Adamantane Skeleton Research Articles

The Structural Characteristics of Compounds Interacting with the Amantadine-Sensitive Drug Transport System at the Inner Blood–Retinal Barrier

Blood-to-retina transport across the inner blood-retinal barrier (BRB) is a key determinant of retinal drug concentration and pharmacological effect. Recently, we reported on the amantadine-sensitive drug transport system, which is different from well-characterized transporters, at the inner BRB. Since amantadine and its derivatives exhibit neuroprotective effects, it is expected that a detailed understanding of this transport system would lead to the efficient retinal delivery of these potential neuroprotective agents for the treatment of retinal diseases. The objective of this study was to characterize the structural features of compounds for the amantadine-sensitive transport system. Inhibition analysis conducted on a rat inner BRB model cell line indicated that the transport system strongly interacts with lipophilic amines, especially primary amines. In addition, lipophilic primary amines that have polar groups, such as hydroxy and carboxy groups, did not inhibit the amantadine transport system. Furthermore, certain types of primary amines with an adamantane skeleton or linear alkyl chain exhibited a competitive inhibition of amantadine uptake, suggesting that these compounds are potential substrates for the amantadine-sensitive drug transport system at the inner BRB. These results are helpful for producing the appropriate drug design to improve the blood-to-retina delivery of neuroprotective drugs.

Adamantane-Substituted Purines and Their β-Cyclodextrin Complexes: Synthesis and Biological Activity.

Cyclin-dependent kinases (CDKs) play an important role in the cell-division cycle. Synthetic inhibitors of CDKs are based on 2,6,9-trisubstituted purines and are developed as potential anticancer drugs; however, they have low solubility in water. In this study, we proved that the pharmaco-chemical properties of purine-based inhibitors can be improved by appropriate substitution with the adamantane moiety. We prepared ten new purine derivatives with adamantane skeletons that were linked at position 6 using phenylene spacers of variable geometry and polarity. We demonstrated that the adamantane skeleton does not compromise the biological activity, and some of the new purines displayed even higher inhibition activity towards CDK2/cyclin E than the parental compounds. These findings were supported by a docking study, which showed an adamantane scaffold inside the binding pocket participating in the complex stabilisation with non-polar interactions. In addition, we demonstrated that β-cyclodextrin (CD) increases the drug’s solubility in water, although this is at the cost of reducing the biochemical and cellular effect. Most likely, the drug concentration, which is necessary for target engagement, was decreased by competitive drug binding within the complex with β-CD.

Homoadamantane and Adamantane Acylphloroglucinols from Hypericum hirsutum.

1H NMR-guided fractionation of the petroleum ether extract of the aerial parts from Hypericum hirsutum yielded to the isolation of 19 polyprenylated polycyclic acylphloroglucinols. Structure elucidation based on 1D and 2D NMR spectroscopy together with high-resolution electrospray ionization mass spectroscopy revealed 14 acylphloroglucinols with a homoadamantane scaffold (1: -14: ), while 5 further compounds showed an adamantane skeleton (15: -19: ). Except for hookerione C (15: ), all isolated metabolites are hitherto unknown. While structurally-related metabolites have been isolated from other Hypericum species, it is the first report of admantan and homoadamantan type acylphloroglucinols in section Taeniocarpium Jaub. & Spach (Hypericaceae). The isolated compounds have been tested in a crystal violet-based in vitro assay on their properties to reduce the proliferation of human microvascular endothelial cells compared to hyperforin as the positive control. They showed a moderate reduction of proliferation with IC50 values in the range ~ 3 - 22 µM, with the homoadamantane-based compounds 2: and 4: being the most active. In addition, inhibition of the TNF-α-induced ICAM-1 expression was determined for 1: - 5, 7,: and 10: - 12: . Substances 3: and 12: reduced the ICAM-1 expression significantly (to 46.7% of control for 3: , 62.3% for 12,: at 50 µM).

Synthesis and Bioactivity of Thiosemicarbazones Containing Adamantane Skeletons.

