Applications of Cucurbit[n]urils (n=7 or 8) in Pharmaceutical Sciences and Complexation of Biomolecules

Cucurbit[7]uril (CB[7]) and cucurbit[8]uril (CB[8]) are two key members of the cucurbit[n]uril (CB[n]) family of macrocycles. Because of the good water solubility of CB[7] and the unique ternary binding properties of CB[8], these two macrocycles have attracted increasing attentions in recent years. In particular, many promising reports of exciting applications regarding CB[7] and CB[8] have emerged in the pharmaceutical sciences and complexations of biomolecules, which has become one of the most important areas of potential applications of CB[n]s. This review summarizes the applications of macrocyclic CB[7], CB[8] and their derivatives as supramolecular platforms that have been developed in recent years within the field of pharmaceutical sciences and biomolecular sciences, and discusses the current challenges and future prospects of this area.     

Stimuli-responsive Supra-biomolecular Nanoassemblies of Cucurbit[7]uril with Bovine Serum Albumin: Drug Delivery and Sensor Applications

Construction and characterization of stimuli-responsive supra-biomolecular nanoassembly between cucurbit[7]uril (CB7) and bovine serum albumin (BSA), uptake and release of doxorubicin (DOX) in live cells, the enhanced sensitivity of brilliant green (BG) and the metal ion-induced relocation of neutral red (NR) dye to BSA have been discussed in this review. The fluorescence intensity of DOX is largely quenched in the presence of nanoassembly which recovers with adamantylamine or by changing the pH of the solution, indicating the significant uptake and release of DOX. Whereas, the interaction of BG with CB7-BSA assembly leads to a huge fluorescence enhancement ∼350-fold through ternary complex formation. In another study, the supramolecular pK_a tuning of nanoassembly encapsulated NR dye with metal ion and the consequent relocation of NR from CB7 cavity to the hydrophobic pocket of BSA have been demonstrated. All these studies show promising applications in drug delivery and on-off sensor.     

Inclusion Complexes of Hymexazol with Three Different Cucurbit[n]uril: Preparation,and Physicochemical and Antifungal Characterization

Host-guest inclusion complexes of hymexazol with three different cucurbit[n]uril, cucurbit[7]uril (Q[7]), hemimethyl-substituted cucurbit[6]uril (HHMeQ[6]), and twisted cucurbit[14]uril (tQ[14]) have been investigated by means of ¹H NMR spectroscopy, quadrupole-time of flight mass spectrometry (Q-TOF), and isothermal titration calorimetry (ITC). ¹H NMR experimental results revealed that hymexazol resides within the respective cavities of the selected Q[n], and mass spectrometric experimental results revealed that it interacts with these three Q[n] through the formation of 1 : 1 inclusion complexes. ITC experimental results indicated moderate binding constants. In vitro assays showed that the complexation of hymexazol by the Q[n] increased its inhibitory effect on the mycelia growth of Botrytis cinerea Pers.     

Organocatalytic formation of optically active polymers: enantioselective aldol reaction of aldehyde‐containing copolymers in the presence of l‐proline

Monomers containing benzaldehyde units were synthesized by esterification of 4‐hydroxybenzaldehyde and 4‐(2‐hydroxyethoxy)benzaldehyde with methacryloyl chloride. These monomers were copolymerized free radically with N‐isopropylacrylamide using 2,2′‐azobis(2‐methylpropionitrile) as an initiator. The monomers and copolymers, respectively, were modified with acetone in an organocatalytic aldol reaction in the presence of l ‐proline to induce stereogenic centers. The aldol condensates were characterized by their optical rotatory power. © 2014 Society of Chemical Industry     

An Organocatalytic Domino Thia‐Michael/Aldol Condensation Reaction: Highly Enantioselective Synthesis of Functionalized Dihydrothiophenes

An organocatalytic domino thia‐Michael/aldol condensation reaction of α, β‐unsaturated aldehydes with 1, 4‐dithiane‐2,5‐diol catalyzed by chiral diphenylprolinol TMS ether has been developed, which provides a new practical and direct route to chiral dihydrothiophenes with high yields (up to 90%) and excellent enantioselectivities (up to>99% ee). The catalytic mechanism of the domino reaction was further confirmed through the APCI‐MS detection of proposed reaction intermediates.     

Stereoselective Synthesis of Hydropyrano[3,2‐b]indoles via Organocatalytic Asymmetric Inverse‐Electron‐Demand Oxa‐Diels–Alder Reaction

Enantio‐ and diastereoselective inverse‐electron‐demand oxa‐Diels–Alder reactions are described between (Z)‐2‐ylideneoxindoles and aldehydes in the presence of a chiral secondary amine catalyst. The corresponding hydropyrano[3,2‐b]indoles are produced in up to 77% yield with up to 99% ee. Convenient synthetic transformations of the products readily lead to pharmacologically interesting scaffolds bearing multiple functional groups. This method may also provide an alternative approach for the asymmetric synthesis of 2‐spirocyclo‐3‐oxindoles.

