthalanhydride, appeared very useful for preparation of a number of N-substituted phthalimides. Antimicrobial activity of newly obtained derivatives such as, for example, 4-(adamant-1-ylethylenoxycarbonyl)-N-(L-phenylalanyl)phthalimide or 4-(adamant-1-ylmethylenoxycarbonyl)-N-(L-leucyl)-phthalimide was tested against Staphylococcus aureus, Bacillus sp., Micrococcus flavus and Enterococcus faecium. The minimal inhibitory concentrations for these compounds against Bacillus cereus were 15 and 8 microg/ml, respectively.

Adamantane↗
PubMed1984

Purification of the membrane-spanning tryptic peptides of the alpha polypeptide from sodium and potassium ion activated adenosinetriphosphatase labeled with 1-tritiospiro[adamantane-4,3'-diazirine].

Five long, membrane-spanning tryptic peptides from the alpha polypeptide of sodium and potassium ion activated adenosinetriphosphatase [(Na+ + K+)-ATPase] have been purified. (Na+ + K+)-ATPase, isolated from canine kidney, was exposed to ultraviolet light in the presence of a high concentration of 1-tritiospiro[adamantane-4,3'-diazirine], a carbene precursor that partitions into the bilayer of the membrane. The alpha polypeptide, modified with 1.2 mol of [3H]adamantylidene (mol of polypeptide)-1, was isolated and digested with trypsin. Digestion with trypsin ensures that membrane-spanning sequences remain intact during the digestion, since lysine and arginine, being extremely hydrophilic, rarely appear in the membrane-embedded regions of membrane proteins. This digestion produced radioactive tryptic peptides greater than 25 residues in length. The tryptic digest of the labeled alpha polypeptide was chromatographed on Sephadex LH-60 in ethanol-formic acid, 4:1. The majority of the radioactivity (87%) eluted with distribution coefficients corresponding to peptides longer than melittin (26 residues), whereas 73% of the protein traveled with distribution coefficients corresponding to peptides less than 30 residues in length. Five radioactive peptides were further purified by high-pressure liquid chromatography, and each peptide displayed a unique, hydrophobic amino-terminal sequence. No other candidates could be found when a search for additional membrane-spanning peptides was conducted. Gel filtration of the tryptic peptides from the alpha polypeptide of (Na+ + K+)-ATPase labeled with 5-[125I]iodo-1-naphthyl azide, a lipophilic nitrene precursor, produced no additional radioactive components. Amino-terminal sequences and amino acid compositions of the five purified peptides are presented.

Adamantane↗
PubMed2005

Tuning tetranuclear manganese-oxo core electronic properties: adamantane-shaped complexes synthesized by ligand exchange.

A series of adamantane-shaped [Mn4O6]4+ aggregates has been prepared. Ligand substitution reactions of [Mn4O6(bpea)4](ClO4)4 (1) with tridentate amine and iminodicarboxylate ligands in acetonitrile affords derivative clusters [Mn4O6(tacn)4](ClO4)4 (4), [Mn4O6(bpea)2(dien)2](ClO4)4)(5), [Mn4O6(Medien)4](ClO4)4 (6), [Mn4O6(tach)4](ClO4)4 (7), [Mn4O6(bpea)2(me-ida)2] (8), [Mn4O6(bpea)2(bz-ida)2] (9), [Mn4O6(bpea)2((t)bu-ida)2] (10), and [Mn4O6(bpea)2((c)pent-ida)2] (11) generally on the order of 10 min with retention of core nuclearity and oxidation state. Of these complexes, only 4 had been synthesized previously. Characterization of two members of this series by X-ray crystallography reveals that compound 7 crystallizes as [Mn4O6(tach)4](ClO4)4 x 3CH3CN x 4.5H2O in the cubic space group Fmm and compound 11 crystallizes as [Mn4O6(bpea)2((c)pent-ida)2].7MeOH in the monoclinic space group C2/c. The unique substitution chemistry of 1 with iminodicarboxylate ligands afforded asymmetrically ligated complexes 8-11, the mixed ligand nature of which is most likely unachievable using self-assembly synthetic methods. A special feature of the iminodicarboxylate ligand complexes 8-11 is the substantial site differentiation of the oxo bridges of the [Mn4O6]4+ cores. While there are four site-differentiated oxo bridges in 8, the solution structural symmetry of 8H+ reveals essentially a single protonation isomer, in contrast to the observation of two protonation isomers for 1H+, one for each of the site-differentiated oxo bridges in 1. Magnetic susceptibility measurements on 4, 7, 8, and 9 indicate that each complex is overall ferromagnetically coupled, and variable-field magnetization data for 7 and 9 are consistent with an S = 6 ground state. Electrochemical analysis demonstrates that ligand substitution of bpea affords accessibility to the Mn(V)(Mn(IV))3 oxidation state.

