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1.
Molecules ; 27(24)2022 Dec 07.
Article in English | MEDLINE | ID: mdl-36557785

ABSTRACT

Preferential enrichment (PE) is a crystallization process, starting from either a racemic of slightly enantio-enriched solution (ca. +5%) that results in a high enantiomeric excess in the liquid phase (>+90%ee) and a slight opposite excess in the deposited crystals (−2 to −5%ee). The mechanism(s) of this symmetry-breaking phenomenon is (are) still a matter of debate since it eludes rationalization by phase diagram formalism. In this publication, we thoroughly reinvestigate the PE phenomenon of arginine fumarate by using a new approach: the process is monitored by introducing isotopically labeled arginine enantiomers into the crystallization medium to better understand the mass exchanges during crystallization. These experiments are supported by chiral HPLC-MS/MS. This study permits re-evaluating the criteria that were thought mandatory to perform PE. In particular, we show that PE occurs by a continuous exchange between the solution and the crystals and does not require the occurrence of a solvent-mediated solid−solid phase transition.


Subject(s)
Arginine , Tandem Mass Spectrometry , Crystallization/methods , Phase Transition , Stereoisomerism
2.
Chempluschem ; 87(3): e202100521, 2022 Feb 03.
Article in English | MEDLINE | ID: mdl-35112809

ABSTRACT

Invited for this month's cover are the collaborating groups of Dr. Yoshiaki Uchida from Osaka University, Japan, Prof. Rui Tamura and Prof. Masahito Sugiyama from Kyoto University, Japan and Dr. Dmitrii G. Mazhukin from Novosibirsk State University, Russia. The cover picture depicts a contrast between localized spins and conductive ions in the newly-synthesized ionic liquid crystalline (ILC) nitroxide radicals. The ILC droplet of the new compounds is magnetically manipulable. More information can be found in the Full Paper by Yoshiaki Uchida, Rui Tamura, and co-workers.

3.
Chempluschem ; 87(3): e202100352, 2022 Mar.
Article in English | MEDLINE | ID: mdl-34636499

ABSTRACT

With a view to fabricating a new remote input-output system by applying functional ionic liquid crystalline (ILC) materials, we have developed novel ILC compounds containing a nitroxide radical unit in the organic cations, which show an enantiotropic smectic A (SmA) phase. We have implemented the magnetic manipulation of a droplet of one of the ILC compounds on the basis of the intermolecular magnetic interactions between radical moieties. This ILC monoradical compound shows a 55 % larger increase in paramagnetic susceptibility at the solid-to-LC melting point in the first heating process than the non-ionic LC monoradical compounds. It is most likely owing to the nanosegregation of strongly bonded ionic and non-ionic moieties. The increased molar magnetic susceptibility is preserved not only in the SmA phase but also in the isotropic liquid and solid phases during the first cooling process.

4.
Chemistry ; 25(71): 16405-16413, 2019 Dec 18.
Article in English | MEDLINE | ID: mdl-31566820

ABSTRACT

A new entry of chiral anti-hyperlipoproteinemia drug is reported, showing an excellent preferential enrichment (PE) phenomenon which is not caused by a polymorphic transition during crystallization, but is proposed to occur by a novel mechanism involving partially irregular stacking of R and S homochiral two-dimensional (2D) sheets with a large dipole moment, followed by selective redissolution of one homochiral 2D sheet into the mother liquor during crystallization. The cocrystal composed of (RS)-2-{4-[(4-chlorophenoxy)methyl]phenoxy}propionic acid (CPPPA) and achiral isonicotinamide exhibited a substantial enrichment in the mother liquor up to 93 % ee by simply repeating recrystallization under nonequilibrium conditions using high supersaturation. Furthermore, the deposited crystals with low ee values obtained at the end of PE experiment were second harmonic generation (SHG)-positive, indicating the formation of homochiral domains in the deposited crystals, which reflects the proposed mechanism of PE.

