RESUMEN
A P-C bond-forming reaction between silyl phosphonites and Morita-Baylis-Hillman acetates (MBHAs) is explored as a general alternative towards medicinally relevant ß-carboxyphosphinic structural motifs. Conversion rates of diversely substituted MBHAs to phosphinic acids 9 or 14 that were recorded by using (31) Pâ NMR spectroscopy revealed unexpected reactivity differences between ester and nitrile derivatives. These kinetic profiles and DFT calculations support a mechanistic scenario in which observed differences can be explained from the "lateness" of transition states. In addition, we provide experimental evidence suggesting that enolates due to initial P-Michael addition are not formed. Based on the proposed mechanistic scenario in conjunction with DFT calculations, an interpretation of the E/Z stereoselectivity differences between ester and nitriles is proposed. Synthetic opportunities stemming from this transformation are presented, which deal with the preparation of several synthetically capricious phosphinic building blocks, whose access through the classical P-Michael synthetic route is not straightforward.
RESUMEN
ß-Cyclodextrin (ß-CD) dimers have been prepared using the bioorthogonal Staudinger ligation for the first time. In addition to a known linker, methyl 2-(diphenylphosphanyl)terephthalate, a doubly active linker was specifically developed that enabled connection of two ß-CD units in a single step and in aqueous/organic media, under mild conditions and with good yields. A three-carbon spacer between the ß-CD torus and the azido group was required for facile dimer formation. The products, as studied by NMR spectroscopy, were found to adopt closed conformations by intramolecular self-inclusion. On the other hand, association via intermolecular binding was also observed in aqueous solution, confirmed by DOSY NMR experiments. Despite self-inclusion, the ß-CD cavities were capable of guest encapsulation, as shown by titration experiments: the binding constant with 1-adamantylamine was similar to that of natural ß-CD. Theoretical calculations for isolated molecules (PM3 level of theory) and in the presence of solvent [water, PM3(COSMO)] as well as DFT calculations suggested that the compounds prefer to adopt conformations which bring the phenyl groups either inside the ß-CD cavity (inclusion) or over its narrow side (vicinal). Thus, Staudinger ligation could be the method of choice for linking CDs exhibiting (i) ease of preparation in aqueous media, in short steps, under mild conditions and in good yields, (ii) satisfactory aqueous solubility and independent binding capacity of the cavities.
RESUMEN
Highly resistant bacteria producing metallo-ß-lactamases (MBLs) to evade ß-lactam antibiotics, constitute a major cause of life-threatening infections world-wide. MBLs exert their hydrolytic action via Zn2+ cations in their active center. Presently, there are no approved drugs to target MBLs and combat the associated antimicrobial resistance (AMR). Towards this issue, we have prepared a family of cyclodextrins substituted with iminodiacetic acid (IDA) on their narrow side, while the wider side is either unmodified or per-2,3-O-methylated. The molecules form strong coordination complexes with Zn2+ or Ga3+ cations in aqueous solution. Free and metal-complexed compounds have been thoroughly characterized regarding structures, pH-dependent ionization states, distribution of species in solution, pKa values and metal-binding constants. At neutral pH the multi-anionic hosts bind up to four Zn2+ or Ga3+ cations. In vitro, 50 µΜ of the compounds achieve complete re-sensitization of MBL-producing Gram-negative clinical bacterial strains resistant to the carbapenems imipenem and meropenem. Moreover, the radioactive complex [67Ga]Ga-ß-IDACYD prepared, displays high radiochemical purity, sufficient stability both overtime and in the presence of human plasma apo-transferrin, thus providing an invaluable tool for future biodistribution and pharmacokinetic studies of ß-IDACYDin vivo, prerequisites for the development of therapeutic protocols.
Asunto(s)
Antiinfecciosos , Complejos de Coordinación , Ciclodextrinas , Humanos , Distribución Tisular , Cationes , Complejos de Coordinación/farmacología , Ciclodextrinas/farmacología , ZincRESUMEN
The systematic analysis of groundwater in the Greek island of Skiathos revealed a seasonal increase of total mercury concentrations after the extensive groundwater abstraction during the busy and heavily touristic summer months. This contamination was accompanied by a corresponding increase of the chloride content of groundwater, attributed to seawater intrusion into the freshwater-depleted aquifer within mercury-rich bedrock. The effects of elevated concentrations of chloride anions in the mobilization of mercury and its speciation were addressed by geochemical equilibrium modeling, considering cinnabar (HgS) as the mineral source of mercury. Adsorption onto hydrous ferric oxide (Fe2O3·H2O) was a necessary ingredient of the geochemical model for bringing the calculated concentrations in agreement with field measurements, after optimization of the cinnabar/adsorbent mass ratio to a value of 4.9 × 10-8. The speciation of mercury was found to depend on the acidity and redox status as well as on the chloride content of groundwater. Mercury concentrations in the groundwater of Skiathos rise above the World Health Organization limit of 1 µg L-1 for a seawater intrusion higher than 3 %, with HgCl2 being the dominant species followed by HgClOH, HgCl3- and HgCl42-. The assumed concentration of dissolved organic matter in groundwater had a negligible impact on the mercury speciation and its mobilization by chloride.
