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PubMed2003

Spiro[pyrrolidine-2,2'-adamantanes]: synthesis, anti-influenza virus activity and conformational properties.

Synthetic spiro[pyrrolidine-2,2'-adamantanes] 2, 3, 11, 15, 12, 16, 18, 20 were evaluated in vitro and found to be active anti-influenza virus A compounds; the effect of the position of C-Me pyrrolidine ring substituent on antiviral activity was examined. Pyrrolidine 5-Me substitution appears to be optimal for H(2)N(2) strain activity. From the four different possible protonated conformers, experimental observation using NMR spectroscopy and molecular mechanics calculations demonstrated only a pair of conformers A(+)H (N-Me (ps-ax), C-Me (ps-eq)) and B(+)H ((N-Me ps-ax, C-Me ps-ax)) which can contribute to the biological activity of C-Me, N-Me protonated derivatives 15(+)H, 16(+)H and 20(+)H. The relative populations were calculated from NMR spectra. For compounds 15(+)H and 20(+)H conformer A(+)H (cis dimethyl orientation) is the major one whereas a similar population of conformers A(+)H and B(+)H (trans dimethyl orientation) was observed for compound 16(+)H. Since this new series is characterized by a lipophilic part, that is the pyrrolidine ring, in addition to adamantane, that can interact with influenza A M2 protein, an ultimate future goal would be the in vitro mapping of M2 lipophilic pocket.

Adamantane↗
PubMed1991

Crystal structures of cytochrome P-450CAM complexed with camphane, thiocamphor, and adamantane: factors controlling P-450 substrate hydroxylation.

X-ray crystal structures have been determined for complexes of cytochrome P-450CAM with the substrates camphane, adamantane, and thiocamphor. Unlike the natural substrate camphor, which hydrogen bonds to Tyr96 and is metabolized to a single product, camphane, adamantane and thiocamphor do not hydrogen bond to the enzyme and all are hydroxylated at multiple positions. Evidently the lack of a substrate-enzyme hydrogen bond allows substrates greater mobility in the active site, explaining this lower regiospecificity of metabolism as well as the inability of these substrates to displace the distal ligand to the heme iron. Tyr96 is a ligand, via its carbonyl oxygen atom, to a cation that is thought to stabilize the camphor-P-450CAM complex [Poulos, T. L., Finzel, B. C., & Howard, A. J. (1987) J. Mol. Biol. 195, 687-700]. The occupancy and temperature factor of the cationic site are lower and higher, respectively, in the presence of the non-hydrogen-bonding substrates investigated here than in the presence of camphor, underscoring the relationship between cation and substrate binding. Thiocamphor gave the most unexpected orientation in the active site of any of the substrates we have investigated to date. The orientation of thiocamphor is quite different from that of camphor. That is, carbons 5 and 6, at which thiocamphor is primarily hydroxylated [Atkins, W. M., & Sligar, S. G. (1988) J. Biol. Chem. 263, 18842-18849], are positioned near Tyr96 rather than near the heme iron. Therefore, the crystallographically observed thiocamphor-P-450CAM structure may correspond to a nonproductive complex. Disordered solvent has been identified in the active site in the presence of uncoupling substrates that channel reducing equivalents away from substrate hydroxylation toward hydrogen peroxide and/or "excess" water production. A buried solvent molecule has also been identified, which may promote uncoupling by moving from an internal location to the active site in the presence of highly mobile substrates.

Adamantane↗
PubMed2003

Nanoscale tripodal 1,3,5,7-tetrasubstituted adamantanes for AFM applications.

The synthesis of four novel nanoscale 1,3,5,7-tetrasubstituted adamantanes 22 and 25-27 designed for atomic force microscopy (AFM) applications is described. Each tetrahedrally shaped molecule incorporates a broad tripodal base made up of three identical legs that terminate with a sulfur-containing moiety, which is either a 4-acetylsulfanylmethylphenyl unit or else a (1,2,5-dithiazepan-1-yl)phenyl unit. The sulfur atoms are intended for eventual binding of the molecule multivalently to the apex of a gold-coated commercial AFM tip through formation of multiple S-Au bonds. In each molecule, the fourth terminus is a para-substituted benzoic acid methyl ester that is designed to scan the sample. We demonstrate that 27 is sufficiently large and rigid to be imaged by a conventional AFM tip. Adamantanes 22 and 25-27 may also find application as chemically well-defined nanoscale objects for calibration of AFM tips.