Adamantane↗
PubMed2002

FTIR spectra and normal-mode analysis of a tetranuclear manganese adamantane-like complex in two electrochemically prepared oxidation states: relevance to the oxygen-evolving complex of photosystem II.

The IR spectra and normal-mode analysis of the adamantane-like compound [Mn(4)O(6)(bpea)(4)](n+) (bpea = N,N-bis(2-pyridylmethyl)ethylamine) in two oxidation states, Mn(IV)(4) and Mn(III)Mn(IV)(3), that are relevant to the oxygen-evolving complex of photosystem II are presented. Mn-O vibrational modes are identified with isotopic exchange, (16)O-->(18)O, of the mono-micro-oxo bridging atoms in the complex. IR spectra of the Mn(III)Mn(IV)(3) species are obtained by electrochemical reduction of the Mn(IV)(4) species using a spectroelectrochemical cell, based on attenuated total reflection [Visser, H.; et al. Anal. Chem. 2001, 73, 4374-4378]. A novel method of subtraction is used to reduce background contributions from solvent and ligand modes, and the difference and double-difference spectra are used in identifying Mn-O bridging modes that are sensitive to oxidation state change. Two strong IR bands are observed for the Mn(IV)(4) species at 745 and 707 cm(-1), and a weaker band is observed at 510 cm(-1). Upon reduction, the Mn(III)Mn(IV)(3) species exhibits two strong IR bands at 745 and 680 cm(-1), and several weaker bands are observed in the 510-425 cm(-1) range. A normal-mode analysis is performed to assign all the relevant bridging modes in the oxidized Mn(IV)(4) and reduced Mn(III)Mn(IV)(3) species. The calculated force constants for the Mn(IV)(4) species are f(r)(IV)= 3.15 mdyn/A, f(rOr) = 0.55 mdyn/A, and f(rMnr) = 0.20 mdyn/A. The force constants for the Mn(III)Mn(IV)(3) species are f(r)(IV)= 3.10 mdyn/A, f(r)(III)= 2.45 mdyn/A, f(rOr) = 0.40 mdyn/A, and f(rMnr) = 0.15 mdyn/A. This study provides insights for the identification of Mn-O modes in the IR spectra of the photosynthetic oxygen-evolving complex during its catalytic cycle.

Adamantane↗
PubMed2003

Twisted amide reduction under Wolff-Kishner conditions: synthesis of a benzo-1-aza-adamantane derivative.

A synthesis of 4,5-benzo-1-aza-tricyclo[4.3.1.1(3,8)]undecane (1), a benzo-1-aza-adamantane derivative, is described and features a previously unknown application of the Wolff-Kishner reduction of a nonresonance stabilized or "twisted" amide. An intermediate amino ester is converted to a severely "twisted amide", which, when exposed to hydrazine in alcohol, provides the corresponding "twisted" amino hydrazone. Wolff-Kishner conditions (KOH/ethylene glycol, 200 degrees C) provide the reduced target 1 without hydrolysis to amino acid derivatives. These operations are conveniently performed in a single flask in high yield.

Adamantane↗
PubMed2005

Solutes probe hydration in specific association of cyclodextrin and adamantane.

Using microcalorimetry, we follow changes in the association free energy of beta-cyclodextrin (CD) with the hydrophobic part of adamantane carboxylate (AD) due to added salt or polar (net-neutral) solutes that are excluded from the molecular interacting surfaces. Changes in binding constants with solution osmotic pressure (water activity) translate into changes in the preferential hydration upon complex formation. We find that these changes correspond to a release of 15-25 solute-excluding waters upon CD/AD association. Reflecting the preferential interaction of solute with reactants versus products, we find that changes in hydration depend on the type of solute used. All solutes used here result in a large change in the enthalpy of the CD-AD binding reaction. In one class of solutes, the corresponding entropy change is much smaller, while in the other class, the entropy change almost fully compensates the solute-specific enthalpy. For many of the solutes, the number of waters released correlates well with their effect on air-water surface tensions. We corroborate these results using vapor pressure osmometry to probe individually the hydration of reactants and products of association, and we discuss the possible interactions and forces between cosolute and hydrophobic surfaces responsible for different kinds of solute exclusion.

Adamantane↗
PubMed1975

Biologically active polycycloalkanes. 1. Antiviral adamantane derivatives.

