We report on the synthesis and characterization using high‐resolution rotational spectroscopy of three bulky thioethers that feature an adamantyl group connected to a sulfur atom. Detailed ...experimental and theoretical structures are provided and compared with the 1,1′‐diadamantyl ether. In addition, we expand on previous findings concerning microsolvation of adamantyl derivatives by investigating the cluster formation between these thioethers and a water molecule. The investigation of such clusters provides valuable insights into the sulfur‐centered hydrogen bonding in thioethers with increasing size and steric repulsion.
Oxygen or Sulfur: Three adamantyl thioethers are synthesized. Their structures and monohydrated complexes are characterized by rotational spectroscopy. Exchanging the oxygen atom by sulfur slightly distorts the molecular structure. Adducts with water are formed in a similar way with either the oxygen or the sulfur derivatives, highlighting the capability of sulfur to act as a good hydrogen bond acceptor in bulky structures of this type.
We report the synthesis of quaternary (di)cationic triamantane derivatives
G1
and
G3
by the permethylation of the corresponding primary ammonium ions
G2
and
G4
. The complexation behaviors of
G1
-
G4
...toward CB7 and CB8 were examined by
1
H NMR spectroscopy, which reveals that CB8 is capable of fully encapsulating
G1
-
G4
whereas CB7 forms inclusion complexes with
G1
,
G2
, and
G4
but cannot fully encapsulate the central hydrophobic core of the bis-quaternary ammonium ion
G3
. The geometries of the CB
n
-guest complexes were determined by analyzing the complexation induced changes in chemical shifts and were further confirmed by molecular modelling using the Conformer-Rotamer Ensemble Sampling Tool (CREST) based on the GFN methods. Finally, the complexation thermodynamics were determined by a combination of
1
H NMR competitive experiments, direct isothermal titration calorimetry (ITC) measurements, and competitive ITC titrations using a tight binding ternary complex as a competitor.
Cationic triamantanes exhibit ultratight binding toward CB7 and CB8 as evidenced by
1
H NMR spectroscopy, isothermal titration calorimetry, and computations.
A series of adamantane functionalized diaza-lariat ethers 1-6 have been prepared and alkali metal picrate extraction profiles determined. The ability of aza-crown ethers 1- 6 to extract the alkali ...metal picrates was compared with that of diaza-18-crown-6 (7) and N,N'-dibenzodiaza- 18-crown-6 (8). Na.sub.+ and K.sup.+ transport across bulk liquid membrane was also measured. The results of alkali metal cation extraction experiments showed that lariat ethers 2 and 3, in which the adamantane molecule is linked to the diaza-18-crown-6 by amine bond, have better complexation abilities for all cations compared to the parent crown ethers 7 and 8, as well as a significantly higher selectivity for K.sup.+ than diaza-18-crown-6. However, diazalariat ether 1 showed reduced, and 4-6 negligible extractability towards any of the alkali cations. Monte Carlo conformational analysis pointed to the importance of conformational flexibility of the investigated compounds for their extraction ability of alkali cations. (doi: 10.5562/cca2100) Keywords: diaza-bibracchial lariat ethers, adamantane functionalized crown ethers, metal ion complexation, metal ion transport, Monte Carlo conformational search
Multidrug resistance (MDR) is a widespread phenomenon exhibited by many cancers and represents a fundamental obstacle for successful cancer treatments. Tumour cells commonly achieve MDR phenotype ...through overexpression and/or increased activity of ABC transporters. P-glycoprotein transporter (P-gp, ABCB1) is a major cause of MDR and therefore represents a valuable target for MDR reversal. Several naturally occurring potassium ionophores (e.g. salinomycin) were shown to inhibit P-gp effectively. We have previously shown antitumour activity of a number of 18-crown-6 ether compounds that transport potassium ions across membranes. Here we present data on P-gp inhibitory activity of 16 adamantane-substituted monoaza- and diaza-18-crown-6 ether compounds, and their effect on MDR reversal in model cell lines. We show that crown ether activity depends on their lipophilicity as well as on the linker to adamantane moiety. The most active crown ethers were shown to be more effective in sensitising MDR cells to paclitaxel and adriamycin than verapamil, a well-known P-gp inhibitor. Altogether our data demonstrate a novel use of crown ethers for inhibition of P-gp and reversal of MDR phenotype.
The Cover Feature illustrates similarities and differences between oxygen and sulfur when being part of bulky molecules, as detected by high‐resolution rotational spectroscopy. While the change from ...oxygen to sulfur does not affect much the structure of the compounds, their microhydrated complexes highlight a difference in hydrogen bond formation capabilities. More information can be found in the Research Article by Pablo Pinacho, Marina Šekutor, Melanie Schnell, and co‐workers.