Adamantane↗
PubMed2004

Synthesis of well-defined tower-shaped 1,3,5-trisubstituted adamantanes incorporating a macrocyclic trilactam ring system.

We describe the synthesis of two novel well-defined tower-shaped 1,3,5-trisubstituted adamantanes 30 and 33 that incorporate a macrocyclic trilactam ring system. Each nanoscale molecule has a broad tripodal base consisting of three identical sulfur-containing termini as the tripod feet, 4-acetylsulfanylmethylphenyl units in the case of 30 and 3,5-bis(acetylsulfanylmethyl)phenyl units in the case of 33. The sulfur atoms are designed to bind the molecules trivalently to the apex of a gold-coated commercial AFM tip through formation of three S-Au bonds. The rigid adamantane-derived head unit with a single hydrogen atom at the apex is designed to scan the sample. Molecules 30 and 33 are synthesized from 1,3,5-triethynyladamantane by a series of Sonogashira coupling reactions involving terminal alkynes and aryl iodides. A macrocyclic trilactam unit is included for added rigidity. We demonstrate that molecule 30 is sufficiently large and rigid to be visualized by a conventional AFM tip. These nanoscale molecules may also find application as chemically well-defined nanoscale objects for calibration of AFM tips.

Adamantane↗
PubMed2004

Photochemical preparation of 1,3,5,7-tetracyanoadamantane and its conversion to 1,3,5,7-tetrakis(aminomethyl)adamantane.

New adamantane derivatives 1 and 2 that bear functionalized one-carbon extensions at all four bridgehead positions have been prepared. Radical nucleophilic substitution (S(RN)1) reaction of 1,3,5,7-tetrabromoadamantane with cyanide produces 1,3,5,7-tetracyanoadamantane (1), which was reduced with borane reagents to 1,3,5,7-tetrakis(aminomethyl)adamantane (2). Improvements in the preparation of 1,3,5,7-tetrahaloadamantanes (halogen = Br, Cl, I) are also reported. [structure--see text]

Adamantane↗
PubMed2004

Synthesis of rigid multivalent scaffolds based on adamantane.

An efficient route to novel 1,3,5,7-tetrasubstituted derivatives of adamantane is described. This route starts from adamantane and gives the tetrafunctionalized derivative 9 in eight steps with an overall yield of 23%. These tetrahedrally shaped molecules possess three identical arms terminated by an activated carboxylic acid derivative and a protected amino function in the 1-position. We propose these tetravalent cage compounds such as 9 as scaffolds for the assembly of ligand/marker conjugates for studies of multivalent ligand receptor interactions. [reaction: see text]

Adamantane↗
PubMed2004

Bowdichine, a new diaza-adamantane alkaloid from Bowdichia virgilioides.

A novel alkaloid named bowdichine (1), only the third with a diaza-adamantane skeleton containing an unusual N-acetyl enamine moiety, and the known alkaloids acosmine (2), ormosanine (3) and podopetaline (4) have been isolated from the stem bark of Bowdichia virgilioides. The structures were elucidated on the basis of spectral data, mainly 1D and 2D NMR of the diaza-adamantane alkaloids 1 and 2.

Adamantane↗
PubMed1987

Adamantane derivatives: a new class of insulin secretagogues.

