Advancing ophthalmic delivery of flurbiprofen via synergistic chiral resolution and ion-pairing strategies

Flurbiprofen(FB),a nonsteroidal anti-inflammatory drug,is widely employed in treating ocular inflammation owing to its remarkable anti-inflammatory effects.However,the racemic nature of its commercially available formulation(Ocufen^(R))limits the full potential of its therapeutic activity,as the(S)-enantiomer is responsible for the desired antiinflammatory effects.Additionally,the limited corneal permeability of FB significantly restricts its bioavailability.In this study,we successfully separated the chiral isomers of FB to obtain the highly active(S)-FB.Subsequently,utilizing ion-pairing technology,we coupled(S)-FB with various counter-ions,such as sodium,diethylamine,trimethamine(TMA),and l-arginine,to enhance its ocular bioavailability.A comprehensive evaluation encompassed balanced solubility,octanol-water partition coefficient,corneal permeability,ocular pharmacokinetics,tissue distribution,and in vivo ocular anti-inflammatory activity of each chiral isomer salt.Among the various formulations,S-FBTMA exhibited superior water solubility(about 1–12 mg/ml),lipid solubility(1<lgP_(ow)<3)and corneal permeability.In comparison to Ocufen^(R),S-FBTMA demonstrated significantly higher in vivo antiinflammatory activity and lower ocular irritability(such as conjunctival congestion and tingling).The findings from this research highlight the potential of chiral separation and ion-pair enhanced permeation techniques in providing pharmaceutical enterprises focused on drug development with a valuable avenue for improving therapeutic outcomes.

Chiral Resolution of β-dl-Phenylalanine Using Chiral Macrocyclic Nickel(Ⅱ) Complexes

The reactions of chiral four-coordinated nickel（Ⅱ） complex [Ni（RR-L）]（ClO4）2/[Ni（SS- L）]（ClO4）2 with β-dl-phenylalanine in acetonitrile/water gave a six-coordinated enantiomer of [Ni（RR-L）（β-d-HPhe）]（ClO4）2（1） and [Ni（SS-L）（β-l-HPhe）]（ClO4）2（2）, respectively（L = 5,5,7, 12,12,14-hexamethyl-1,4,8,11-tetraazacyclotetradecane, HPhe = phenylalanine）. Single-crystal X-ray diffraction analyses revealed that the nickel（Ⅱ） atom displays a distorted octahedral coordination geometry by coordinating with four nitrogen atoms of L in a folded configuration, and two carboxylate oxygen atoms of β-d/l-HPhe in cis-position in both complexes. The monomers of [Ni（RR-L）（β-d-HPhe）]2＋ and [Ni（SS-L）（β-l-HPhe）]2＋ are connected through intermolecular hydrogen bonds to generate one-dimensional zigzag chains, respectively. The homochiral natures of 1 and 2 are confirmed by the results of CD spectroscopy.

Chiral resolution of furofuran lignans and their derivatives from the stems of Dendrobium'Sonia'

Five new furofuran lignans and their derivatives,(-)-glaberide I 4-O-β-D-glucopyranoside(1a),(+)-glaberide I 4-O-β-D-glucopyranoside(1b),(+)-glaberide I 7'-ethoxy-4-O-β-D-glucopyranoside(2a),(-)-glaberide I 7'-ethoxy-4-O-β-D-glucopyranoside(2b),and(-)-isoeucommin A(3b),along with fifteen known analogs were isolated from the stems of Dendrobium'Sonia'.These compounds were classified into ten pairs of enantiomers or diastereoisomers via chiral resolution,and their structures were determined based on extensive spectroscopic data.Their absolute configurations were determined by hydrolysis,comparison of experimental and calculated electronic circular dichroism(ECD)data,and single-crystal X-ray diffraction analysis.The isolates were evaluated for their ability to inhibit nitric oxide(NO)production in RAW264.7 cells.Among them,syringaresinol(5)exhibited prominent inhibition activity,with an IC50 value of 28.4±3.0μmol·L~(-1),and there was a slight difference between 5a,5b and the racemic mixture 5.