5.
Nanotechnology ; 30(22): 224002, 2019 May 31.
Article in English | MEDLINE | ID: mdl-30743248

ABSTRACT

Metal-free magnetic mixed micelles (mean diameter: 16 nm) composed of biocompatible surfactant Tween 80 and hydrophobic pyrrolidine-N-oxyl radical were prepared by mixing them in phosphate-buffered saline. The magnetic mixed micelles were characterized by dynamic light scattering and small angle neutron scattering measurements. The stability of the micelles is found to depend on the length of alkyl side chain in the nitroxide compounds and degree of unsaturation in the hydrophobic chain in the surfactant. The size of the mixed micelle can be tuned by changing the molar ratio of Tween 80 and nitroxyl radical. In view of theranostic application of the micelle, the cytotoxicity and stability in a physiological environment was investigated; the mixed micelle exhibited no cytotoxicity, high colloidal stability and high resistance towards reduction by large excess ascorbic acid. The in vitro and in vivo magnetic resonance imaging (MRI) revealed sufficient contrast enhancement in the proton longitudinal relaxation time (T 1) weighted images. In addition, hydrophobic fluorophores and an anticancer drug are stably encapsulated in the mixed micelles and showed fluorescence (FL) upon reduction by ascorbic acid and cytotoxicity to cancer cells, respectively. For example, the paclitaxel-loaded mixed micelles efficiently suppressed cancer cell growth. Furthermore, they were found to give higher MRI contrast (higher r 1 value) in vitro than the micelles without paclitaxel. The magnetic mixed micelles presented here are promising theranostic agents in nanomedicine due to their high biocompatibility and high resistivity towards reduction as well as functioning as a drug carrier in therapy and MR or FL imaging probe in diagnosis.

6.
Pharmaceutics ; 11(1)2019 Jan 19.
Article in English | MEDLINE | ID: mdl-30669485

ABSTRACT

Metal-free magnetic mixed micelles (mean diameter: < 20 nm) were prepared by mixing the biocompatible non-ionic surfactant Tween 80 and the non-toxic, hydrophobic pyrrolidine-N-oxyl radicals bearing a D-glucosamine unit in pH 7.4 phosphate-buffered saline (PBS). The time-course stability and in vitro magnetic resonance imaging (MRI) contrast ability of the mixed micelles was found to depend on the length of the alkyl chain in the nitroxide radicals. It was also confirmed that the mixed micelles exhibited no toxicity in vivo and in vitro and high stability in the presence of a large excess of ascorbic acid. The in vivo MRI experiment revealed that one of these mixed micelles showed much higher contrast enhancement in the proton longitudinal relaxation time (T1) weighted images than other magnetic mixed micelles that we have reported previously. Thus, the magnetic mixed micelles presented here are expected to serve as a promising contrast agent for theranostic nanomedicines, such as MRI-visible targeted drug delivery carriers.

7.
Chemistry ; 24(65): 17293-17302, 2018 Nov 22.
Article in English | MEDLINE | ID: mdl-30378204

ABSTRACT

A unique superparamagnetic-like behavior and a large "positive magneto-LC effect" were observed in the solid phases and the hexagonal columnar (Colh ) liquid crystalline (LC) phase, respectively, of novel achiral non-π-delocalized nitroxide diradical compounds (R,S)-1, which showed polymorphism in the solid phases (solids I and II). The SQUID magnetization measurement revealed that (1) (R,S)-1 containing a small amount of racemic diastereomers (R*,R*)-1 possessed an unusual and large temperature-independent magnetic susceptibility (χTIM >0) component in the original nanocrystalline solid I that was responsible for the observed superparamagnetic-like behavior under low magnetic fields and did not arise from the contamination by extrinsic magnetic metal or metal ion impurities, besides ordinary temperature-dependent paramagnetic susceptibility (χpara >0) and temperature-independent diamagnetic susceptibility (χdia <0) components, (2) a large increase in molar magnetic susceptibility (χM ) (positive magneto-LC effect) that occurred at the solid I-to-liquid crystal transition upon heating was preserved as an additional χTIM increase in the resulting polymorphic nanocrystalline solid II by cooling, and (3) such unique magnetic phenomena were induced by thermal processing for (R,S)-1 or by adding a small amount of (R*,R*)-1 to (R,S)-1 as the impurity.

8.
J Phys Chem B ; 122(29): 7409-7415, 2018 07 26.
Article in English | MEDLINE | ID: mdl-30001130

ABSTRACT

We synthesized new chiral all-organic liquid crystalline (LC) compounds with nitroxide (NO) and hydroxy (OH) groups, which form intermolecular hydrogen bonds between the NO and OH groups. The LC compounds show hexagonal columnar phases at room temperature, which solidify as LC glasses at low temperature. The experimental magnetic susceptibility of each of the compounds in the LC and isotropic phases is larger than that theoretically estimated on the simple assumption about the amount of the spins, whereas it accords with the theoretical one in the LC glass state. It is called magneto-LC effects. The difference between experimental and theoretical magnetic susceptibilities gradually increases as temperature increases through the LC glass state-to-LC phase transition. It suggests that molecular mobility is one of the origins of the magneto-LC effects.