Convenient methods for the synthesis of 1-substituted 3-adamantyl chlorides and bromides (2), 1-adamantylphenols and -cresols (3), and 1-adamantylacetic (6) as well as 1,3-adamantanediacetic (11) acids are described. Several novel derivatives were synthesized from these key intermediates: adamantylcyclohexanols (4) and -cyclohexanones (5) from adamantylphenols (3), and esters (7,12, and 22), amides (13 and 18), thioamides (9 and 16), amidine (10), nitrile (15), and amines (14 and 17) from 1-adamantanecarboxylic (19) and -acetic (6) acids and 1,3-adamantanediacetic acid (11). Some adamantylpyrimidines (24) and -purines (25 and 26) were also prepared. Antiviral activities of the compounds obtained in this work and a series of new 1-adamantyl alkyl ketones synthesized before, together with those of some known adamantane derivatives, were tested in vitro on monolayer culture of chick ambryo fibroblasts against Newcastle disease virus.

Adamantane↗
PubMed2006

Computational studies of ethynyl- and diethynyl-expanded tetrahedranes, prismanes, cubanes, and adamantanes.

B3LYP/6-31+G(d) and MP2/6-31+G(d) computations were performed on a series of ethynyl- and diethynyl-expanded tetrahedranes, prismanes, cubanes and adamantanes. Every ethynyl expansion reduces the ring strain energy of the cage. The deprotonation energies of the cage poly-ynes are exceptionally low; we estimate that the gas-phase deprotonation energy of the diethynyl-expanded cubane is about 309 kcal mol(-1). The ring and cage poly-ynes can serve as effective hosts of either lithium or sodium cation, where the best host maximizes the number of interactions of alkynyl groups with the cation at an ideal distance. Last, the vertical excitation energies of the poly-ynes and their conjugate bases suggest that the alkynyl groups are interacting through space. The poly-ynes express a broad range of absorption energies, indicating that these molecules are potential targets in expressly designed optical applications.

Adamantane↗
PubMed2006

C-glycoside clustering on calix[4]arene, adamantane, and benzene scaffolds through 1,2,3-triazole linkers.

A route has been paved toward the preparation of triazole glycocluster libraries via the copper(I)-catalyzed modern version of the classical Huisgen 1,3-dipolar cycloaddition of azides to alkynes. Up to four 1,4-disubstituted 1,2,3-triazole rings bearing carbon-linked glycosyl fragments were constructed on various scaffolds via multiple cycloadditions of suitably polyfunctionalized calix[4]arene, adamantane, and benzene derivatives with ethynyl and azidomethyl C-glycosides. Each cycloaddition occurred with high regioselectivity to give exclusively the 1,4-disubstituted triazole ring in very high yield up to an average value of 98%. The high degree of efficiency of this approach and its wide scope constitute a simple and practical means for the attachment of various sugar units to polyfunctionalized substrates.

Adamantane↗
PubMed2006

Electron paramagnetic resonance study of the mononuclear Al species formed in the reaction of Al atoms and cyclopropylamine at 77 k in an adamantane matrix.

Ground-state Al atoms have been reacted with cyclopropylamine (CpNH2) in an adamantane matrix at 77 K. The four paramagnetic species generated in the reaction have been studied by electron paramagnetic resonance (EPR) spectroscopy and their magnetic parameters extracted from the EPR spectra. The isotropic Al hyperfine interactions (hfis) for these radicals vary from 801 to 962 MHz and are consistent with values previously reported for structurally similar Al-centered radicals. The major species formed in the reaction has a highly anisotropic a tensor indicative of an Al-centered radical with a substantial amount of the unpaired spin density residing in the Al 3p orbital. In addition, there is EPR evidence that the insertion products, CpNH(AlH) and CpAlNH2, are formed in the reaction, suggesting that Al atoms can activate the N-H and C-N bonds of amines. It has been shown that a molecule of CpNH2 coordinates to CpNH(AlH), causing the Al, N and H hfi of the N-H insertion product to decrease. The values of the nuclear hfis calculated for the insertion products, using a density functional theory (DFT) method, are comparable to the experimental values.

Adamantane↗
PubMed2005

Two mechanisms of action of the adamantane derivative IEM-1460 at human AMPA-type glutamate receptors.