Direct Optical Resolution of Chiral Pesticides by High Performance Liquid Chromatography

Enantiomer separation is one of the most important prerequisites for the investigation of environmental enantioselective behavior for chiral pesticides.The enantiomeric separation of three chiral pesticides,indoxacarb,lambda-cyhalothrin,and simeconazole,were studied on cellulose tris-(3,5-dimethylphenyl-carbamate)-coated chiral stationary phase(CDMPC-CSP) using high-performance liquid chromatography under normal phase condition.The effects of chromatographic conditions,such as the mobile phase composition including the concentration and type of alcohol modifiers in hexane,flow rate and column temperature,on enantiomer separation were examined.The thermodynamical mechanism of enantioseparation and chiral recognition mechanism were discussed.Better separation were achieved using 20% n-propanol for indoxacarb,2% iso-butanol for lambda-cyhalothrin,and 20% iso-propanol for simeconazole as modifiers in hexane at 25℃ with the selectivity factor(a) of 1.69,1.82 and 1.70,respectively.The resolution factor(Rs) decreased as the flow rate increased from 0.4 to 1.1 ml·min-1.The retention factor(k') and selectivity factor for the enantiomers of analytes decreased as temperature increased.The lna-1/T plots for racemic chiral pesticides were linear in the range of 15-35℃ in hexane/iso-propanol and the chiral separation was controlled by enthalpy.Hydrogen bonding,π-π and dipole-dipole interactions between enantiomers and CDMPC-CSP play an important role in chiral identification,and the fitting of the asymmetric portion of solutes in a chiral cavity or channel of the CSP is also important.

Lipase immobilized on HOOC-MCF:A highly enantioselective catalyst for transesterification resolution of (R,S)-1-phenylethanol

Pseudomonas cepacia lipase （PSL） immobilized on the carboxyl-functionalized meso-cellular foams （HOOC-MCF） was used for the transesterification resolution of （R,S）-l-phenylethanol in organic solvent. The results showed that the ee value of （S）-1- phenylethanol and （R）-1-phenylethyl acetate reached 99% with 50% conversion of 1-phenylethanol using toluene as solvent. Furthermore, it was found that PSL/HOOC-MCF exhibited high enantioselectivity in organic solvent with log P ≤ 2 such as toluene and hexane.

Chiral basket-handle porphyrin-Co complexes for the catalyzed asymmetric cycloaddition of CO_2 to epoxides

The catalytic synthesis of cyclic carbonates via the cycloaddition of CO2 to epoxides is a standard methodology for CO2 fixation.For this purpose,chiral basket-handle porphyrin-Co complexes were devised,prepared,and fully characterized by nuclear magnetic resonance,mass spectrometry,Fourier transform infrared spectroscopy,ultraviolet-visible spectroscopy,and specific rotation.The proposed metalloporphyrin catalysts were synthesized with either 1,1'-bi-2-naphthol or L-phenylalanine,which have different chirality,and then applied to the coupling of propylene oxide and CO2 for generating chiral cyclic carbonates with good enantioselectivity under extremely mild conditions in the presence of tetrabutyl ammonium chloride as a co-catalyst.The good enantioselectivity in the cycloaddition reaction is attributed to a synergistic interplay between the chiral porphyrin catalysts and the substrate.The mechanism and enantioselectivity of the asymmetric cycloaddition reaction is discussed.

Chiral Isothiourea-Catalyzed Acylative Dynamic Kinetic Resolution of 3-Hydroxyphthalides for Enantioselective Synthesis of Phthalidyl Esters

Comprehensive Summary Phthalides serve as core structures pervasive in a wide array of natural products and drug molecules,which display a diverse array of biological activities.We report herein a highly efficient dynamic kinetic resolution of 3-hydroxyphthalides by chiral isothioureas(ITUs)catalyzed asymmetric acylation,facilitating the effective synthesis of a variety of chiral phthalidyl esters with good yields and enantioselectivities.Notably,this reaction features mild reaction conditions,expansive substrate scope as well as good functional group compatibility.In addition,the practicality of this method is underscored by the large-scale synthesis,reduced catalyst loading experiment and the synthesis of the chiral phthalidyl ester prodrug.

Attempt to Resolute Chiral Clusters by Optically Active Hydrazide

A new kind of hydrazone (I) diastereoisomers was prepared with enantiomeric hydazide (II) and chiral cluster (III), which was characterized by HMBC. Unfortunately, the mixture could not be separated into pure diastereoisomer. This could be a direction to separate the racemic chiral clusters.

Study on extraction kinetics ofα-cyclopentylmandelic acid enantiomers with hydroxyethyl-β-cyclodextrin as chiral selector

In this work,the kinetic study on reactive extraction ofα-cyclopentylmandelic acid(α-CPMA)enantiomers was performed in a Lewis cell using hydroxyethyl-β-cyclodextrin(HE-β-CD)as chiral selector.The enantioselective complexation equilibrium between HE-β-CD andα-CPMA enantiomers was studied by phase solubility method.The important process parameters affecting the initial extraction rate were separately studied and the reaction rate equations were deduced.The optimal conditions for kinetic study were as follows:stirring speed of 75 r·min^(-1),interfacial area of 12.56 cm^2,pH of 2.5,initial HE-β-CD concentration of 0.05 mol·L^(-1),initialα-CPMA concentration of 5 mmol·L^(-1),and temperature of 278 K.The reaction has been found to be first order inα-CPMA and second order in HE-β-CD with the forward rate constants of 2.056×10^(-3)m^6·mol^(-2)·s^(-1)and 1.459×10^(-3)m^6·mol^(-2)·s^(-1)for(S)-α-CPMA and(R)-α-CPMA,respectively.The complexation equilibrium constants were evaluated as 61 L·mol^(-1) and 117 L·mol^(-1)for(S)-α-CPMA and(R)-α-CPMA,and the intrinsic enantioselectivity is estimated as 1.92.

