Kratom Alkaloids: A Blood-Brain Barrier Specific Membrane Permeability Assay-Guided Isolation and Cyclodextrin Complexation Study.

Mitragynine is an "atypic opioid" analgesic with an alternative mechanism of action and a favorable side-effect profile. Our aim was to optimize the alkaloid extraction procedure from kratom leaves and to determine and isolate the most relevant compounds capable of penetrating the central nervous system. The PAMPA-BBB study revealed that mitragynine and its coalkaloids, speciociliatine, speciogynine, and paynantheine, possess excellent in vitro BBB permeability.

Cyclodextrin-Enabled Enantioselective Complexation Study of Cathinone Analogs.

The characteristic alkaloid component of the leaves of the catnip shrub () is cathinone, and its synthetic analogs form a major group of recreational drugs. Cathinone derivatives are chiral compounds. In the literature, several chiral methods using cyclodextrins (CDs) have been achieved so far for diverse sets of analogs; however, a comprehensive investigation of the stability of their CD complexes has not been performed yet.

Enantioseparation and quantitative determination of two homologous beta amino acids found in Fabaceae plants.

Non-protein amino acids are important metabolites of the Fabaceae family, possessing valuable biological effects in addition to their toxic properties. We have previously identified two non-protein amino acids homoproline and homopipecolic acid in Ononis species for the first time, and herein the study was extended to investigate further Fabaceae species (O. spinosa, O.

Single Isomer -Heterocyclic Cyclodextrin Derivatives as Chiral Selectors in Capillary Electrophoresis.

In order to better understand the chiral recognition mechanisms of positively charged cyclodextrin (CD) derivatives, the synthesis, the p determination by H nuclear magnetic resonance (NMR)-pH titration and a comparative chiral capillary electrophoretic (CE) study were performed with two series of mono-substituted cationic single isomer CDs. The first series of selectors were mono-(6--pyrrolidine-6-deoxy)-β-CD (PYR-β-CD), mono-(6--piperidine-6-deoxy)-β-CD (PIP-β-CD), mono-(6--morpholine-6-deoxy)-β-CD (MO-β-CD) and mono-(6--piperazine-6-deoxy)-β-CD (PIPA-β-CD), carrying a pH-adjustable moiety at the narrower rim of the cavity, while the second set represented by their quaternarized, permanently cationic counterparts: mono-(6--(-methyl-pyrrolidine)-6-deoxy)-β-CD (MePYR-β-CD), mono-(6--(-methyl-piperidine)-6-deoxy)-β-CD (MePIP-β-CD), mono-(6--(-methyl-morpholine)-6-deoxy)-β-CD (MeMO-β-CD) and mono-(6--(4,4--dimethyl-piperazine)-β-CD (diMePIPA-β-CD). Based on pH-dependent and selector concentration-dependent comparative studies of these single isomer -heterocyclic CDs presented herein, it can be concluded that all CDs could successfully be applied as chiral selectors for the enantiodiscrimination of several negatively charged and zwitterionic model racemates.

Enantioseparation of solriamfetol and its major impurity phenylalaninol by capillary electrophoresis using sulfated gamma cyclodextrin.

R-solriamfetol is a recently approved drug used for the treatment of excessive sleepiness associated with narcolepsy and sleep apnea. Herein, a capillary electrophoretic method was developed, enabling the simultaneous analysis of the API and its S-enantiomer in addition to the enantiomers of its major impurity phenylalaninol. Twenty-nine different cyclodextrins (CDs), including native, neutral, and charged ones were screened as potential chiral selectors, and the best results were obtained with sulfated CDs.

Single isomer cyclodextrins as chiral selectors in capillary electrophoresis.