Adamantane derivatives were found to increase insulin release in vitro. Mouse islets were used to study the mechanisms and molecular requirements of that hitherto unrecognised property. At a non-stimulatory concentration of glucose (3 mM), 1-adamantanamine (1 mM) reversibly inhibited 86Rb efflux from islet cells, depolarized the beta-cell membrane, induced electrical activity, stimulated 45Ca uptake and efflux, and triggered insulin release. Omission of extracellular Ca2+ abolished the secretory response but only partially inhibited the acceleration of 45Ca efflux. At a stimulatory concentration of glucose (10 mM), 1-adamantanamine reversibly increased 86Rb efflux, potentiated electrical activity (lengthening of the slow waves with spikes), augmented 45Ca uptake and efflux, and increased insulin release. The effects of adamantanamine were dose-dependent, with a threshold concentration of 10 microM for stimulation release. 2-Adamantanamine was as potent as 1-adamantanamine. In contrast, substitution of the amino group by a carboxyl group (1-adamantanecarboxylic acid) decreased the effectiveness by about 65%, and substitution by a hydroxyl group (1-adamantanol) suppressed it. It is concluded that adamantane derivatives bearing an amino group decrease K+ permeability of the beta-cell membrane and thereby cause depolarization. This activates voltage-dependent Ca channels, permits Ca2+ influx and eventually stimulates insulin release. They may also mobilize cellular Ca2+, but this effect is not sufficient to cause release.

Adamantane↗
PubMed2006

Resistance to anti-influenza drugs: adamantanes and neuraminidase inhibitors.

Development of effective drugs for the treatment or prevention of epidemic and pandemic influenza is important in order to reduce its impact. Adamantanes and neuraminidase inhibitors are two classes of anti-influenza drugs available for influenza therapy currently. However, emergence of resistance to these drugs has been detected, which raises concerns regarding their widespread use. In this review, resistance to the adamantanes and neuraminidase inhibitors will be discussed in relation to both epidemic and pandemic influenza viruses.

Adamantane↗
PubMed1999

[Adamantane derivatives enhancing body's resistance to emergencies].

A total of 329 novel adamantane derivatives have been synthesized and pharmacologically studied. Among them, the compounds containing halogen-containing aromatic radicals in the second position show the most pronounced effect on animal resistance to the emergencies induced by its habitat and performance. N-(2-adamantyl)-N-(para-bromphenyl)amine (bromantane) possesses a low toxicity, a high ability to enhance the physical and operant working maintenance of animals, to accelerate its recovery in developed fatigue, in hyperthermia and hypoxia in particular. 2-(para-chlorobenzoylamine)adamantane (chlodantane) has the processes of a rapid-action adaptogenic agent by enhancing the resistance of animals to various physical and toxically chemical noxious agents. The two compounds have immunostimulating effects in secondary stress-induced immunodeficiencies whose mechanism of action is a membranous protective activity.

Adamantane↗
PubMed2000

Synthesis and antimicrobial activity of new adamantane derivatives I.

A series of fourteen derivatives of adamantane was synthesised. The new compound 4-(adamant-1-ylmethoxycarbonyl)phthalanhydride obtained from 1-adamantane-methanol and trimellitic anhydride chloride appeared very useful for preparation of a number of N-substituted phthalimides. Antimicrobial activity of the newly obtained derivatives such as, for example, 4-(adamant-1-ylmethoxycarbonyl)-N-(5-carboxypentamethylene)p hthalimide or 4-(adamant-1-ylmethoxycarbonyl)-N-(L-alanyl)phthalimide was tested against Staphylococcus aureus, Bacillus sp., Micrococcus flavus and Enterococcus faecium. The minimal inhibitory concentration (MIC) for these compounds against S. aureus were 0.022 and 0.05 microg/ml, respectively.

Adamantane↗
PubMed2001

Therapeutical effect of modified adamantane copolymer compounds: study of molecular mechanisms.

Copolymers of N-polyvinylpyrrolidone-acrylic acid (AB-1) and adamantane derivatives are known to possess marked antiviral activity in in vitro and in ovo models. Among the constructed preparations of AB-1 modified by adamantane derivatives some, especially AB-4 (modified by deitiforin), were found to show more extended antiviral activity and to inhibit markedly virus reproduction in susceptible permissive cell cultures and chicken embryos. In AB-4 treated cells and allantoic sacs, virus titers (influenza virus, herpes virus, and HIV) and virus antigen concentration were decreased. On the other hand, herpes virus-specific thymidine kinase and of DNA-polymerases isolated from Escherichia coli, Plectonema boryanum, and herpes virus type 1 infected murine brain tissue retained their activity after incubation with AB-4 or AB-2. The compounds investigated, in view of their effect on virus reproduction, are thought to be prospective as antiviral agents.

