- New chiral stationary phases for liquid chromatography based on small molecules: Development, enantioresolution evaluation and chiral recognition mechanisms
-
Recently, we reported the development of new chiral stationary phases (CSPs) for liquid chromatography (LC) based on chiral derivatives of xanthones (CDXs). Based on the most promising CDX selectors, 12 new CSPs were successfully prepared starting from suitable functionalized small molecules including xanthone and benzophenone derivatives. The chiral selectors comprising one, two, three, or four chiral moieties were covalently bonded to a chromatographic support and further packed into LC stainless-steel columns (150?×?2.1?mm I.D.). The enantioselective performance of the new CSPs was evaluated by LC using different classes of chiral compounds. Specificity for enantioseparation of some CDXs was observed in the evaluation of the new CSPs. Besides, assessment of chiral recognition mechanisms was performed by computational studies using molecular docking approach, which are in accordance with the chromatographic parameters. X-Ray analysis was used to establish a chiral selector 3D structure.
- Phyo, Ye' Zaw,Teixeira, Joana,Tiritan, Maria Elizabeth,Cravo, Sara,Palmeira, Andreia,Gales, Luís,Silva, Artur M.S.,Pinto, Madalena M.M.,Kijjoa, Anake,Fernandes, Carla
-
-
- New chiral stationary phases based on xanthone derivatives for liquid chromatography
-
Six chiral derivatives of xanthones (CDXs) were covalently bonded to silica, yielding the corresponding xanthonic chiral stationary phases (XCSPs). The new XCSPs were packed into stainless-steel columns with 150 x 4.6 mm i.d. Moreover, the greening of the chromatographic analysis by reducing the internal diameter (150 x 2.1 mm i.d.) of the liquid chromatography (LC) columns was also investigated. The enantioselective capability of these phases was evaluated by LC using different chemical classes of chiral compounds, including several types of drugs. A library of CDXs was evaluated in order to explore the principle of reciprocity as well as the chiral self-recognition phenomenon. The separation of enantiomeric mixtures of CDXs was investigated under multimodal elution conditions. The XCSPs provided high specificity for the enantiomeric mixtures of CDXs evaluated mainly under normal-phase elution conditions. Furthermore, two XCSPs were prepared with both enantiomers of the same xanthonic selector in order to confirm the inversion order elution.
- Fernandes, Carla,Tiritan, Maria Elizabeth,Cravo, Sara,Phyo, Ye’ Zaw,Kijjoa, Anake,Silva, Artur M.S.,Cass, Quezia B.,Pinto, Madalena M.M.
-
p. 430 - 442
(2017/07/25)
-
- New chiral derivatives of xanthones: Synthesis and investigation of enantioselectivity as inhibitors of growth of human tumor cell lines
-
A highly efficient and practical methodology for synthesis of new chiral derivatives of xanthones (CDXs) in enantiomerically pure form has been developed According to this approach, thirty CDXs (3-32) were synthesized by coupling a carboxyxanthone (1) and a carboxymethoxyxanthone (2) with both enantiomers of commercially available chiral building blocks, namely six amino alcohols, one amine and one amino ester The activation of the carboxylic acid group of the xanthonic scaffold was carried out with the coupling reagent O-(benzotriazol-1-yl)-N-N-N′-N′-tetramethyluronium tetrafluoroborate (TBTU), in the presence of a catalytic amount of TEA in anhydrous THF The coupling reactions with the chiral blocks were performed at room temperature with short reactions times, excellent yields (ranging from 94% to 99%), and very high enantiomeric excess The synthesized CDXs were evaluated for their effect on the in vitro growth of three human tumor cell lines, namely A375-C5 (melanoma), MCF-7 (breast adenocarcinoma), and NCI-H460 (non-small cell lung cancer) The most active compound was CDX 15 being active in all human tumor cell lines with values of GI50 of 32.15 ± 2.03 μM for A375-C5, 22.55 ± 1.99 μM for MCF-7, and 14.05 ± 1.82 μM for NCI-H460 Nevertheless, some CDXs showed cell-type selectivity Furthermore, the growth inhibitory effects, in some cases, demonstrated to be depending on the stereochemistry of the CDXs An interesting example was observed with the enantiomers 3 and 4, which demonstrated high enantioselectivity for MCF-7 and NCI-H460 cell lines It can be inferred that the effects on the growth of the human tumor cell lines can be ascribed not only to the nature and positions of substituents on the xanthonic scaffold but also to the stereochemistry of the CDXs Some considerations regarding structure-activity relationship within this class of compounds will be highlighted
- Fernandes, Carla,Masawang, Kamonporn,Tiritan, Maria Elizabeth,Sousa, Emília,De Lima, Virgínia,Afonso, Carlos,Bousbaa, Hassan,Sudprasert, Wanwisa,Pedro, Madalena,Pinto, Madalena M.