Chiral Recognition and Resolution Based on Helical Polymers

Helical polymers have attracted a great deal of attention and been extensively investigated due to their various applications.One of the most importa nt applicati ons of helical polymers is chiral recog nition and resolutio n ofe nan tiomersforthe reas on that a pair of e nan tiomers is comm only with differe nt physiological and toxicological behaviors in biological systems.Helical polymers usually prese nt un expected high chiral recogniti on ability to a variety of racemic compo unds.Whatzs more,the chiral recog nition and resolution abilities of the system are depe ndent on the highly ordered helical structures of the helical polymers.This mini review mainly focuses on the recent progress in chiral recognition and resolution based on helical polymers.The synthetic methodology for helical polymers is firstly discussed briefly.Then recent advances of chiral recog nition and resoluti on systems based on helical polymers,especially polyacetylenes and polyisocya nides,are described.We hope this mini review will in spire more in terest in developing helical polymers and en courage further advances in chiral-related disciplines.

Thermodynamic Resolution of Pharmaceutical Precursor Modafinil Acid on the Basis of Chiral-at-Metal Strategy

Chiral-at-metal strategy was developed to resolve the essential sulfoxide pharmaceutical intermediates R-modafinil acid and its ana-logues with high yields and ee values.The efficient resolution process was achieved based on the diastereoselective discrimination caused by hydrogen bond and intramolecular π-π interaction between chiral-at-metal center and the coordinated chiral sulfoxide ligands.Moreover,the chiral Ir(lll)receptor can be reused with complete retention of their configurations and without the loss of reaction activity and enantioselectivity.This work provides a new access to synthesize R-modafinil acid as well as its analogues and develops the application of chiral-at-metal strategy in chiral resolution.

Boron-Stereogenic Compounds:Synthetic Developments and Opportunities

Comprehensive Summary The 21st century has witnessed a continuous evolution in the development of boron-stereogenic chemistry.Since the 1990s,various innovations for the synthesis of tetracoordinate boron-stereogenic compounds,which exhibited great potential applications,have been demonstrated by synthetic chemists.This paper reviews the significant progress and recent advances towards the assembly of enantioenriched boron-stereogenic compounds,and hopes to shed light on new perspectives and inspire further research in this emerging field.

Sarcocinerenoids A—J,Eight Rare Capnosane-Type and Two New Cage-Type Cembranoids with Promoting Angiogenesis Activity from the South China Sea Soft Coral Sarcophyton cinereum

Backgroundand Originality Content,Cembranoids are a structurally diverse class of diterpenoids commonly occurring in marine and terrestrial organisms.(+)-Cembrene was the first reported cembranoid diterpenoid discovered in 1962,l and more than 1400 cembranoid diterpenoids have been identified in the last six decades,[2]Cembranoids are characterized by a 14-membered carbocyclic ring,an isopropyl group and three methyl groups,which form their core carbon skeleton.Enzymatic processes such as oxidation,oxidative rearrangements and transannular cyclizations occur in organisms,leading to the formation of distinctive specialized metabolites such as epoxide,lactone,ester,furan,pyrane and other ringbased cembranoids.[2-3]

Triple Aza[6]helicenes with Circularly Polarized Luminescence:N-Alkylation as a Tool to Tune the Chiroptical Properties

Recently,multiple helicenes have attracted enormous attention due to their exceptionally distorted conjugated architectures,appealing optical properties and unique spatial stacking patterns.The electronic and optical properties of multiple helicenes could be modulated by heteroatom doping.Herein,the first triple aza[6]helicene was reported by an intramolecular oxidation reaction,which exhibited highly distorted propeller-like geometry revealed by single crystal X-ray diffraction analysis.In comparison to the reported triple oxa[6]helicene,the triple aza[6]helicene demonstrated increased quantum yield(5.5%),and chiroptical properties with a|gabs|value of 0.012 and a|glum|value of 3.0×10^(-3).Furthermore,the stability and chiroptical properties of the triple aza[6]helicene could be enhanced by N-alkylation.

