Anthony I. Day

A Method for Synthesizing Partially Substituted Cucurbit[n]uril

A novel approach to cucurbituril synthesis is described where partial substitution is introduced into cucurbit[n]uril. The identification of homologues (and their substitution) in reaction mixtures is achieved by a combination of ESMS and the use of the molecular probes (guests) 1,4-dioxane and 1,9-octanediamine. A unique symmetrical hexamethylcucurbit[3,3]uril, the major product, was isolated and characterized.

Solubilisation and cytotoxicity of albendazole encapsulated in cucurbit[n]uril

The aqueous solubilities of albendazole encapsulated in cucurbit[6, 7 and 8]urils (Q[6], Q[7] and Q[8]) have been determined by (1)H NMR spectroscopy, and the effect of encapsulation on their cytotoxicities evaluated. Encapsulation in Q[6] and Q[7] increased the aqueous solubility of albendazole by 2000-fold, from 3 microM to 6 mM at pH 6.6, while Q[8]-encapsulation increased the solubility to over 2 mM. Encapsulation in Q[7] and Q[8] induced significant upfield shifts for the albendazole propyl and benzimidazole resonances, compared to those observed for Q[6]-binding and what would normally be expected for the respective functional groups. The upfield shifts indicate that the albendazole propyl and benzimidazole protons are located within the Q[7] and Q[8] cavity upon encapsulation. Alternatively, encapsulation in Q[6] only induced a large upfield shift for the albendazole carbamate methyl resonance, indicating that the drug associates with Q[6] at its portals, with only the carbamate group within the cavity. Simple molecular models based on the observed relative changes in chemical shift could be constructed that were consistent with the conclusions from the NMR experiments. Cytotoxicity assays against human colorectal cells (HT-29), human ovarian cancer cells (1A9) and the human T-cell acute lymphoblastic leukaemia cells (CEM) indicated that encapsulation in Q[7] did not significantly reduce the in vitro anti-cancer activity of albendazole.

Cucurbituril binding of trans-[{PtCl(NH3)2}2(µ-NH2(CH2)8NH2)]2+ and the effect on the reaction with cysteine

The effect of encapsulation by cucurbiturils Q[7] and Q[8] on the rate of reaction of the anti-cancer dinuclear platinum complex trans-[{PtCl(NH3)2}2(micro-NH2(CH2)8NH2)]2+ with the model biological nucleophiles glutathione and cysteine has been examined by NMR spectroscopy. It was expected that the octamethylene linking chain would fold inside the cucurbituril host and hence position the reactive platinum centres close to the cucurbituril portals, and thereby, confer resistance to degradation by biological nucleophiles. The upfield shifts of the resonances from the methylene protons in the linking ligand observed in 1H NMR spectra of the platinum complex upon addition of either Q[7] or Q[8] indicate that the cucurbituril is positioned over the linking ligand, with the Pt(II) centres projecting out of the portal. Furthermore, the relative changes in chemical shift of the methylene resonances suggest that the octamethylene linking chain folds within the cucurbituril cavity, particularly in Q[8]. Simple molecular models, based on the observed relative changes in chemical shift, could be constructed that were consistent with the proposed folding of the linking ligand within the cucurbituril cavity. Encapsulation by Q[7] was found to reduce the rate of reaction of the platinum complex with glutathione. Encapsulation by Q[7] and Q[8] was also found to reduce the rate of reaction of the platinum complex with cysteine, with Q[8] slowing the reaction to a greater extent than Q[7], consistent with the inferred encapsulation geometries. Encapsulation of dinuclear platinum complexes within the cucurbituril cavity may provide a novel way of reducing the reactivity and degradation of these promising chemotherapeutic agents with blood plasma proteins.

Preparation of glycoluril monomers for expanded cucurbit[n]uril synthesis

Abstract Glycoluril derivatives bearing free ureidyl groups ( 1 ) and bis(cyclic ethers) ( 2 ) are the fundamental building blocks for the synthesis of cucurbituril, its derivatives, and its congeners. The known derivatives of 1 and 2 fall into two main classes—those bearing alkyl or aryl functional groups on their convex face. In this paper we present a third class of glycolurils, namely those bearing substituents that are electron withdrawing in character. This class of compounds carries carboxylic acid derived functional groups on their convex face and are derived from diesters 1e and 2e . An improved synthesis of 1e and 2e is reported and their modification described. For example, 1e and 2e are converted into secondary amides ( 10–15 ) by heating in solutions of the neat primary amines. The secondary amides can be transformed into imides ( 19–22 , 24 , 25 ) by heating with PTSA in ClCH2CH2Cl. The isolation of these compounds in pure form in high yields is accomplished by simple and scalable washing or recrystallization procedures. We also present the X-ray crystallographic characterization of bis(cyclic ethers) 2e , 8 , and 22 . We anticipate that the ready availability of ester, carboxylate, acid, secondary amide, imide, and tertiary amide derivatives of 1 and 2 will expand the scope of the synthesis of cucurbituril derivatives by providing a new class of building blocks with electron withdrawing substituents.