-
p. 1049 - 1062
(2014/02/14)
-
- Enantioresolution of chiral derivatives of xanthones on (S,S)-Whelk-O1 and l -phenylglycine stationary phases and chiral recognition mechanism by docking approach for (S,S)-Whelk-O1
-
The resolution of seven enantiomeric pairs of chiral derivatives of xanthones (CDXs) on (S,S)-Whelk-O1 and l-phenylglycine chiral stationary phases (CSPs) was systematically investigated using multimodal elution conditions (normal-phase, polar-organic, and reversed-phase). The (S,S)-Whelk-O1 CSP, under polar-organic conditions, demonstrated a very good power of resolution for the CDXs possessing an aromatic moiety linked to the stereogenic center with separation factor and resolution factor ranging from 1.91 to 7.55 and from 6.71 to 24.16, respectively. The chiral recognition mechanisms were also investigated for (S,S)-Whelk-O1 CSP by molecular docking technique. Data regarding the CSP-CDX molecular conformations and interactions were retrieved. These results were in accordance with the experimental chromatographic parameters regarding enantioselectivity and enantiomer elution order. The results of the present study fulfilled the initial objectives of enantioselective studies of CDXs and elucidation of intermolecular CSP-CDX interactions. Copyright
- Fernandes, Carla,Palmeira, Andreia,Santos, Alexandre,Tiritan, Maria Elizabeth,Afonso, Carlos,Pinto, Madalena M.
-
-
- Synthesis of new chiral xanthone derivatives acting as nerve conduction blockers in the rat sciatic nerve
-
The synthesis and structure elucidation of three new chiral xanthone (9H-xanthon-9-one) derivatives (2-4) are fully reported. The coupling reactions of the synthesized building block 6-methoxy-9-oxo-9H-xanthene-2-carboxylic acid (1) with two enantiomerically pure amino alcohols ((S)-(+)-valinol and (S)-(+)-leucinol) and one amine ((S)-(-)-α-4-dimethylbenzylamine), were carried out using the coupling reagent O-(benzotriazol-1-yl-)-N,N,N′, N′-tetramethylluronium tetrafluoroborate (TBTU). The coupling reactions were performed with yields higher than 97% and enantiomeric excess higher than 99%. The structures of the compounds were established by IR, MS, and NMR ( 1H, 13C, HSQC, and HMBC) techniques. Taking into account that these new chiral xanthone derivatives have molecular moieties structurally very similar to local anaesthetics, the ability to block compound action potentials (CAP) at the isolated rat sciatic nerve was also investigated. Nerve conduction blockade might result from a selective interference with Na + ionic currents or from a non-selective modification of membrane stabilizing properties. Thus, the mechanism, by which the three chiral xanthone derivatives cause conduction blockade in the rat sciatic nerve and their ability to prevent hypotonic haemolysis, given that erythrocytes are non-excitable cells devoid of voltage-gated Na+ channels, are also described. Data suggest that nerve conduction blockade caused by newly-synthesized xanthone derivatives might result predominantly from an action on Na+ ionic currents. This effect can be dissociated from their ability to stabilize cell membranes, which became apparent only upon increasing the concentration of compounds 2-4 to the higher micromolar range.
- Fernandes, Carla,Pinto, Madalena M.,Tiritan, Maria Elizabeth,Oliveira, Laura,Leitao, Luis,Pozzi, Angelo,Noronha-Matos, Jose Bernardo,Correia-De-Sa, Paulo
-
p. 1 - 11,11
(2020/07/31)
-