Adamantane↗
PubMed2003

[HIV-inhibiting activity of polyanion matrices and related substances containing adamantane and norbornene pharmacophores].

Analysis of molecular mechanisms of HIV-infection and targets for therapeutic intervention allowed to offer strategy for design of new effective anti-HIV/AIDS agents on the basis of two key principles: 1) intervention to infectious process beginning from the earliest stages of the virus penetration into cells; 2) blockade of not only one but several molecular targets of the HIV life cycle. The paper presents the results of the in vitro investigation of the anti-HIV activity (against several HIV-1 strains, including AZT-resistant ones) of new generation complex substances synthesized with application of the molecular substrategy for bifunctional inhibitors on the basis of a combination of nonspecific antiviral active polymeric anions with selective virus sensitive membranotropic pharmacophores of the adamantane and norbornene lines. The HIV-1 inhibiting potential of polymeric carboxylic acids (PKA) of various nature: synthetic polymeric analogues of succinic acid and carboxymethylated dextran was evaluated. It was shown that the antiviral action of PKA is located at the initial stages of HIV-1 penetration into cells and is markedly defined by balance of electrostatic activity and conformational mobility of the macromolecules. This corresponds to the evidence of the negatively charged macromolecules ability to bind the positively charged V3 loop within the viral protein gp120, preventing the HIV-1 adsorption on the surface of permissive cells. Chemical conjugation of the PKA with derivatives of the adamantane (amantadine and rimantadine analogues) or norbornene (related to deitiforin and natural bicyclic therpenoids) via spacer groups provides synergistic elevation of the anti-HIV-1 activity, first of all for the flexible chain PKA. The obtained result experimentally confirmed the theoretically predicted expansion of the anti-HIV-1 action of the bifunctional kind antivirals due to cooperation of the electrostatic potential of PKA with the virus specific hydrophobic activity needed to block postadsorption events of the HIV-1 life cycle, including both the virus penetration into cells and the virus posterity release from the infected cells. Additional cooperation of PKA with some special vectors targeted towards "Raft" domains of cellular membranes, epicentres for natural location of initial and completed stages of the HIV-1 replication cycle was also shown promising. The structure-function optimized samples exhibit high indexes of anti-HIV-1 selectivity up to IS50 = 10000.

Adamantane↗
PubMed2006

The antitumor effect of a novel differentiation inducer, 2, 2-Bis (4-(4-amino-3-hydroxyphenoxy) phenyl) adamantane (DPA), in combinatory therapy on human colon cancer.

An adamantane derivative, 2, 2-Bis (4-(4-amino-3-hydroxyphenoxy) phenyl) adamantane (DPA), was found to inhibit the growth of several cancer cell lines in the National Cancer Institute (NCI) Anticancer Drug Screen system. Our previous study showed that DPA inhibited the growth of human colon cancer cell Colo 205 xenografts. DPA-treated cells were arrested at G(0)/G(1), and the DPA-induced cell growth inhibition was irreversible after removal of DPA. Moreover, no acute toxicity was observed after an intra-peritoneal challenge of DPA in nude mice weekly. In this study, we examined the in vivo therapeutic potential of DPA combined with clinical chemotherapeutic agent CPT-11 in Colo 205 cell xenografts. The in vitro cytostatic and differentiative effects of DPA on human colon cancer cells was also evaluated. DPA exerted growth inhibitory activities in vitro against three human colon cancer cell lines (Colo 205, HT-29, and HCT-15). DPA-treated cells showed a more adhesive epithelial phenotype. The differentiation markers of carcinoembryonic antigen (CEA) and fibronectin (FN) were significantly increased in colon cancer cells after treatment with DPA. Further studies showed the induction of p21/Cip1, p27/Kip1, E-cadherin and dephosphorylated p120ctn expression was involved in DPA-induced anticancer effects. Interestingly, DPA-induced elevation of p21/Cip1 was independent of the induction of p53 in Colo 205 cells. in vivo results demonstrated that DPA enhanced the in vivo anticancer activity of the chemotherapeutic agent, CPT-11, by elevation of p53-independent p21/Cip1 and p27/Kip1 expression. Our results suggest that DPA appears to be a new potentially less toxic modality of cancer combinatory therapy.