Reaction of 4-(1-adamantyl)-3-thiosemicarbazide (1) with numerous substituted acetophenones and benzaldehydes yielded the corresponding thiosemicarbazones containing adamantane skeletons. The synthesized compounds were evaluated for their in vitro activities against some Gram-positive and Gram-negative bacteria, and the fungus Candida albicans, and cytotoxicity against four cancer cell lines (Hep3B, HeLa, A549, and MCF-7). All of them showed good antifungal activity against Candida albicans. Compounds 2c, 2d, 2g, 2j and 3a, 3e, 3g displayed significant inhibitory activity against Enterococcus faecalis. Compounds 2a, 2e, 2h, 2k and 3j had moderate inhibitory potency against Staphylococcus aureus. Compounds 2a, 2e and 2g found so good inhibitory effect on Bacillus cereus. Compounds 2d and 2h, which contain (ortho) hydroxyl groups on the phenyl ring, were shown to be good candidates as potential agents for killing the tested cancer cell lines, i.e., Hep3B, A549, and MCF-7. Compounds 2a–c, 2f, 2g, 2j, 2k, 3g, and 3i were moderate inhibitors against MCF-7.

Synthesis of Adamantane Aminoethers with Antitubercular Potential.

Intrigued by the fact that aminoadamantane derivatives, bearing the active 1,2-ethylenediamine moiety, are promising antitubercular agents, we report herein the synthesis and the antitubercular evaluation of N,N'-substituded-4,4'-[adamantane-2,2-diyl]bis(phe-noxyalkylamines) 1a-g, N,N'-substituded-4,4'-[adamantane-1,3-diyl]bis(phenoxyalkylamines) 2a-f, N,N'- substituded-[4-(1-adamantyl)phenoxy]alkylamines 3a-d and N,N'-substituded-[4-(2-adamantyl)- phenoxy]alkylamines 4a,b. A substituted diarylmethane moiety was introduced on the adamantane skeleton of the new derivatives. The synthesis of the above compounds involved the nucleophilic attack of the corresponding phenoxide, to the appropriate aminoalkylchloride hydrochloride under heating. The double substituted adamantane derivatives with an aminoether side chain exhibit significant activity against Mycobacterium tuberculosis. The length and the nature of the amino end of the side chain influence the antitubercular activity. The double phenolic substitution of the adamantane scaffold and the aminoether side chain with a three-methylene spacer between the phenoxy group and the nitrogen atom present the better results. (analogues 1f,g and 2e,f). These findings merit further investigation aiming at the design of more potent adamantane antituberculars, bearing a number of different substituents on the diarylmethane pharmacophore, which will also be translocated to other posititions on the adamantane ring.

Synthesis and Solution Properties of Adamantane Containing Quaternary Ammonium Salt-type Cationic Surfactants: Hydrocarbon–based, Fluorocarbonbased and Bola–type

Quaternary ammonium salt-type cationic surfactants with an adamantyl group (hydrocarbon-type; CnAdAB, fluorocarbon-type; CmFC3AdAB, bola-type; Ad-s-Ad, where n, m and s represent hydrocarbon chain lengths of 8-16, fluorocarbon chain lengths of 4-8, and spacer chain length of 10-12) were synthesized via quaternization of N, N-dimethylaminoadamantane and n-alkyl bromide or 1, n-dibromoalkane. Conductivity and surface tension were measured to characterize the solution properties of the synthesized adamantyl group-containing cationic surfactants. In addition, the effects of hydrocarbon and fluorocarbon chain lengths and spacer chain length between headgroups on the measured properties were evaluated by comparison with those of conventional cationic surfactants. The critical micelle concentration (CMC) of CnAdAB and Ad-s-Ad was 2/5 of that for the corresponding conventional surfactants CnTAB and bola-type surfactants with similar number of carbons in the alkyl or alkylene chain; this was because of the increased hydrophobicity due to the adamantyl group. A linear relationship between the logarithm of CMC and the hydrocarbon chain length for CnAdAB was observed, as well as for CnTAB. The slope of the linear correlation for both surfactants was almost the same, indicating that the adamantyl group does not affect the CMC with variations in the hydrocarbon chain length. Similar to conventional surfactants CnTAB, the hydrocarbon-type CnAdAB is highly efficient in reducing the surface tension of water, despite the large occupied area per molecule resulting from the relatively bulky structure of the adamantane skeleton. On the other hand, the bola-type Ad-s-Ad resulted in increased surface tension compared to CnAdAB, indicating that the curved chain between adamantyl groups leads to poor adsorption and orientation at the air-water interface.

