This review summarizes achievements in the synthesis of 1,2-disubstituted adamantane derivatives by the construction of the tricyclic framework either by total synthesis or by ring expansion/contraction reactions of corresponding adamantane homologues. It is intended to complement reviews focusing on the preparation of 1,2-disubstituted derivatives by C-H functionalization methods.

• Klíčová slova
• adamantane, alkyl shifts, diamondoids, homoadamantane, noradamantane, protoadamantane, rearrangement, ring contraction, ring expansion, total synthesis,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Adamantane, the smallest diamondoid molecule with a symmetrical cage, contains two distinct carbon sites, CH and CH2. The ionization/excitation of the molecule leads to the cage opening and strong structural reorganization. While theoretical predictions suggest that the carbon site CH primarily causes the cage opening, the role of the other CH2 site remains unclear. In this study, we used advanced experimental Auger electron-ion coincidence techniques and theoretical calculations to investigate the fragmentation dynamics of adamantane after resonant inner-shell photoexcitation. Our results demonstrate that some fragmentation channels exhibit site-sensitivity of the initial core-hole location, indicating that different carbon site excitations could lead to unique cage opening mechanisms.

• Klíčová slova
• AE–PICO/PIPICO coincidence, adamantane, inner-shell fragmentation, site-selectivity,
• Publikační typ
• časopisecké články MeSH

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.

• Klíčová slova
• 2,6,9-trisubstituted purine, adamantane, cyclin-dependent kinase, cytotoxicity, molecular docking, β-cyclodextrin,
• MeSH
• adamantan chemie   MeSH
• beta-cyklodextriny chemie   MeSH
• buňky K562 MeSH
• cyklin-dependentní kinasa 2 antagonisté a inhibitory   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• protinádorové látky chemie   farmakologie   MeSH
• puriny chemie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adamantan MeSH
• beta-cyklodextriny MeSH
• CDK2 protein, human MeSH Prohlížeč
• cyklin-dependentní kinasa 2 MeSH
• inhibitory proteinkinas MeSH
• protinádorové látky MeSH
• puriny MeSH

Purine nucleosides represent an interesting group of nitrogen heterocycles, showing a wide range of biological effects. In this study, we designed and synthesized a series of 6,9-disubstituted and 2,6,9-trisubstituted purine ribonucleosides via consecutive nucleophilic aromatic substitution, glycosylation, and deprotection of the ribofuranose unit. We prepared eight new purine nucleosides bearing unique adamantylated aromatic amines at position 6. Additionally, the ability of the synthesized purine nucleosides to form stable host-guest complexes with β-cyclodextrin (β-CD) was confirmed using nuclear magnetic resonance (NMR) and mass spectrometry (ESI-MS) experiments. The in vitro antiproliferative activity of purine nucleosides and their equimolar mixtures with β-CD was tested against two types of human tumor cell line. Six adamantane-based purine nucleosides showed an antiproliferative activity in the micromolar range. Moreover, their effect was only slightly suppressed by the presence of β-CD, which was probably due to the competitive binding of the corresponding purine nucleoside inside the β-CD cavity.

• Klíčová slova
• adamantane, antiproliferative activity, glycosylation, nucleoside, purine, β-cyclodextrin,
• MeSH
• adamantan * farmakologie   MeSH
• beta-cyklodextriny * farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nukleosidy farmakologie   chemie   MeSH
• purinové nukleosidy farmakologie   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adamantan * MeSH
• beta-cyklodextriny * MeSH
• nukleosidy MeSH
• purinové nukleosidy MeSH

The adamantane moiety is the structural backbone of numerous compounds and its discovery launched a new field of chemistry studying the approaches to the synthesis as well as the physicochemical and biological properties of organic polyhedral compounds with practical application in the pharmaceutical industry. Adamantane derivatives have proven to be very potent compounds in a wide range of applications from systemic to topical therapy. This review summarizes the currently available adamantane derivatives in clinical practice (amantadine, memantine, rimantadine, tromantadine, adapalene, saxagliptin, vildagliptin), focusing on mechanisms of action, pharmacokinetics, pharmacodynamics and clinical trials. The adamantane-based compounds presented in this manuscript have been approved for a wide spectrum of indications (antivirals, antidiabetics and against Alzheimer's and Parkinson's disease). Each of the compounds proved to be of vital importance in their therapeutic indication for numerous patients worldwide. This review also considers the mechanisms of side effects to deliver a complete perspective on current treatment options.