9.
Chemistry ; 23(62): 15713-15720, 2017 Nov 07.
Article in English | MEDLINE | ID: mdl-28815766

ABSTRACT

With a view to developing a theranostic nanomedicine for targeted drug delivery systems visible by magnetic resonance (MR) imaging, robust metal-free magnetic nanoemulsions (mean particle size less than 20 nm) consisting of a biocompatible surfactant and hydrophobic, low molecular weight 2,2,5-trimethyl-5-(4-alkoxy)phenylpyrrolidine-N-oxyl radicals were prepared in pH 7.4 phosphate-buffered saline (PBS). The structure of the nanoemulsions was characterized by electron paramagnetic resonance spectroscopy, and dynamic light scattering and small-angle neutron-scattering measurements. The nanoemulsions showed high colloidal stability, low cytotoxicity, enough reduction resistance to excess ascorbic acid, and sufficient contrast enhancement in the proton longitudinal relaxation time (T1 ) weighted MR images in PBS in vitro (and preliminarily in vivo). Furthermore, the hydrophobic anticancer drug paclitaxel could be encapsulated inside the nanoparticles, and the resulting paclitaxel-loaded nanoemulsions were efficiently incorporated into HeLa cells to suppress cell growth.


Subject(s)
Antineoplastic Agents, Phytogenic/chemistry , Drug Carriers/chemistry , Magnetite Nanoparticles/chemistry , Nitrogen Oxides/chemistry , Paclitaxel/chemistry , Animals , Antineoplastic Agents, Phytogenic/toxicity , Ascorbic Acid/chemistry , Brain/diagnostic imaging , Cell Proliferation/drug effects , Dynamic Light Scattering , Electron Spin Resonance Spectroscopy , HeLa Cells , Humans , Hydrophobic and Hydrophilic Interactions , Magnetic Resonance Imaging , Mice , Molecular Weight , Neutron Diffraction , Oxidation-Reduction , Paclitaxel/toxicity , Particle Size , Scattering, Small Angle
10.
Chemistry ; 22(33): 11660-6, 2016 Aug 08.
Article in English | MEDLINE | ID: mdl-27406004

ABSTRACT

The kinetic/thermodynamic origin of preferential enrichment (PE), which is a spontaneous enantiomeric resolution phenomenon applicable to racemic crystals, is described. The mechanism of PE, which was unveiled with respect to the first-generation of chiral organic compounds showing PE, has been interpreted in terms of a nonlinear complexity phenomenon including two unique processes: a solvent-assisted solid-to-solid polymorphic transition and subsequent selective redissolution of the excess one enantiomer from the transformed disordered crystals into the mother liquor. The present works confirm that PE takes place because of the unique nonlinear solubility properties of the two enantiomers after the occurrence of a polymorphic transition under PE crystallization conditions at high supersaturation. Furthermore, a ternary phase diagram that is consistent with the mechanism of PE is proposed.

11.
Chem Commun (Camb) ; 52(20): 3935-8, 2016 Mar 11.
Article in English | MEDLINE | ID: mdl-26871609

ABSTRACT

The liquid crystalline chiral nitroxide biradical (S,S,S,S)-3 synthesized has shown much larger 'positive magneto-LC effects' in the chiral nematic (N*) phase than the monoradical (S,S)-1.

12.
Soft Matter ; 11(27): 5563-70, 2015 Jul 21.
Article in English | MEDLINE | ID: mdl-26073537

ABSTRACT

An optically active amphiphilic nitroxide radical compound [(S,S,R)-], which contains a paramagnetic (2S,5S)-2,5-dimethyl-2,5-diphenylpyrrolidine-N-oxyl radical group fixed in the inner position together with a hydrophobic long alkyl chain and a hydrophilic (R)-alanine residue in the opposite terminal positions, was found to serve as a low-molecular-weight gelator in H2O to give rise to a spin-labelled physical hydrogel. Characterization of the hydrogel was performed by microscopic (SEM, TEM and AFM) techniques, XRD and SAXS measurements, and IR, UV and CD spectroscopies. The gel-sol transition temperature was determined by EPR spectral line-width (ΔHpp) analysis. Measurement of the temperature dependence of relative paramagnetic susceptibility (χrel) for the hydrogel and sol phases was achieved by means of the double-integration of VT-EPR spectra.


Subject(s)
Hydrogels/chemical synthesis , Nitrogen Oxides/chemistry , Electron Spin Resonance Spectroscopy , Hydrophobic and Hydrophilic Interactions , Pyrrolidines/chemistry , Spin Labels , Stereoisomerism , Transition Temperature
13.
Chirality ; 27(7): 405-10, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25683517

ABSTRACT

By utilizing the preferential enrichment (PE) technique, we achieved an improved enantiomeric resolution of DL-leucine (Leu) using a 1:1 cocrystal (DL-) of DL-Leu and oxalic acid. The crystal structure analysis of DL- indicated the occurrence of a novel type of phase transition and subsequent preferential redissolution of one enantiomer from the resulting crystals into solution.