Tetrasubstituted adamantane derivatives with arylamine groups: Solution-processable hole-transporting and host materials with high triplet energy and good thermal stability for organic light-emitting devices

Four new host/hole-transporting materials, namely 4,4′,4″,4‴-(adamantane-1,3,5,7-tetrayl)tetrakis(N,N-diphenylaniline) (4TPA-Ad, 1),4,4′,4″,4‴-(adamantane-1,3,5,7-tetrayl)tetrakis(N,N-di-p-tolylaniline) (4MTPA-Ad, 2), 1,3,5,7-tetrakis(4-(9H-carbazol-9-yl)phenyl)adamantane (4Cz-Ad, 3) and 1,3,5,7-tetrakis(4-(3,6-di-tert-butyl-9H-carbazol-9-yl)phenyl)adamantane (4tBuCz-Ad, 4), were designed and synthesized by incorporating four electron-donating arylamine units into the rigid adamantane skeleton via a simple C–N coupling reaction. Their thermal, photophysical and electrochemical properties were investigated. The molecular design endows the materials with high triplet energies of ∼3.0eV, good solution processability, high thermal stability and appropriate HOMO levels. Two types of electroluminescent devices using 1–4 as hole-transporting or host materials were fabricated. The device based on 2 as solution-processed hole-transporting material and tris(quinolin-8-yloxy)aluminum as an emitter revealed a maximum current efficiency of 4.2cdA−1, which was comparable with the TAPC-based control device. The sky-blue device employing 2 as solution-processed host material and 4,6-(difluorophenyl)pyridine-N,C2′)picolinate (FIrpic) as an emitter showed a maximum current efficiency of 16.6cdA−1 with Commission Internationale de I’Eclairage (CIE) coordinates of (0.16, 0.32).

ChemInform Abstract: Efficient Synthesis of 2,2,4,4,6,6‐Hexanitroadamantane under Mild Conditions.

AbstractTwo routes to 2,2,4,4,6,6‐hexanitroadamantane (IX) are described.

4,4,8,8‐Tetranitroadamantane‐2,6‐diyl Dinitrate: A High‐Density Energetic Material

AbstractThe novel high‐performance energetic material 4,4,8,8‐tetranitroadamantane‐2,6‐diyl dinitrate has been synthesized and fully characterized. The synthetic strategy features the construction of the adamantane skeleton with different functional groups at adjacent methylene carbon atoms to overcome the problems associated with the ortho effect and steric crowding, and is amenable to the synthesis of other polynitroadamantanes. The experimentally determined physical properties as well as the calculated detonation properties indicate that this compound exhibits high thermal stability (220 °C), high density (1.852 g cm–3), and excellent detonation velocities (8529 m s–1) and pressures (33.43 GPa).

Efficient Synthesis of 2,2,4,4,6,6-Hexanitroadamantane under Mild Conditions

Two strategies have been developed for the synthesis of 2,2,4,4,6,6-hexanitroadamantane (HNA). Both strategies used the readily available diethyl malonate and paraformaldehyde as the starting materials, and utilized acylation followed by intramolecular aldol condensation to construct the adamantane skeleton. The clean nitration to introduce the gem -dinitro groups onto the adamantane skeleton was conducted using dinitrogen pentoxide in refluxing dichloromethane in the presence of urea and 4 A molecular sieves. The acetylation route was accomplished via 12 steps and afforded HNA in an overall yield of 4.7%, and the formylation route was achieved via 11 steps in 14% overall yield.

Network of secondary‐substituted adamantane amines

The set of 42 diastereomeric structures resulting from various degrees of substitution of secondary –CH2– groups by amines –NH– within the adamantane skeleton are investigated. They are placed into a substitution‐reaction network viewed as a partial ordering, and the resultant reaction network (or Hasse diagram) displayed to illustrate different features. Ground‐state ab‐initio total energies of the 42 species are computed. A systematic cluster expansion of these total energies and associated internal energies is described in the context of this partial ordering. The results given support the idea, that recognition of the partial ordering is worthwhile. Copyright © 2013 John Wiley & Sons, Ltd.