Since decades, cyclodextrins are one of the most powerful selectors in chiral capillary electrophoresis for the enantioseparation of diverse organic compounds. This review concerns papers published over the last decade (from 2009 until nowadays), dealing with the capillary electrophoretic application of single isomer cyclodextrin derivatives in chiral separations. Following a brief overview of their synthetic approaches, the inventory of the neutral, negatively and positively charged (including both permanently ionic and pH-tunable ionizable substituents) and zwitterionic CD derivatives is presented, with insights to underlying structural aspects by NMR spectroscopy and molecular modeling.

Synthesis, analytical characterization and capillary electrophoretic use of the single-isomer heptakis-(6-O-sulfobutyl)-beta-cyclodextrin.

This contribution reports the synthesis, characterization and capillary electrophoretic application of heptakis-(6-O-sulfobutyl-ether)-β-cyclodextrin sodium salt, (6-(SB)-β-CD). The compound was obtained through a five-steps synthesis and it represents the first example of single-isomer sulfobutylated cyclodextrin that carries the negatively charged functions exclusively on its primary side and it is unmodified on the lower rim. The purity of each intermediate was determined by appropriate liquid chromatographic methods, while the isomeric purity of the final product was established by an ad-hoc developed HPLC method based on a CD-Screen-IEC column.

Characterization of a single-isomer carboxymethyl-beta-cyclodextrin in chiral capillary electrophoresis.

In this work, the synthesis, characterization, and chiral capillary electrophoretic study of heptakis-(2,3-di-O-methyl-6-O-carboxymethyl)-β-CD (HDMCM), a single-isomer carboxymethylated CD, are presented. The pH-dependent and selector concentration-dependent enantiorecognition properties of HDMCM were investigated and discussed herein. The enantioseparation was assessed applying a structurally diverse set of noncharged, basic, and zwitterionic racemates.

Comparative evaluation of the chiral recognition potential of single-isomer sulfated beta-cyclodextrin synthesis intermediates in non-aqueous capillary electrophoresis.

The enantioselectivity of neutral single-isomer synthetic precursors of sulfated-β-cyclodextrins was studied. Four neutral single-isomer cyclodextrins substituted on the secondary side with acetyl and/or methyl functional groups, heptakis(2-O-methyl-3,6-dihydroxy)-β-cyclodextrin (HM-β-CD), heptakis(2,3-di-O-acetyl-6-hydroxy)-β-cyclodextrin (HDA-β-CD), heptakis(2,3-di-O-methyl-6-hydroxy)-β-cyclodextrin (HDM-β-CD), heptakis(2-O-methyl-3-O-acetyl-6-hydroxy)-β-cyclodextrin (HMA-β-CD), and their sulfated analogs the negatively charged heptakis(2,3-di-O-methyl-6-sulfato)-β-cyclodextrin (HDMS-β-CD) and heptakis(2,3-di-O-acetyl-6-sulfato)-β-cyclodextrin (HDAS-β-CD) were investigated by non-aqueous capillary electrophoresis in the view of enantiodiscrimination for various drugs and related pharmaceutical compounds. The focus of the present work was on the chiral selectivity studies of the neutral derivatives, which are the synthesis intermediates of the sulfated products.

Single-isomer carboxymethyl-γ-cyclodextrin as chiral resolving agent for capillary electrophoresis.

Herein we report on the synthesis, characterization and the novel capillary electrophoretic use of octakis-(2,3-di-O-methyl-6-O-carboxymethyl)-γ-cyclodextrin sodium salt (ODMCM). ODMCM is the first single-isomer carboxymethyl-γ-cyclodextrin that is fully methylated on its secondary side and carries ionizable carboxymethyl functions on its primary side. ODMCM was prepared with high isomeric purity through a four-step synthetic procedure.

Development and validation of a cyclodextrin-modified capillary electrophoresis method for the enantiomeric separation of vildagliptin enantiomers.

The enantiomers of vildagliptin, an orally available and selective dipeptidyl-peptidase-4 inhibitor used for the treatment of type II diabetes, have been separated by CD-modified CZE, using uncoated fused-silica capillary. After screening 13 negatively charged CD derivatives as potential chiral selectors, sulfobutyl-ether-α-CD (SBE-α-CD) was selected for the enantioseparation. For the optimization, a factorial analysis study was performed by orthogonal experimental design.