Subject(s)
Crystallization/methods , Leucine/chemistry , Oxalic Acid/chemistry , Crystallography, X-Ray , Stereoisomerism
14.
Chemistry ; 20(33): 10343-50, 2014 Aug 11.
Article in English | MEDLINE | ID: mdl-25042834

ABSTRACT

An excellent chiral symmetry-breaking spontaneous enantiomeric resolution phenomenon, denoted preferential enrichment, was observed on recrystallization of the 1:1 cocrystal of dl-arginine and fumaric acid, which is classified as a racemic compound crystal with a high eutectic ee value (>95 %), under non-equilibrium crystallization conditions. On the basis of temperature-controlled video microscopy and in situ time-resolved solid-state (13) C NMR spectroscopic studies on the crystallization process, a new mechanism of phase transition that can induce preferential enrichment is proposed.


Subject(s)
Arginine/chemistry , Crystallization , Crystallography, X-Ray , Models, Molecular , Phase Transition , Stereoisomerism
15.
J Phys Chem B ; 117(10): 3054-60, 2013 Mar 14.
Article in English | MEDLINE | ID: mdl-23421451

ABSTRACT

We have designed and synthesized a new chiral paramagnetic liquid crystalline compound with a nitroxide radical moiety showing chiral smectic A (SmA*) and C (SmC*) phases. This compound shows pretransitional layer contraction prior to the SmA*-to-SmC* phase transition in the cooling run. Electron paramagnetic resonance spectroscopy, X-ray diffraction analysis, and polarized optical microscopy reveal that a temperature-dependent conformational change is responsible for the pretransitional layer contraction.

16.
J Phys Chem B ; 116(32): 9791-5, 2012 Aug 16.
Article in English | MEDLINE | ID: mdl-22812516

ABSTRACT

To identify the origin of the magneto-LC effects, which refer to the enhancement of intermolecular magnetic interactions in the LC phases of all-organic radical compounds, we have designed and synthesized H-bonded all-organic radical compounds showing nematic and cholesteric phases for the first time. They show stronger magneto-LC effects than in the same LC phases of analogous covalent-bonded all-organic radical LC compounds. Variable-temperature electron paramagnetic resonance spectroscopy of the hydrogen-bonded compounds reveals that the inhomogeneous intermolecular contacts give rise to the magneto-LC effects.

17.
Chem Commun (Camb) ; 48(22): 2791-3, 2012 Mar 14.
Article in English | MEDLINE | ID: mdl-22315146

ABSTRACT

Nearly racemic ketoprofen, which satisfies the requirements for the occurrence of preferential enrichment, was spontaneously resolved into the two enantiomers by simple crystallization under nonequilibrium conditions using high concentrations.


Subject(s)
Ketoprofen/chemistry , Crystallography, X-Ray , Models, Molecular , Molecular Conformation , Stereoisomerism
18.
Org Lett ; 13(3): 490-3, 2011 Feb 04.
Article in English | MEDLINE | ID: mdl-21174414

ABSTRACT

Described are the syntheses, crystal structures, and solid-gas adsorption behaviors of azacalix[4]arene tetramethyl ether and azacalix[5]arene pentamethyl ether. While the former compound exhibited no adsorption of four main atmospheric components, the latter selectively and rapidly adsorbed CO(2) at ambient temperature and pressure. X-ray crystallographic and potential energy distribution analysis revealed that azacalix[5]arene created an energetically favorable space for CO(2) in its seemingly nonporous crystal, leading to the observed selective CO(2) uptake under ambient conditions.

19.
J Am Chem Soc ; 132(28): 9746-52, 2010 Jul 21.
Article in English | MEDLINE | ID: mdl-20586449

ABSTRACT

An anisotropic and inhomogeneous magnetic interaction (the average spin-spin interaction constant (-)J > 0) was observed in the various liquid crystalline (LC) phases of racemic and nonracemic all-organic radical LC compounds 1a and 1b. We discussed how the LC superstructures induced the magnetic interaction to operate in the LC phases in terms of spin-spin dipole and exchange interactions by means of VT-EPR spectroscopy. The magnitude of the magnetic interaction depended on the type of LC phase, or the superstructure. Furthermore, these radical LC droplets floating on water were commonly attracted to a permanent magnet and moved freely under the influence of this magnet, whereas the crystallized particles of the same compounds never responded to the magnet. The response of the LC droplets to the magnet also varied depending on the type of LC phase, that is, the extent of the magnetic interaction.

20.
Chem Commun (Camb) ; (24): 2812-4, 2008 Jun 28.
Article in English | MEDLINE | ID: mdl-18688319

ABSTRACT

Electron paramagnetic resonance spectroscopy has unmasked for the first time the spin-delocalised doublet- and triplet-ground states of azacalix[4]arene cation radicals.

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