1. Antagonizing glutamatergic neurotransmission by blockade of AMPA-type glutamate receptors (GluR) is a promising pharmacological strategy for neuroprotection in neurodegenerative diseases and acute treatment of stroke. 2. We investigated the interaction of the adamantane derivative IEM-1460 with human wild-type and mutant AMPA-type GluR channels. Different recombinant homooligomeric human AMPA-type GluR channels and a rat nondesensitizing mutant GluR (GluR2 L504Y) channel were expressed in HEK293 cells and investigated using the patch-clamp technique in combination with ultrafast agonist application. 3. When IEM-1460 was coapplied with glutamate, an open channel block mechanism was observed at slow desensitizing GluR2 flip (>/=0.1 mM IEM-1460) and nondesensitizing GluR2 L504Y channels (>/=1 microM IEM-1460). 4. A competitive block of AMPA-type channels was observed with IC(50) values for the dose block curves of 0.1 mM IEM-1460 at human unmutated and 10 microM IEM-1460 at mutant GluR channels. 5. Nondesensitizing GluR2 L504Y channels were used to further characterize the block mechanism. After equilibration with the agonist, a current decay upon coapplication of glutamate and IEM-1460 was observed. The recovery from block was independent of the glutamate and IEM-1460 concentration. The extent of current inhibition as well as the time constant of current decay upon addition of the blocker to the test solution were dependent on agonist concentration; this strongly points to an additional competitive-like block mechanism of IEM-1460 at human AMPA-type GluR channels. 6. The data were interpreted in the frame of a molecular scheme with two binding sites of IEM-1460 at the receptor, one at the unliganded resting and the other at the fully liganded open state of the channels.

Adamantane↗
PubMed2005

2:2 Fe(III):ligand and "adamantane core" 4:2 Fe(III):ligand (hydr)oxo complexes of an acyclic ditopic ligand.

A bis-hydroxo-bridged diiron(III) complex and a bis-mu-oxo-bis-mu-hydroxo-bridged tetrairon(III) complex are isolated from the reaction of 2,6-bis((N,N'-bis-(2-picolyl)amino)methyl)-4-tert-butylphenol (Hbpbp) with iron perchlorate in acidic and neutral solutions respectively. The X-ray structure of the dinuclear complex [{(Hbpbp)Fe([mu-OH)}(2)](ClO(4))(4).2C(3)H(6)O (1.2C3H6O) shows that only one of the metal-binding cavities of each ligand is occupied by an iron(III) atom and two [Fe(Hbpbp)]3+ units are linked together by two hydroxo bridging groups to form a [Fe(III)-(mu-OH)](2) rhomb structure with Fe...Fe = 3.109(1)A. The non-coordinated tertiary amine of Hbpbp is protonated. Magnetic susceptibility measurements show a well-behaved weak antiferromagnetic coupling between the two Fe(III) atoms, J= -8 cm(-1). The tetranuclear complex [(bpbp)(2)Fe(4)(mu-O)(2)(mu-OH)(2)](ClO(4))(4)(2) was isolated as two different solvates .4CH(3)OH and .6H(2)O with markedly different crystal morphologies at pH ca. 6. Complex .4CH(3)OH forms red cubic crystals and .6H(2)O forms green crystalline platelets. The Fe(4)O(6) core of shows an adamantane-like structure: The six bridging oxygen atoms are provided by the two phenolato groups of the two bpbp(-) ligands, two bridging oxo groups and two bridging hydroxo groups. The hydroxo and oxo ligands could be distinguished on the basis of Fe-O bond lengths of the two different octahedral iron sites: Fe-mu-OH, 1.953(5), 2.013(5)A and Fe-mu-O, 1.803(5), 1.802(5)A. The difference in ligand environment is too small for allowing Mossbauer spectroscopy to distinguish between the two crystallographically independent Fe sites. The best fit to the magnetic susceptibility of .4CH(3)OH was achieved by using three coupling constants J(Fe-OPh-Fe)= 2.6 cm(-1), J(Fe-OH-Fe)=-0.9 cm(-1), J(Fe-O-Fe)=-101 cm(-1) and iron(III) single ion ZFS (|D|= 0.15 cm(-1)).

Adamantane↗
PubMed2000

Downregulation of the p75 neurotrophin receptor in tissue culture and in vivo, using beta-cyclodextrin-adamantane-oligonucleotide conjugates.

Formation of complexes with beta-cyclodextrin derivatives via adamantyl groups was found to enhance the uptake and antisense efficacy of phosphorothioate oligos targeted to the p75 neurotrophin receptor in neuronally differentiated PC12 cells. After a 2-week course of systemic administration to mice (by intraperitoneal injection), there was evidence of a pronounced uptake of these oligos by the dorsal root ganglia (DRG), as well as by liver and kidney. There was no uptake by the brain. Consistent with uptake of antisense oligos by the DRG, systemic administration resulted in marked and consistent downregulation of p75 in DRG neurons. These results indicate that cyclodextrin-adamantane-oligo conjugates have great potential as agents to downregulate target genes in neurons, particularly in vivo in the peripheral nervous system.

Adamantane↗