Enantiomeric separation of tapentadol by capillary electrophoresis--study of chiral selectivity manipulation by various types of cyclodextrins.

The chiral recognition of the centrally acting analgesic agent tapentadol and its isomers with various cyclodextrins (CDs) was studied by capillary electrophoresis, focusing on the migration order of four stereoisomers. In the case of non-charged hydroxypropylated CDs (2-hydroxypropyl-β-CD, 2-hydroxypropyl-γ-CD) the beta derivative was able to discriminate the S,R- and R,S-isomers in acidic background electrolyte, whereas the gamma allowed the separation of S,S- and R,R-tapentadol, respectively. Dual CD system containing both hosts was used to separate all of four isomers.

Interactions of non-charged tadalafil stereoisomers with cyclodextrins: capillary electrophoresis and nuclear magnetic resonance studies.

The single isomer drug R,R-tadalafil (Cialis) contains two chiral centers thus four stereoisomers (R,R-, S,S-, S,R- and R,S-tadalafil) exist, however, only the most potent inhibitor, the R,R-tadalafil is in clinical use. In our study, over 20 charged cyclodextrin (CD) derivatives were studied for enantiospecific host-guest type interactions in CD-modified capillary electrophoresis. Tadalafil stereoisomers are non-charged; therefore, their electrophoretic separation poses a challenge.

Qualitative and quantitative analysis of PDE-5 inhibitors in counterfeit medicines and dietary supplements by HPLC-UV using sildenafil as a sole reference.

Due to their popularity, medicinal products containing the phophodiesterase type 5 enzyme (PDE-5) inhibitors sildenafil, vardenafil and tadalafil are often subject to counterfeiting. In addition, illicit herbal dietary supplements adulterated with these substances or their analogs have appeared on the market offering an easy and anonymous sale. This paper describes an analytical method for qualitative and quantitative screening of sildenafil, vardenafil, tadalafil and 11 of their designer analogs in illegal erectile dysfunction products by high-performance liquid chromatography with UV detection (HPLC-UV).

Separation of alogliptin enantiomers in cyclodextrin-modified capillary electrophoresis: a validated method.

The single enantiomer drug, alogliptin (Alo, Nesina®) is a novel, orally available and selective dipeptidyl peptidase-4 inhibitor used for the treatment of type II diabetes. Following its pKa determination by CE-pH titration, a validated chiral CE method has been developed to separate Alo enantiomers. Preliminary screening of the native CDs and their ten derivatives revealed that sulfopropylated-γ-CD, sulfopropylated-β-CD and sulfopropylated-γ-CD, sulfobutyl-ether-β-CD (SBE-β-CD) and sulfobutyl-ether-γ-CD enabled enantioresolution.

Tapentadol enantiomers: Synthesis, physico-chemical characterization and cyclodextrin interactions.

The complete physico-chemical characterization of the single enantiomer analgesic drug R,R-tapentadol was quantitated in terms of protonation macro- and microconstants and octanol-water partition coefficient using pH-potentiometry, UV-pH and (1)H NMR-pH titrations. The protonation macroconstants were found to be logK1=10.59±0.

Separation of vinca alkaloid enantiomers by capillary electrophoresis applying cyclodextrin derivatives and characterization of cyclodextrin complexes by nuclear magnetic resonance spectroscopy.

In this work, the enantiomeric separation of three vinca alkaloid enantiomers (vincamine, vinpocetine and vincadifformine) has been investigated in an aqueous capillary electrophoresis (CE) system using cyclodextrins (CDs). The investigated CDs were the native alpha-, beta-, and gamma-CDs and their hydroxypropylated, randomly methylated, carboxymethylated and sulfobutylated derivatives. The first part of this study consisted of the determination of the apparent averaged complex stability constants with the selected CDs.