Chiral Coordination Metallacycles/Metallacages for Enantioselec-tive Recognition and Separation

In recent years,chiral discrete supramolecular coordination complexes have attracted increasing interest as simple enzyme mimetics owing to their aesthetic architectures and potential applications in chiral science.This review summarizes the recent advances on chiral coordination metallacy-cles/metallacages with inherent cavities for enanti on selective recog nition and separation,including their design principles and synthesis,the in troduc-tion of chirality and functionality,structural adaptability,and host-guest bonding in enantioselective process.Finally,the perspectives on the remain-ing challenges and future opportunities are presented.

Extraction of Phenylalanine Phase Systems Containing Enantiomers by Aqueous Two Combinatorial Chiral Selector

In order to obtain a better enantioselectivity of phenylalanine enantiomers and establish the optimal chiral ex- traction conditions, the distribution behavior was investigated in aqueous two-phase systems which were composed of polyethylene glycol and ammonium sulfate containing combinatorial chiral selector： β-cyclodextrin and HP-β-cyclodextrin. The influence of the molar concentration ratio of combinatorial chiral selectors, the total molar concentration of combinatorial chiral selectors, pH value, buffer type and its concentration were thoroughly studied, respectively. The results show that the enantioselectivity reaches 1.53 under the optimal chiral extraction conditions This extraction is a potential economical and effective way for chiral resolution.

A Concise,Practical Chiral Resolution Approach of Racemic (E)-4,4-Dimethyl-1-(4-nitrophenyl) pent-1-en-3-ol to Its both Enantiomers via Strategy of Diastereomeric Ester Formation and Crystallization Using both N-Boc-D- and N-Boc-L-phenylglycines as Chiral Auxiliaries

Chiral secondary alcohols are an important class of functionalities commonly seen in drugs and other bioactive compounds.In an ongoing drug discovery program in our laboratories,a nitro-bearing racemic allylic secondary alcohol (±)-1 was discovered as a promising drug candidate,and in the following preclinical studies,a concise,reliable,practical synthetic approach to its both enantiomers with high optical purities was greatly needed.In the present study,we developed a chiral resolution approach of (±)-1 to its both enantiomers,i.e.,(+)-1 and (-)-1,via the strategy of diastereomeric ester formation and crystallization using both N-Boc-D- and N-Boc-L-phenylglycines as chiral auxiliaries.The absolute configurations of all the four key intermediates were unambiguously determined by single-crystal X-ray diffraction,providing a solid foundation for the stereochemistry of the present study.The two enantiomers were obtained in high optical purities.This approach is characterized by scalability and practicality and is envisaged to enable the chiral resolution of other racemic secondary alcohols,especially those with labile groups,such as NO_(2);olefinic C=C bond.

Aphamines A-C,dimeric acyclic diterpene enantiomers from Aphanamixis polystachya

Aphamines A-C(1-3),three pairs of acyclic diterpene dimer enantiomers with an unprecedent ploymerization pattern,were discovered from Aphanamixis polystachya by NMR-guided isolation and chiral resolution.The elucidation of their novel carbon skeletons was achieved based on spectroscopic analysis,exciton chirality,and calculated electronic circular dichroism(ECD).Plausible Claisen rearrangement,5-exo-trig cyclization,and reduction reactions may play important roles in the polymeric biosynthesis pathway.Compounds 1 and 3 showed inhibitory effects on nitric oxide(NO)production(IC_(50):6.71-15.36 μmol/L) and reduced the expression of iNOS in LPS-induced RAW 264.7 macrophages.

Applications of the crystallization process in the pharmaceutical industry

The applications of the crystallization technique in the pharmaceutical industry as a purification and separation process for the isolation and synthesis of pure active pharmaceutical ingredients(API),co-crystals,controlled release pulmonary drug delivery,and separation of chiral isomers are briefly discussed using a few case studies.The effect of process variables and solvent on the polymorphism and morphology of stavudine is discussed.The implementation of external control in the form of feedback and real-time optimal control using cooling and antisolvent crystallization of paracetamol in water-isopropyl alcohol is introduced.Two methods to prepare micronsized drug particles,namely,micro-crystallization and polymer-coated API-loaded magnetic nanoparticles for pulmonary drug delivery,are discussed.The significance of co-crystals in drug administration is highlighted using the theophylline-nicotinamide co-crystal system.Resolution of chloromandelic acid derivatives,a racemic compound,is achieved using direct crystallization and diastereomeric salts crystallization.The crystal structures of diastereomeric salts of chloromandelic acid and phenylethylamine are determined.The structure comparison between the less soluble and more soluble salts shows that weak interactions such as CH/πinteractions and van der Waals forces contribute to chiral recognition when the hydrogen bonding patterns are similar.