• MeSH
• adamantan analogy a deriváty   farmakokinetika   terapeutické užití   MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• antivirové látky chemie   farmakokinetika   terapeutické užití   MeSH
• chřipka lidská farmakoterapie   MeSH
• diabetes mellitus 2. typu farmakoterapie   MeSH
• hypoglykemika chemie   farmakokinetika   terapeutické užití   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• adamantan MeSH
• antivirové látky MeSH
• hypoglykemika MeSH

Multi-orthogonal molecular scaffolds can be applied as core structures of bioactive compounds. Here, we prepared four tri-orthogonal scaffolds based on adamantane or proline skeletons. The scaffolds were used for the solid-phase synthesis of model insulin mimetics bearing two different peptides on the scaffolds. We found that adamantane-derived compounds bind to the insulin receptor more effectively (Kd value of 0.5 μM) than proline-derived compounds (Kd values of 15-38 μM) bearing the same peptides. Molecular dynamics simulations suggest that spacers between peptides and central scaffolds can provide greater flexibility that can contribute to increased binding affinity. Molecular modeling showed possible binding modes of mimetics to the insulin receptor. Our data show that the structure of the central scaffold and flexibility of attached peptides in this type of compound are important and that different scaffolds should be considered when designing peptide hormone mimetics.

• Klíčová slova
• Hormone binding, Insulin receptor, Molecular dynamics, Peptidomimetics, Scaffold, Solid-phase peptide synthesis,
• MeSH
• adamantan chemie   MeSH
• inzulin analogy a deriváty   chemická syntéza   metabolismus   MeSH
• kinetika MeSH
• krysa rodu Rattus MeSH
• kvarterní struktura proteinů MeSH
• lidé MeSH
• prolin chemie   MeSH
• receptor inzulinu chemie   metabolismus   MeSH
• simulace molekulární dynamiky MeSH
• stabilita proteinů MeSH
• stereoizomerie MeSH
• techniky syntézy na pevné fázi MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adamantan MeSH
• inzulin MeSH
• prolin MeSH
• receptor inzulinu MeSH

In-capillary derivatization using fluorescamine as the labeling reagent was proposed to enhance the detectability of adamantine drugs (memantine, amantadine and rimantadine) by spectrophotometric detection. Fluorescamine and the drugs were delivered to the capillary electrophoresis instrument at a ratio of 10:1 by zone injection. The derivatization reaction occurred following the application of voltage (20 kV). The derivatized products, hydrolyzed- fluorescamine and excess fluorescamine were separated in 7 min using 100 mM borate buffer (pH 10.0) containing 0.1% w/v of Brij®-35 and 20% v/v of acetonitrile. Validation data showed good linearity (r2 > 0.98), precision (%RSDs < 3.4), and accuracy (recoveries ranging from 98.0 to 102.0%). The detection and quantitation limits are in the range of 6.0-8.5 and 18-25 μM, respectively. The validation data is comparable to reported methods, however, the current method offers better precision with enhanced sensitivity (up to six times). Applications of the method show percent labeled amounts found in the studied samples within 100.6-109.3%, which complied with the United States Pharmacopeia limit (90.0-110.0%). The method was simple, rapid and, automated, which required no extra instrumentation or skillful operators.

• Klíčová slova
• adamantine, fluorescamine, in-capillary derivatization, memantine, rimantadine,
• MeSH
• adamantan analýza   MeSH
• elektroforéza kapilární MeSH
• fluoreskamin chemie   MeSH
• molekulární struktura MeSH
• spektrofotometrie ultrafialová MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adamantan MeSH
• fluoreskamin MeSH

We describe a triflic acid promoted cascade reaction of adamantane derivatives consisting of a decarboxylation of N-methyl protected cyclic carbamates and a subsequent intramolecular nucleophilic 1,2-alkyl shift to generate ring contracted iminium triflates. This reaction expands the family of similar transformations, such as Wagner-Meerwein-, Demjanov-Tiffeneau-, Meinwald- or (semi-)pinacol-rearrangement. It allows the preparation of noradamantane derivatives in a few steps, starting from simple hydroxy-substituted adamantane precursors.

• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

We report a protocol for the one-pot two-step synthesis of noradamantane methylene amines. The first step is the triflic acid-promoted decarboxylation of adamantane carbamates, which causes rearrangement of the adamantane framework to form noradamantane iminium salts, which are reduced to amines in the second separate step.

• Publikační typ
• časopisecké články MeSH

The condensation reaction between Ph2Si(OC(O)CH3)2 and OP(OSiMe3)3 leads to elimination of CH3C(O)OSiMe3 and the formation of the new silicophosphate cage molecule Ph12Si6P4O16 (1) with an adamantane-like core possessing four terminal P═O moieties and six O-SiPh2-O bridging groups. Compound 1 was further reacted with the Lewis acid B(C6F5)3. We observed adduct formation by coordination through the P═O→B bonds and isolated and structurally characterized two new molecules. In the first of them, the adamantane-like cage is preserved and three phosphoryl oxygen atoms coordinate to boranes, forming Ph12Si6O16P4·3B(C6F5)3 (2); the remaining P═O group is inverted toward the cage center pointing along a C3 molecular axis. The molecule is chiral, and the compound 2 crystallizes as a conglomerate of homochiral crystals. Enantiomers 2M and 2P were both structurally characterized. The second adduct resulted from an unexpected reorganization of the Si-O-P linkages in the adamantane cage during the reaction of 1 with 4 equiv of B(C6F5)3. The bis-adduct Ph6Si3O8P2·2B(C6F5)3 (3) was formed with an inorganic core representing half of the parent molecule 1.

• Publikační typ
• časopisecké články MeSH