Inclusion complexes of the antitumour metallocenes Cp2MCl2 (M = Mo, Ti) with cucurbit[n]urils

The encapsulation of the aquated forms of molybdocene dichloride and titanocene dichloride by cucurbit[n]uril (Q[n], where n = 7 and 8) at different pD values has been studied by (1)H NMR spectroscopy and molecular modelling. (1)H NMR titration experiments indicate that both metallocenes form 1 : 1 host-guest complexes with both Q[7] and Q[8]. In these complexes, both the cyclopentadienyl ligands and metal centre are positioned deep within the cucurbituril cavity. In vitro cell proliferation studies using the cancer cell lines MCF-7 and 2008 showed that the encapsulated molybdocene complex was more active than the corresponding free metallocene, with GI(50) values of 210 and 400 muM respectively. However, unexpectedly the encapsulation of Cp(2)MoCl(2(aq))at pD 7 catalysed significant degradation of the cucurbituril framework in the presence of oxygen. Encapsulation of Cp(2)TiCl(2(aq)) by Q[7] greatly slowed the protonolysis of the cyclopentadienyl ligands in aqueous phosphate buffer (pD 7), while encapsulation in Q[8] only slightly retarded the hydrolytic degradation of the metallocene.

Locating the cyclopentano cousins of the cucurbit[n]uril family.

The synthesis of the first family of fully substituted cucurbit[n]uril is discussed, and the structural features of precursor glycolurils are highlighted in their importance to achieving higher homologues. The members of the family, where n = 5-7, have been fully characterized, and increased binding affinities have been identified for dioxane in CyP(6)Q[6] and adamantyl NH(3)(+) in CyP(7)Q[7]. A higher homologue is indicated but not conclusively identified.

Stable cucurbit[5]uril MOF structures as ‘beaded’ rings built on a p-hydroxybenzoic acid template—a small molecule absorption material

p-Hydroxybenzoic acid acts as a template in the presence of KI for the self-assembly of cucurbit[5]uril, which arranges into 6-membered ring structures. These form hexagonal netting sheets, superimposed upon one another to create continuous channels. This solid material is absorbent to volatile organics, ranging in size from methanol to 1,4-dioxane.

Enhanced cytotoxicity of benzimidazole carbamate derivatives and solubilisation by encapsulation in cucurbit[n]uril

The albendazole derivatives (2-methoxyethyl) 5-propylthio-1H-benzimidazole-2-yl carbamate (MEABZ), N1-(2-methoxyethoxycarbonyl)-2-amino-5-propylthiobenzimidazole and N1-(2-methoxyethoxycarbonyl)-2-amino-6-propylthiobenzimidazole (MEABZ isomers A and B) and (2-hydroxyethyl) 5-propylthio-1H-benzimidazole-2-yl carbamate (HEABZ) have been synthesised. The cytotoxicity of these compounds was evaluated against a human colorectal cancer cell line (HT-29) and a human prostate cancer cell line (PC-3). The results demonstrate MEABZ, a new benzimidazole, is up to ten times more cytotoxic than the parent drug albendazole, whereas the MEABZ isomers A and B and HEABZ show no activity. A comparison of the cytotoxicity of these compounds, relative to ABZ, provides structure-activity data for this important class of anticancer agents. The aqueous solubilities of MEABZ encapsulated in Q[n] have been determined by (1)H NMR spectroscopy. The aqueous solubility of MEABZ at a physiologically relevant pH increased by 1200-fold by encapsulation in Q[8], from 8 microM to 9.4 mM, while Q[6,7] encapsulation substantially increased the solubility to more than 2 mM. Encapsulation in Q[7] and Q[8] induced significant upfield shifts for the MEABZ propyl and benzimidazole resonances. The upfield shifts indicate that the propyl and benzimidazole protons are located within the Q[7] and Q[8] cavity upon encapsulation. By contrast, encapsulation in Q[6] induced large upfield shifts for the (1)H resonances from the carbamate functional group, indicating that MEABZ associates with Q[6] at its portals, with only the carbamate group binding within the cavity.

Opposing substitution in cucurbit[6]urils forms ellipsoid cavities: the symmetrical dicyclohexanocucurbit[6]uril is no exception highlighted by inclusion and exclusion complexes

The symmetrical dicyclohexanocucurbit[6]uril has been synthesised by the controlled condensation of the diether of cyclohexanoglycoluril (1) and the dimer of glycoluril (2). The symmetrical dicyclohexanocucurbit[6]uril, (CyH)2Q[6], characterised by the 1H NMR spectroscopy, ESMS and further confirmed by single crystal X-ray diffraction of a cobalt aqua exclusion complex, which demonstrates an ellipsoid cavity. Within a cucurbit[6]uril ellipsoid cavity, an inclusion complex of 5,5′-dimethyl-2,2′-bipyridine adopts a preferred orientation, aligning with the longest axis. The ellipsoid cavity is further supported by semiempirical AM1 gas phase calculations. Preferential orientation of a guest within the ellipsoid cavity of the symmetrical dicyclohexanocucurbit[6]uril

The Effects of Alkali Metal Cations on Product Distributions in Cucurbit[n]uril Synthesis

Alkali metal cations act as templates in the synthesis ofcucurbit[n]uril, Q[n], for n = 5–8, either from a preformed oligomer precursor, ordirectly from glycoluril and formaldehyde. Q[5] has been synthesised and isolated as anunusual, water-insoluble potassium salt complex. The formation of this new complexis a convenient method for isolating Q[5] as a salt from Q[n] mixtures. The complexis a convenient, high yielding source of Q[5].