Hydration of Adamantane Skeleton: Water Assembling around Amantadine and Halo-substituted Adamantanes

Abstract We performed Monte Carlo simulations to reveal the water distributions around adamantane derivatives. Adamantane derivatives attract water molecules, and specific water distributions are observed around the skeleton. Perfluoroadamantane attracts water more than adamantane.

ChemInform Abstract: Extended Pseudoasymmetry and Geometric Prochirality Clarifying the Scope of the Concepts of Holantimers and Stereoisograms

AbstractReview: 56 refs.

Solvent distributions, solvent orientations and specific hydration regions around 1-adamantyl chloride and adamantane in aqueous solution

Ab initio molecular orbital theory and Monte Carlo method with molecular mechanics are used to calculate the hydration numbers and solvent configurations around 1-adamantyl chloride in 324 water molecules. In the highest probability region for distribution of water molecules, a water molecule forms two hydrogen bonds with Cl and the adamantane skeleton; in the second highest probability region, a water molecule is located at the rear side. The CH⋯O interaction in the rear side is enhanced by the Cl substitution. The water orientation in the rear side of 1-adamantyl chloride is different from that around a hydrophobic adamantane molecule.

Stereochemistry of 2,6‐Diaminoadamantane Salts: Transannular Interactions

AbstractA series of bisprimary, bistertiary, and bisquaternary adamantane‐2,6‐diammonium salts were synthesized from adamantane‐2,6‐dione starting material. Conversion of the dione to a dioxime followed by H2/PtO2 hydrogenation afforded 2,6‐diaminoadamantane dihydrochloride 2a. Reductiveamination of 2a with aqueous formaldehyde (H2/PtO2) gave rac‐N,N,N′,N′‐tetramethyl‐2,6‐diaminoadamantane dihydrochloride salt 3. Diffusion of acetone into a solution of 3 in methanol gave 2.5 hydrate crystals in a triclinic P$\bar {1}$ cell, which had two molecules of opposite handedness and five water molecules in the asymmetric unit. Diamine 2a with excess CH3I yielded rac‐N,N,N,N′,N′,N′‐hexamethyladamantane‐2,6‐diaminium diiodide quaternary salt 4a. Diiodide 4a with molecular bromine gave the corresponding dibromide 4b. Acetone diffusion into a solution of 4a (or 4b) in methanol gave isostructural monohydrate crystals in orthorhombic Pnma cells. An enantiomeric pair of 4a,4b (2RS,6RS)‐diaminium ions is disordered about the mirror plane, since chiral cation occupancy of this location requires symmetry that cannot be fulfilled. In solution, all the cations had C2 symmetry, as detected by NMR spectroscopy, whereas an approximate C2 symmetry was observed in crystals. RmS(G) quantification of crystallographic pseudo‐symmetry shows high fidelity for pseudo‐inversion symmetry between cations of opposite handedness in crystal 3, and for pseudo‐C2 symmetry within adamantane skeletons of crystals 3, 4a, and 4b. Axial NMe3 or NHMe2 groups on adamantane‐2 (or ‐6‐)‐positions suffer cis‐1,3‐diaxial repulsion, very similar to that involving axial tBu or iPr groups and H(axial) protons on cyclohexane. These transannular steric interactions tilt the NMe3 units outward by about 19°, while NHMe2 groups slant outward by a smaller and more usual 7°.

ChemInform Abstract: Computer-Assisted Structural Elucidation. Alkaloids with a Novel Diaza-adamantane Skeleton from the Seeds of Acosmium panamense (Fabaceae).

