Study On Competitive Supramolecular Interaction Of Drug Molecules With Cucurbit[n]uril And Its Analytical Applications

Recently, the cucurbit[n]uril (CB[n]) family has grown to includehomologues (CB[5]–CB[10]), derivatives, congeners, and analogueswhose sizes span and exceed the range available with the α-, β-, andγ-cyclodextrins. They may now have a wide range of applicationsincluding in molecular recognition, self-assembly, molecularswitches, molecular machines, drug carriers, nanotechnology andadvanced materials. However, little attention has been devoted totheir potential analytical applications. Spectrofluorometry isconsidered as the most convenient analytical technique inpharmaceutical analysis, owing to its inherent simplicity, highsensitivity, and availability in most quality-controlled and clinicallaboratories. However, the most of drugs are non-fluorescent inaqueous solutions. Hence, the development of a fast, simple, andhighly sensitive spectrofluorimetric method for the determination ofnon-fluorescent or weakly fluorescent drugs in aqueous solutions ishighly desirable. The aim of this study is to develop a fluorescentprobe method with high sensitivity for the determination of somedrugs based on the competition between the probe and the analytesmolecules for occupancy of the CB[7] cavity. The content of thispaper are as follows:1. The synthesis, physicochemical properties, recognition properties, and applications of CB[n]s are briefly reviewed. Theprogress of CB[n]s analytical applications are also summarized.2. The inclusion of the antibacterial drug coptisine (COP) and theantiviral drugs amantadine (AMA) and rimantadine (RIM) by CB[7]has been studies by fluorescence spectrometry,1H nuclearmagnetic resonance spectroscopy and molecular modeling. Allthree drugs form1:1host-guest complexes with CB[7]. Thecompetitive supramolecular interaction of two antiviral drugs (AMAand RIM) and COP with CB[7] was also studied. AMA and RIM arenon-fluorescent in aqueous solutions. This property makes theirdetermination through direct fluorescent method impossible. Basedon the significant quenching of the supramolecular complexfluorescence intensity, a fluorescent probe method of highsensitivity and selectivity was developed to determine AMA or RIMin their pharmaceutical dosage forms and in urine samples withgood precision and accuracy. The linear range of the method wasfrom0.004μg mL1to1.000μg mL1with a limit of detection rangingfrom0.0012μg mL1to0.0013μg mL1. This shows that theproposed method has promising potential for therapeuticmonitoring and pharmacokinetics and for clinical application.3. The cholinergic drug carbachol (CCH) is non-fluorescent inaqueous solution. This property makes its determination throughdirect fluorescent method impossible. The antibacterial drugberberine (BER) exhibits very weak fluorescence emissions inaqueous solution. However, In acidic medium and room temperature,BER can react with CB[7] to form stable complex and thefluorescence intensity of the complex was greatly enhanced. The dramatic quenching of the fluorescence intensity of CB[7]-BERcomplex was observed with the addition of CCH. The competitivesupramolecular interaction between CCH and BER for occupancy ofthe CB[7] cavity was studied by spectrofluorometry,1H NMR, andmolecular modeling calculation. Based on the significant quenchingof the supramolecular complex fluorescence intensity, a simple,rapid, and sensitive fluorescence probe method for thedetermination of CCH in pharmaceutical dosage form and inbiological fluids was developed. The linear range of the method wasfrom0.01μg mL1to1.5μg mL1. The limit of detection was0.003μgmL–1. This shows that the proposed method has promising potentialfor quality control, forensic identification, drug abuse or therapeuticmonitoring, pharmacokinetics, and clinical application.4. The histamine H1receptor antagonist astemizole (AST) isnon-fluorescent in aqueous solution. This property makes itsdetermination through direct fluorescent method impossible. Thecompeting reactions and the supramolecular interactionmechanisms between AST and the antiviral drug palmatine (PAL) asthey fight for occupancy of the CB[7] cavity, were studied usingspectrofluorimetry,1H NMR, and molecular modeling calculations.The association constants of the complexes formed between thehost and the guest were determined. Based on the significantquenching of the supramolecular complex fluorescence intensity, afluorescent probe method of high sensitivity and selectivity wasdeveloped to determine AST in its pharmaceutical dosage forms andin urine samples with good precision and accuracy. The linear rangeof the method was from0.02μg mL1to2.2μg mL1. The detection limit was0.007μg mL–1. This shows that the proposed method haspromising potential for therapeutic monitoring andpharmacokinetics and for clinical application.5. The hypoglycemic agent gliclazide (GLZ) is non-fluorescent inaqueous solution. This property makes its determination throughdirect fluorescent method impossible. The dramatic quenching ofthe fluorescence intensity of CB[7]-PAL complex was observed withthe addition of GLZ. The competing reactions and thesupramolecular interaction mechanisms between GLZ and PAL asthey fight for occupancy of the CB[7] cavity, were studied usingspectrofluorimetry,1H NMR, and molecular modeling calculations.The association constants of the complexes formed between thehost and the guest were determined. Based on the significantquenching of the supramolecular complex fluorescence intensity, afluorescent probe method of high sensitivity was developed todetermine GLZ in its pharmaceutical dosage forms and in humanplasmas with good precision and accuracy. The linear range of themethod was from0.003μg mL1to2.100μg mL1. The limit ofdetection was0.001μg mL–1. This shows that the proposed methodhas promising potential for therapeutic monitoring andpharmacokinetics and for clinical application.6. The supramolecular interactions of three anti-arrhythmicdrugs sotalol, labetalol and esmolol with CB[7] were studied byusing spectrophotometry and nuclear magnetic resonancespectroscopy. All three drugs form1:1host-guest complexes withCB[7]. There binding constants were1.85×104M1,7.67×104M1and1.80x104M1, respectively. Encapsulation inside CB[7] shifted the pKa of sotalol and labetalol towards higher value. The obtainedpKa shifts were1.4and0.45units, respectively.