Asunto(s)
Agua Subterránea , Mercurio , Contaminantes Químicos del Agua , Monitoreo del Ambiente , Agua Dulce , Mercurio/análisis , Agua de Mar , Contaminantes Químicos del Agua/análisisRESUMEN
Rate coefficients, k, for the gas-phase reactions of Cl atoms and NO(3) radicals with 2,3,3,3-tetrafluoropropene, CF(3)CFâCH(2) (HFO-1234yf), and 1,2,3,3,3-pentafluoropropene, (Z)-CF(3)CFâCHF (HFO-1225ye), are reported. Cl-atom rate coefficients were measured in the fall-off region as a function of temperature (220-380 K) and pressure (50-630 Torr; N(2), O(2), and synthetic air) using a relative rate method. The measured rate coefficients are well represented by the fall-off parameters k(0)(T) = 6.5 × 10(-28) (T/300)(-6.9) cm(6) molecule(-2) s(-1) and k(∞)(T) = 7.7 × 10(-11) (T/300)(-0.65) cm(3) molecule(-1) s(-1) for CF(3)CFâCH(2) and k(0)(T) = 3 × 10(-27) (T/300)(-6.5) cm(6) molecule(-2) s(-1) and k(∞)(T) = 4.15 × 10(-11) (T/300)(-0.5) cm(3) molecule(-1) s(-1) for (Z)-CF(3)CâCHF with F(c) = 0.6. Reaction product yields were measured in the presence of O(2) to be (98 ± 7)% for CF(3)C(O)F and (61 ± 4)% for HC(O)Cl in the CF(3)CFâCH(2) reaction and (108 ± 8)% for CF(3)C(O)F and (112 ± 8)% for HC(O)F in the (Z)-CF(3)CFâCHF reaction, where the quoted uncertainties are 2σ (95% confidence level) and include estimated systematic errors. NO(3) reaction rate coefficients were determined using absolute and relative rate methods. Absolute measurements yielded upper limits for both reactions between 233 and 353 K, while the relative rate measurements yielded k(3)(295 K) = (2.6 ± 0.25) × 10(-17) cm(3) molecule(-1) s(-1) and k(4)(295 K) = (4.2 ± 0.5) × 10(-18) cm(3) molecule(-1) s(-1) for CF(3)CFâCH(2) and (Z)-CF(3)CFâCHF, respectively. The Cl-atom reaction with CF(3)CFâCH(2) and (Z)-CF(3)CFâCHF leads to decreases in their atmospheric lifetimes and global warming potentials and formation of a chlorine-containing product, HC(O)Cl, for CF(3)CFâCH(2). The NO(3) reaction has been shown to have a negligible impact on the atmospheric lifetimes of CF(3)CFâCH(2) and (Z)-CF(3)CFâCHF. The energetics for the reaction of Cl, NO(3), and OH with CF(3)CFâCH(2) and (Z)-CF(3)CFâCHF in the presence of O(2) were investigated using density functional theory (DFT).