Overexpression of ABC transporters, such as ABCB1 and ABCG2, plays an important role in mediating multidrug resistance (MDR) in cancer. This feature is also attributed to a subpopulation of cancer ...stem cells (CSCs), having enhanced tumourigenic potential. ABCG2 is specifically associated with the CSC phenotype, making it a valuable target for eliminating aggressive and resistant cells. Several natural and synthetic ionophores have been discovered as CSC-selective drugs that may also have MDR-reversing ability, whereas their interaction with ABCG2 has not yet been explored. We previously reported the biological activities, including ABCB1 inhibition, of a group of adamantane-substituted diaza-18-crown-6 (DAC) compounds that possess ionophore capabilities. In this study, we investigated the mechanism of ABCG2-inhibitory activity of DAC compounds and the natural ionophores salinomycin, monensin and nigericin. We used a series of functional assays, including real-time microscopic analysis of ABCG2-mediated fluorescent substrate transport in cells, and docking studies to provide comparative aspects for the transporter–compound interactions and their role in restoring chemosensitivity. We found that natural ionophores did not inhibit ABCG2, suggesting that their CSC selectivity is likely mediated by other mechanisms. In contrast, DACs with amide linkage in the side arms demonstrated noteworthy ABCG2-inhibitory activity, with DAC-3Amide proving to be the most potent. This compound induced conformational changes of the transporter and likely binds to both Cavity 1 and the NBD–TMD interface. DAC-3Amide reversed ABCG2-mediated MDR in model cells, without affecting ABCG2 expression or localization. These results pave the way for the development of new crown ether compounds with improved ABCG2-inhibitory properties.
The synthesis of novel cage-functionalized cryptands 1–5 containing adamantane-, 2-oxaadamantane- or noradamantane-moiety i.e., 1,3-diethyladamantano2.2.0cryptand (1), ...1,3-diethoxyadamantano2.2.2cryptand (2), 1,3-di(ethyloxy)methyladamantano2.2.2-cryptand (3), 1,3-di(ethyloxy)methyl-2-oxaadamantano2.2.3cryptand (4), and 1,2-diethyloxynoradamantano2.2.2cryptand (5) and their alkali metal binding properties are reported. The results obtained by extraction experiments showed that all the cryptands displayed lower extraction capabilities than the parent 2.2.2cryptand. However, cryptands 1 and 2 showed much higher selectivity toward K+ than the reference 2.2.2cryptand. When the third bridge is enlarged by two additional CH2-groups as well as by two oxygen atoms, as in cryptands 3 and 4, the complexational abilities for bigger cations (K+, Rb+ and Cs+) are enhanced. Cryptand 5 displayed very good extraction capabilities of all cations, but showed practically no selectivity towards any of the alkali metal cation. The experimental findings are corroborated by calculation studies consisting of force field based conformational search using Monte Carlo method followed by investigation of the stabilities of the complexes of cryptands with Na+ and K+ metal ions in chloroform by means of quantum chemical calculations at the density functional theory level.
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Kinon-metidi (QM, naziv po IUPAC-u: kinometani) su reaktivni međuprodukti koji su povezani s biološkom aktivnosti brojnih prirodnih i sintetski dobivenih spojeva. Njihova aktivnost temelji se na ...inhibiciji enzima ili, češće, na alkilaciji/križnom povezivanju DNA. QM se mogu generirati termičkim metodama, ali veliku prednost imaju fotokemijske metode, jer pružaju mogućnost prostorne i vremenske kontrole nad njihovim stvaranjem. Za konačni cilj – primjenu u fotokemoterapiji od presudne je važnosti razvoj prekursora za generiranje QM-a. Ovim pregledom bit će dan uvid u fotokemijske metode generiranja QM-a i razvoj njihove primjene u fotokemoterapiji.
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Kinon-metidi (QM, naziv po IUPAC-u: kinometani) su reaktivni međuprodukti koji zauzimaju vrlo značajno mjesto u organskoj kemiji. Njihova primjena u organskoj sintezi je veoma velika, što je dovelo ...do razvoja velikog broja metoda za njihovo generiranje. Korisni su i u stereoselektivnim reakcijama, čime im je otvoren put za primjenu u totalnoj sintezi, nerijetko struktura koje su već pokazale značajnu biološku aktivnost. Ovim pregledom dan je uvid u metode sintetskog (termičkog) generiranja QM-a te njihovu primjenu u organskoj sintezi, s osvrtom na biološka svojstva samih QM-a ili produkata koji se iz njih dobivaju u sintezi.
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Upon sensitized irradiation of N-phthalimido dipeptides containing l- or d-phenylalanine, enantioselective cyclization to diazamacrocycles takes place (ee >99%). The high optical purity of the ...products was explained by the memory of chirality effect. The chirality is preserved owing to the axial chirality of the biradical intermediate formed. An insight into the origin behind the enantioselective cyclization of the intermediate was given by density functional calculations. The very high enantiomeric excess in this type of photocyclization establishes it as a new method for the enantioselective synthesis of different large aza-heterocycles.
![Cucurbit[8]uril forms tight...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/1144-0546/small "Cucurbit[8]uril forms tight inclusion complexes with cationic triamantanes")
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