     

Diastereo‐ and Enantioselective Synthesis of a Novel Tetracyclic Ring System via an Organocatalytic One‐Pot Reaction

An efficient , asymmetric, one‐pot synthesis of a novel tetracyclic ring system incorporating both chroman and bicyclo[2.2.2]octane structural units was established through sequential reaction of nitroolefin enoates and α,β‐unsaturated ketones. Six stereogenic centers including two quaternary stereocenters were formed with excellent diastereo‐ and enantioselectivity.     

Chiral Quaternary Ammonium Aryloxide/N,O‐Bis(trimethyl‐ silyl)acetamide Combination as Efficient Organocatalytic System for the Direct Vinylogous Aldol Reaction of (5H)‐Furan‐2‐one Derivatives

A chiral quaternary ammonium amide was generated in situ from N,O‐bis(trimethylsilyl)acetamide (BSA) as non‐nucleophilic Brønsted base precursor and the combination of chiral quaternary ammonium halide/sodium aryloxide as chiral Lewis base. This system was applied to an anti‐selective organocatalytic direct vinylogous aldol (ODVA) reaction of (5H)‐furan‐2‐one derivatives with aldehydes. Several 5‐(1′‐hydroxy)‐γ‐butenolides were obtained in good diastereomeric ratios (up to 95/5) and excellent enantioselectivities (up to 94%) with both aliphatic or (hetero)aromatic aldehydes, so providing a rare example of general and efficient conditions for the ODVA reaction.     

Diastereo‐ and Enantioselective Direct Aldol Reactions in Aqueous Medium: A New Highly Efficient Proline‐Sugar Chimeric Catalyst

A new synthetic catalyst, capable of acting like an enzyme in the accomplishment of direct aldol reactions, is presented. Excellent results, in terms of chemical yields and diastereo‐/enantiomeric ratios, are reported for the catalyzed additions of cyclohexanone to variously substituted benzaldehydes.     

An Enantioselective Three‐Component Sulfa‐Michael/Aldol Cascade Reaction and its Application to the Synthesis of Thioaryl Substituted (−)‐Bestatin Derivatives

An efficient catalytic asymmetric three‐component sulfa‐Michael/aldol cascade reaction has been developed using a chiral multi‐functional catalyst. This reaction provided facile access to γ‐sulfur‐β‐nitro‐α‐hydroxy esters bearing three consecutive linear stereocenters in high yields (up to 97%) with excellent diastereo‐ (up to >97:3 dr) and enantioselectivities (>99% ee). These compounds were readily converted into 2‐nitroallylic alcohols and potentially bioactive γ‐sulfur‐β‐amino‐α‐hydroxy esters, which could be further used for the synthesis of Bestatin derivatives.

     

The Effect of Cucurbit[7]uril on the Antitumor and Immunomodulating Properties of Oxaliplatin and Carboplatin

Cucurbit[7]uril (CB[7]) is a molecular container that may form host–guest complexes with platinum(II) anticancer drugs and modulate their efficacy and safety. In this paper, we report our studies of the effect of CB[7]–oxaliplatin complex and the mixture of CB[7] and carboplatin (1:1) on viability and proliferation of a primary cell culture (peripheral blood mononuclear cells), two tumor cell lines (B16 and K562) and their activity in the animal model of melanoma. At the same time, we studied the impact of platinum (II) drugs with CB[7] on T cells and B cells in vitro. Although the stable CB[7]–carboplatin complex was not formed, the presence of cucurbit[7]uril affected the biological properties of carboplatin. In vivo, CB[7] increased the antitumor effect of carboplatin, but, at the same time, increased its acute toxicity. Compared to free oxaliplatin, its complex with CB[7] shows a greater cytotoxic effect on tumor cell lines B16 and K562, while in vivo, the effects of the free drug and encapsulated drug were comparable. However, in vivo studies also demonstrated that the encapsulation of oxaliplatin in CB[7] lowered the toxicity of the drug.     

Synthesis of PVC‐TEPA‐supported proline derivative and its catalytic behavior in the direct asymmetric aldol reaction

PVC‐TEPA‐supported L ‐proline catalyst has been synthesized and characterized by IR. It is developed as an efficient catalyst for the direct asymmetric aldol reaction of unmodified ketones with various aldehydes in the presence of water at 0°C. The corresponding aldol products were obtained with high yields (up to 94%) and good enantioselectivities (up to 97% ee) on optimized conditions. Recycling investigations have shown that this material can be reused without loss of catalytic activity and stereoselectivity for at least 15 cycles. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

The Application of a Recyclable Organocatalytic System to the Asymmetric Domino Michael/Henry Reaction in Aqueous Media

A new type of pyrrolidine‐based organocatalyst has been developed and found to be very effective for the domino Michael/Henry reaction in aqueous solvents. For the reaction involving pentane‐1,5‐dial and various nitroolefins, good yields (65–85%) and excellent enantioselectivities (99%) were obtained using this catalyst. In addition, the catalyst could be recycled up to four times resulting in good yields and up to seven times with good enantioselectivity.     