Three alkaloids, acosmine 1, acosmine acetate 2 and panacosmine 3 with a n~wel diaza- adamantane skeleton and an unusual N-acetyl enamine moiety, have been i.~lated from the :'seeds of Acosmium panamense (Benth.). The structures were a~embled on the basis of COSY, HMQC and HMBC data with the assistance of the LSD structure elucidation Ix'ogram. Proton-nitrogen HMBC experiments supl~rt the ~ structures. Other isolated compounds include 4ot-angeloyloxy-31~- hydroxy-131~-methoxylupanine 4, a new compound, and the known alkaloids lupanine and multiflorine. © 1999 Elsevier Science Ltd. All rights reserved. Acosmium panamense (Benth.) Yakovlev (Fabaceae) 1, known as Sweetia panamense 2, is a tall tree originating in central America, li'om Mexico to Venezuela. In central America, the bitter bark has been used in traditional medicine as a remedy for diseases such as syphilis and malaria 3. The hard wood of A. panamense is used as building material. A. panamense was introduced into Ali'ica in the Congo (Kinshasa) under the erroneous name A. brachystachya 4. Chemical investigation of the root bark resulted in the isolation of the alkaloids sweetenine ~ and 4~-hydroxysparteine 5. More recently methoxylated quinolizidine alkaloids have been described 6. This article describes the results of a chemical investigation of the seeds of A. panamense. The ground seeds ofA. panamense were first defatted and then submitted to alkaloid .separation by means of acid-base extraction 7. Purification of the alkaloid mixtures by column chromatography on silica gel led to the isolation of six compounds. The known alkaloids lupanine and multiflorine were identified by comparison of their spectra with literature data s. The structure elucidation of the lbur new compounds is described below. The El mass spectrum of acosmine 1 reveals an (MI + ion at mlz 359. The regular and J-modulated 13C NMR spectra show 21 carbons (I methyl, 10 methylenes, 8 methines and 2 non-protonated carbons) bearing a total of 31 hydrogen atoms. A proton at 5 7.4 ppm (NH) is not bound to a carbon atom as indicated by the ~H-~3C HSQC spectrum. The odd mass of the molecular ion imposes an odd number of hydrogen and nitrogen

2,5-Dioxopyrrolidin-1-yl adamantane-1-carboxylate

The title compound, C15H19NO4, contains one crystallographically independent mol­ecule in the asymmetric unit. The N—O—C—O torsion angle is 1.97 (9)°. The two pairs of vicinal H atoms that lie above or below the plane defined by the five-membered pyrrolidine-2,5-dione ring are an average of 6.57 (5)° from being eclipsed. The average absolute C—C—C—C torsion angle in the adamantane skeleton, in which each fused cyclo­hexane ring is in a chair configuration, is 59.99 (5)°. The crystal packing is unremarkable.

Synthesis of functionalized adamantanes from fluoroadamantanes

Selective introduction of functional groups on the tert-carbon of adamantane was performed by substitution with fluorides. A methyl, phenacyl, aryl, cyclohexyl, alkoxy, or azido group was introduced into the adamantane skeleton without influencing the other functional groups present. Various functionalized adamantanes were synthesized using this scheme. A fluorinated analog of memantine (3-fluoro-5,7-dimethyl-1-adamantylammonium acetate 25) was synthesized from methyl 3,5-dimethyladamantane-1-carboxylate 6.

N-(2-Hydroxyethyl)-N-(tricyclo[3.3.1.13,7]dec-2-yl)benzamide

The title adamantane derivative, C19H25NO2, was synthesized as part of a study into potential anti­tuberculosis agents. The adamantane skeleton displays shorter than normal C—C bond lengths ranging between 1.5230 (15) and 1.5329 (16) Å. The structure displays O—H⋯O hydrogen bonding and an inter­digitated layered packing structure with distinct hydro­philic and hydro­phobic regions.

DFT investigation on heats of formation and group interactions of polyisocyanoadamantanes with respect to isocyano substituents

Heats of formation (HOFs) and strengths of group interactions for 19 polyisocyanoadamantanes were obtained by using the density functional theory (DFT). The adamantane skeleton was chosen for a reference compound in the process of designing isodesmic reactions. It was found that the HOF increases 213–252 kJ/mol for each additional number of the isocyano group being added to the adamantane skeleton. The HOFs slightly deviate from the group additivity with respect to the isocyano group. The distance between isocyano groups influences the values of HOFs. The disproportionation energies of neighbor isocyano groups in polyisocyanoadamantanes are in the range of 10.3–15.8 kJ/mol, which are also slightly related to the substituent numbers. The average interaction energy between nearest neighbor –NC group in decaisocyanoadamantane is 10.34 kJ/mol at the B3LYP/6-311G ∗∗ level. The relative stability related to the number of isocyano groups of the title compounds was evaluated based on the calculated HOFs, the energy gaps between the frontier orbitals, the bond orders of the C–NC and C–C bonds, and bond dissociation energies.