RESUMEN
Novel -type cyclodextrin (CD) derivatives, , and , bearing 6, 7 and 8 bis(carboxymethyl)amino (iminodiacetic acid) groups, respectively, were prepared, and their complexation with Eu(iii), Tb(iii) and Gd(iii) ions was studied. Luminescence titrations and mass spectrometry showed formation of multimetal complexes ( 2 to 3, mainly 3 and exactly 4 metal ions), whereas luminescence lifetime measurements revealed the presence of exchangeable water molecules. Semiempirical quantum mechanical calculations, performed by the PM3 method and assessed by DFT calculations on model ligands, indicated efficient multi-metal complexation, in agreement with the experiment. The structures showed coordination of the metal ions in the outer primary side of the CDs via 4 carboxylate O atoms, 2 N atoms and a glucopyranose O atom per metal ion. Coordination of water molecules was also predicted, in accordance with experimental results. Calculated bond lengths and angles were in agreement with literature experimental values of lanthanide complexes. Calculated energies showed that complex stability decreases in the order > > . (1)H NMR molecular relaxivity measurements for the Gd(iii) complexes of , or in water afforded values 4 to 10 times higher than the relaxivity of a commercial contrast agent at 12 MHz, and 6 to 20 times higher at 100 MHz. Solutions of and Gd(iii) complexes in human blood plasma displayed relaxivity values at 100 MHz 7 and 12 times, respectively, higher than the commercial agent. MTT tests of the Gd(iii) complexes using human skin fibroblasts did not show toxicity. Attempts to supramolecularly sensitize the luminescence of the lanthanide complexes using various aromatic CD guests were ineffective, evidently due to large guest-metal distances and inefficient inclusion. The described lanthanide complexes, could be useful as contrast agents in MRI.
Asunto(s)
Medios de Contraste/química , Complejos de Coordinación/química , Ciclodextrinas/química , Ácido Edético/química , Elementos de la Serie de los Lantanoides/química , Línea Celular , Supervivencia Celular , Medios de Contraste/síntesis química , Medios de Contraste/farmacología , Complejos de Coordinación/síntesis química , Complejos de Coordinación/farmacología , Ciclodextrinas/síntesis química , Ciclodextrinas/farmacología , Ácido Edético/síntesis química , Ácido Edético/farmacología , Europio/química , Gadolinio/química , Gadolinio/farmacología , Humanos , Elementos de la Serie de los Lantanoides/síntesis química , Elementos de la Serie de los Lantanoides/farmacología , Ligandos , Luminiscencia , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Terbio/químicaRESUMEN
The gas-phase reaction of atomic chlorine with diiodomethane was studied over the temperature range 273-363 K with the very low-pressure reactor (VLPR) technique. The reaction takes place in a Knudsen reactor at pressures below 3 mTorr, where the steady-state concentration of both reactants and stable products is continuously measured by electron-impact mass spectrometry. The absolute rate coefficient as a function of temperature was given by k = (4.70 +/- 0.65) x 10-11 exp[-(241 +/- 33)/T] cm3molecule-1s-1, in the low-pressure regime. The quoted uncertainties are given at a 95% level of confidence (2sigma) and include systematic errors. The reaction occurs via two pathways: the abstraction of a hydrogen atom leading to HCl and the abstraction of an iodine atom leading to ICl. The HCl yield was measured to be ca. 55 +/- 10%. The results suggest that the reaction proceeds via the intermediate CH2I2-Cl adduct formation, with a I-Cl bond strength of 51.9 +/- 15 kJ mol-1, calculated at the B3P86/aug-cc-pVTZ-PP level of theory. Furthermore, the oxidation reactions of CHI2 and CH2I radicals were studied by introducing an excess of molecular oxygen in the Knudsen reactor. HCHO and HCOOH were the primary oxidation products indicating that the reactions with O2 proceed via the intermediate peroxy radical formation and the subsequent elimination of either IO radical or I atom. HCHO and HCOOH were also detected by FT-IR, as the reaction products of photolytically generated CH2I radicals with O2 in a static cell, which supports the proposed oxidation mechanism. Since the photolysis of CH2I2 is about 3 orders of magnitude faster than its reactive loss by Cl atoms, the title reaction does not constitute an important tropospheric sink for CH2I2.