Adamantane↗
PubMedDate not supplied

[Tranquilizing activity of adamantane derivatives].

It was established in experiments on mice and rats carried out according to conventional procedures that 13 adamantane derivatives have a greater tranquilizing activity than amantadine, 3-bromadamantoyl-1 diazomethane exerting a stronger effect than trioxazin. Two adamantane derivatives were found to have an anticonvulsant activity.

Adamantane↗
PubMedDate not supplied

[Effect of amantadine (1-aminoadamantane) and remantadine (alpha-methyl-1-adamantane methyl amine) hydrochlorides on formation of influenza A viral proteins].

Inhibitory effect of amantadine (I-amino adamantane) and remantadine (alpha-methyl-1-adamantane methylamine) hydrochlorides on reproduction of influenza A virus as well as, in particular, on formation of virus specific proteins was studied in cell culture. These drugs were dissimilar; they resembled each other in the patients of their effect as a function of the course of administration into the cells infected with the virus. Both preparations inhibited the synthesis of virus specific proteins exhibiting distinct effects under conditions of preliminary or immediate administration following the infection. At the same time, the inhibitory properties of remantadine were maintained at the subsequent period after infection; these were not observed in the amantadine treatment.

Adamantane↗
PubMed1994

[The blockade of glutaminergic and cholinergic ion channels by adamantane derivatives].

It has been shown that a homologous series of adamantane derivatives of general structure Ad-CH2-N+H2-(CH2)5-N+R3, where Ad, adamantane, R varied from H (hydrogen) to t-Bu (tertiary butyl), blocks the open state of postsynaptic activated channels. In the presence of the drugs studied the decay of evoked cholinergic postsynaptic currents in frog neuromuscular junction could be fitted by two exponentials. However, the rate constants of interaction of blocker with channel did not depend on the R structure and membrane potential. The rate of blockade of glutamatergic postsynaptic currents in insect neuromuscular junction increased as the radicals at nitrogen atom became heavier, but was independent on membrane potential. The drugs studied affected in voltage dependent manner the kinetic properties of single channels (recorded in outside-out patches excised from cultured neurones of embryonic rat brain cortex) induced by NMDA application. Each of these compounds evoked fast flickering of single channels between an open and blocked state. Drugs effectively prevented the convulsions evoked by intraventricular injection of NMDA into mouse brain. The compound IEM-1754 that was the most potent blocker in the experiments on NMDA-activated single channels possessed six times higher anticonvulsant activity than dizocilpine (MK-801).

Adamantane↗
PubMed1995

Novel adamantane derivatives act as blockers of open ligand-gated channels and as anticonvulsants.

We examined the influence of the molecular structure of four novel adamantane derivatives on their ability to block the channels of nicotinic acetylcholine (ACh) and N-methyl-D-aspartate (NMDA) receptors. The structure of the drugs is Ad-CH2-N+H2-(CH2)5-R, where Ad is adamantane and R was varied from ammonium (IEM-1754) to tert-butyldimethylammonium (IEM-1857) radical. The compounds induced double-exponential decays of postsynaptic currents in frog muscles and flickering of NMDA-activated channels, suggesting that each drug acts as a fast open-channel blocker at both types of receptors. The equilibrium dissociation constants (Kd) of the drugs for ACh-activated channels at -80 mV were similar, whereas the Kd values for NMDA-activated channels at -80 mV were 2-10 times lower. Several observations suggested that occupation of either type of channel by these compounds inhibited channel closure; the time constant (tau) of the slow component of the decay of postsynaptic currents in the presence of each compound was greater than the control tau, the IC50 of IEM-1754 for inhibition of NMDA-activated whole-cell currents was > 20 times larger than its Kd for the open channel, and a transient increase in NMDA-activated whole-cell currents was observed after washout of IEM-1754. Thus, these drugs appear to act on nicotinic ACh and NMDA receptors via similar mechanisms, although the voltage dependence of block suggested that the drugs bind at a more superficial site in the ACh-activated channel. All compounds also potently prevented NMDA-induced convulsions in mice. The ED50 of IEM-1754 was 4 times lower than the ED50 of MK-801.

Adamantane↗