Organocatalytic Multiple Cascade Reactions: A New Strategy for the Construction of Enantioenriched Tetrahydrocarbazoles

A novel cascade Friedel–Crafts alkylation/Michael addition/aromatization reaction of 2‐vinylindoles with α,β‐unsaturated aldehydes has been developed for the construction of functionalized tetrahydrocarbazoles. The products were obtained in up to 97% yield and with excellent stereoselectivities (ee up to>99%, dr up to>99:1).     

Organocatalytic Asymmetric Aldol Reaction of Ketones with β,γ‐Unsaturated α‐Keto Esters: An Efficient Access to Chiral Tertiary Alcohol Skeletons

This update describes a highly efficient organocatalytic aldol reaction of ketones and β,γ‐unsaturated α‐keto esters for constructing the chiral tertiary alcohol motif. With the application of 9‐amino(9‐deoxy)epi‐Cinchona alkaloid and an acidic additive as catalysts, both acyclic and cyclic ketones react with β,γ‐unsaturated α‐keto esters smoothly to afford aldol adducts in good to excellent yields and asymmetric induction. This protocol offers a new pathway for the construction of adjacent chiral carbon centers and the synthesis of chiral β‐hydroxy carbonyl compounds.     

Y型分子筛的金属离子改性水热化学研究

采用密度泛函理论研究金属离子(La~(3+),Ce~(3+),Y~(3+),Ga~(3+),Cr~(3+),Zn~(2+),Cu~(2+))改性Y型分子筛的水热化学。结果表明,金属离子取代Y型分子筛骨架Al的能力较弱,以M(OH)(Z-1)+形式存在的金属离子能够进入分子筛β笼,且更倾向定位于β笼Ⅰ'位,增强分子筛Al和相邻骨架O原子之间的作用力,提高分子筛的结构稳定性。探讨制备金属离子改性Y型分子筛应考虑金属离子性能和金属离子与分子筛骨架元素的作用。     

Enantioselective One‐Pot Reaction: Organocatalyzed Synthesis of Fully Functionalized Oxabicyclo[2.2.2]octanes with Seven Contiguous Stereocenters

An enantioselective one‐pot Michael/Michael/Henry/hemiacetalization reaction between α,β‐unsaturated aldehydes, α‐ketoamides, and nitroalkenes under mild conditions catalyzed by a diarylprolinol silyl ether has been developed. The sequential methodology provides a direct approach to a wide range of fully substituted chiral oxabicyclo[2.2.2]octanes with seven contiguous stereocenters in moderate to excellent yields (up to 99%), high to excellent diastereoselectivities (up to >25:1 dr), and high to excellent enantioselectivities (up to 99% ee).

     

A Polystyrene‐Supported,Highly Recyclable Squaramide Organocatalyst for the Enantioselective Michael Addition of 1,3‐Dicarbonyl Compounds to β‐Nitrostyrenes

A chiral squaramide has been supported onto a polystyrene (PS) resin through a copper‐catalyzed azide–alkyne cycloaddition (CuAAC) reaction and used as a very active, easily recoverable and highly reusable organocatalyst for the asymmetric Michael addition of 1,3‐dicarbonyl compounds to β‐nitrostyrenes. The PS‐supported squaramide could be recycled up to 10 times.     

Theoretical studies of the CNx nanotube with four-nitrogen divacancy (4ND) defects

The formation energies, electronic properties, and applications in hydrogen storage of four-nitrogen divacancy (4ND) defects in a series of CNTs are investigated by density functional theory (DFT) calculations. We find that the formation energies of 4ND defects in the (n, 0) CNT are always smaller than those of the (n, n) CNT, suggesting that the formers might be easily formed. For (n, n) CNTs, the formation energies of 4ND defect are nearly independent of the tube diameters for s, while the values increase monotonically with the increased tube diameters in (n, 0) CNTs. Furthermore, the incorporation of 4ND structures to the CNT introduces the acceptor states to the band structures, resulting in the decrease of the band gaps of pure CNTs in various ways. By studying the hydrogen adsorption on the Ca-dispersed CN_x nanotube with 4ND structures, we suggest that up to five H₂ molecules can be bound to per Ca atom with the adsorption energy of −0.263 eV. The present results indicate that the Ca-dispersed CN_x nanotube with 4ND defects might be a promising candidate as hydrogen storage media.