RESUMEN
Positively charged cyclodextrins (PCCDs) are molecular carriers of particular interest for their ability to readily enter into cancer cells. Of main interest, guanidino- and aminoalkyl- PCCDs can be conveniently synthesized and form stable and strong inclusion complexes with various active molecules bearing phosphate groups. We have addressed here the challenge to deliver into cancer cells phosphorylated gemcitabine drugs well known for their instability and inability to permeate cell membranes. NMR data corroborated by semiempirical theoretical calculations have shown that aminoalkyl-CDs form sufficiently stable complexes with both mono- and tri-phosphate forms of gemcitabine by simple mixing of the compounds in aqueous solution at physiological pH. Confocal microscopy and radioactivity counting experiments revealed that the developed systems enabled phosphorylated gemcitabine to penetrate efficiently into aggressive human breast cancer cells (MCF7), eventually leading to a substantial reduction of IC50 values. Moreover, compared to free drugs, phosphorylated metabolites of gemcitabine encapsulated in PCCDs displayed improved in vitro activities also on the aggressive human cancer cells CCRF-CEM Ara-C/8 C, a nucleoside transport-deficient T leukemia cell line. The current study offers the proof-of-principle that phosphorylated nucleoside drugs could be efficiently transported by PCCDs into cancer cells.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Neoplasias de la Mama/metabolismo , Ciclodextrinas/metabolismo , Desoxicitidina/análogos & derivados , Resistencia a Antineoplásicos , Linfoma de Células T/metabolismo , Transporte Biológico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Ciclodextrinas/química , Citarabina/farmacología , Desoxicitidina/farmacología , Femenino , Humanos , Linfoma de Células T/tratamiento farmacológico , Linfoma de Células T/patología , Modelos Teóricos , Fosforilación , Células Tumorales Cultivadas , GemcitabinaRESUMEN
Twelve Schiff bases of methoxy-substituted salicylaldehyde have been examined by crystallographic and spectroscopic methods, as well as by DFT theoretical calculations in order to investigate the effect of the substituent's position on the keto-enol equilibrium in the crystalline state. Four out of the 10 structurally characterized compounds with methoxy substitution on the para and/or ortho positions with respect to the aldimine bridge and deriving from aliphatic amines or alkylarylamines are found as cis-keto tautomers and form dimers. In contrast, the five pure enol tautomers derive either from aliphatic or alkylarylamines and are meta substituted or from aniline or benzylamine and are para and/or ortho methoxy substituted. The DFT calculations support the crystallographic results and, moreover, they have shown that keto and enol tautomers are affected differently by the relative arrangement of the monomers. Overall, the DFT calculations point to a plausible hypothesis for the stabilization of the keto form in the crystalline state: In cases with a sufficiently low enol-keto energy difference of the isolated monomers, as when the methoxy group is at ortho and/or para positions with respect to the aldimino group, extra stabilization of the keto form is derived from molecular association, thus leading to its crystallization.
Asunto(s)
Compuestos de Sulfhidrilo/química , beta-Ciclodextrinas/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Células MCF-7 , Óxido Nítrico/química , Óxido Nítrico/metabolismo , Óxido Nítrico/toxicidad , Fotólisis , Teoría Cuántica , Temperatura , beta-Ciclodextrinas/síntesis químicaRESUMEN
The reaction kinetics of chlorine atoms with a series of partially fluorinated straight-chain alcohols, CF(3)CH(2)CH(2)OH (1), CF(3)CF(2)CH(2)OH (2), CHF(2)CF(2)CH(2)OH (3), and CF(3)CHFCF(2)CH(2)OH (4), were studied in the gas phase over the temperature range of 273-363 K by using very low-pressure reactor mass spectrometry. The absolute rate coefficients were given by the expressions (in cm(3) molecule(-1) s(-1)): k(1) = (4.42 +/- 0.48) x 10(-11) exp(-255 +/- 20/T); k(1)(303) = (1.90 +/- 0.17) x 10(-11), k(2) = (2.23 +/- 0.31) x 10(-11) exp(-1065 +/- 106/ T); k(2)(303) = (6.78 +/- 0.63) x 10(-13), k(3) = (8.51 +/- 0.62) x 10(-12) exp(-681 +/- 72/T); k(3)(303) = (9.00 +/- 0.82) x 10(-13) and k(4) = (6.18 +/- 0.84) x 10(-12) exp(-736 +/- 42/T); k(4)(303) = (5.36 +/- 0.51) x 10(-13). The quoted 2sigma uncertainties include the systematic errors. All title reactions proceed via a hydrogen atom metathesis mechanism leading to HCl. Moreover, the oxidation of the primarily produced radicals was investigated, and the end products were the corresponding aldehydes (R(F)-CHO; R(F) = -CH(2)CF(3), -CF(2)CF(3), -CF(2)CHF(2), and -CF(2)CHFCF(3)), providing a strong experimental indication that the primary reactions proceed mainly via the abstraction of a methylenic hydrogen adjacent to a hydroxyl group. Finally, the bond strengths and ionization potentials for the title compounds were determined by density functional theory calculations, which also suggest that the alpha-methylenic hydrogen is mainly under abstraction by Cl atoms. The correlation of room-temperature rate coefficients with ionization potentials for a set of 27 molecules, comprising fluorinated C2-C5 ethers and C2-C4 alcohols, is good with an average deviation of a factor of 2, and is given by the expression log(k) (in cm(3) molecule(-1) s(-1)) = (5.8 +/- 1.4) - (1.56 +/- 0.13) x (ionization potential (in eV)).