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ABSTRACT: INTRODUCTION:: To evaluate whether calabadion 1, an acyclic member of the Cucurbit[n]uril family of molecular containers, reverses benzylisoquinoline and steroidal neuromuscular-blocking agent effects. METHODS:: A total of 60 rats were anesthetized, tracheotomized, and instrumented with IV and arterial catheters. Rocuronium (3.5 mg/kg) or cisatracurium (0.6 mg/kg) was administered and neuromuscular transmission quantified by acceleromyography. Calabadion 1 at 30, 60, and 90 mg/kg (for rocuronium) or 90, 120, and 150 mg/kg (for cisatracurium), or neostigmine/glycopyrrolate at 0.06/0.012 mg/kg were administered at maximum twitch depression, and renal calabadion 1 elimination was determined by using a H NMR assay. The authors also measured heart rate, arterial blood gas parameters, and arterial blood pressure. RESULTS:: After the administration of rocuronium, resumption of spontaneous breathing and recovery of train-of-four ratio to 0.9 were accelerated from 12.3 ± 1.1 and 16.2 ± 3.3 min with placebo to 4.6 ± 1.8 min with neostigmine/glycopyrrolate to 15 ± 8 and 84 ± 33 s with calabadion 1 (90 mg/kg), respectively. After the administration of cisatracurium, recovery of breathing and train-of-four ratio of 0.9 were accelerated from 8.7 ± 2.8 and 9.9 ± 1.7 min with placebo to 2.8 ± 0.8 and 7.6 ± 2.1 min with neostigmine/glycopyrrolate to 47 ± 13 and 87 ± 16 s with calabadion 1 (150 mg/kg), respectively. Calabadion 1 did not affect heart rate, mean arterial blood pressure, pH, carbon dioxide pressure, and oxygen tension. More than 90% of the IV administered calabadion 1 appeared in the urine within 1 h. CONCLUSION:: Calabadion 1 is a new drug for rapid and complete reversal of the effects of steroidal and benzylisoquinoline neuromuscular-blocking agents.
Anesthesiology 03/2013; · 5.36 Impact Factor
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ABSTRACT: Climbing the cucurbit ladder: Cucurbit[6]uril dimers (connected gray cylinders; see scheme) were prepared by condensation of glycoluril hexamer with the appropriate tetraaldehydes. The self-assembly process between these dimers and oligoviologen compounds (blue) in water leads to a supramolecular ladder with the dimensions and molecular weight typical of small proteins.
Angewandte Chemie International Edition 02/2013; · 13.45 Impact Factor
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ABSTRACT: Be My Guest: Two acyclic cucurbit[n]uril-type receptors that carry SO(3) (-) -groups bind tightly to several commonly used neuromuscular blocking agents, such as rocuronium, in aqueous solution as revealed by direct and competitive UV/Vis binding assays. One of these containers functions as a potent reversal agent for rocuronium-induced neuromuscular block in rats.
Angewandte Chemie International Edition 10/2012; · 13.45 Impact Factor
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ABSTRACT: The building block synthesis of a derivative of CB[6] that bears a reactive propargyloxy group and its functionalization by click chemistry to yield 1 which contains a covalently attached isobutylammonium group is presented. Compound 1 undergoes self-assembly to yield a cyclic [c2] daisy chain assembly (1(2)) in water. The behavior of 1(2) in response to various stimuli (e.g., guests and CB[n] receptors) is described.
Organic Letters 05/2012; 14(12):3072-5. · 5.86 Impact Factor
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ABSTRACT: We describe the stepwise construction of an 8-component self-sorted system (1 - 8) by the sequential addition of components. This process occurs via a large number of states (28 = 256) and even a larger number of pathways (8! = 40320). A pathway (5, 6, 7, 8, 4, 3, 2, then 1) that is self-sorted at every step along the way has been demonstrated experimentally. Another pathway (1, 8, 3, 5, 4, 7, 2, then 6) resembles a game of musical chairs and exhibits interesting shuttling of guest molecules among hosts. The majority of pathways
- unlike the special ones described above - proceed through several non self-sorted states. We characterized the remainder
of the 40320 pathways by simulation using Gepasi and describe the influence of concentration and binding constants on the
fidelity of the self-sorting pathways.
04/2012; 1(1):1-13.
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ABSTRACT: The solubility characteristics of 40-70% of new drug candidates are so poor that they cannot be formulated on their own, so new methods for increasing drug solubility are highly prized. Here, we describe a new class of general-purpose solubilizing agents-acyclic cucurbituril-type containers-which increase the solubility of ten insoluble drugs by a factor of between 23 and 2,750 by forming container-drug complexes. The containers exhibit low in vitro toxicity in human liver, kidney and monocyte cell lines, and outbred Swiss Webster mice tolerate high doses of the container without sickness or weight loss. Paclitaxel solubilized by the acyclic cucurbituril-type containers kills cervical and ovarian cancer cells more efficiently than paclitaxel alone. The acyclic cucurbituril-type containers preferentially bind cationic and aromatic drugs, but also solubilize neutral drugs such as paclitaxel, and represent an attractive extension of cyclodextrin-based technology for drug solubilization and delivery.
Nature Chemistry 01/2012; 4(6):503-10. · 20.52 Impact Factor
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ABSTRACT: The recognition properties of acyclic cucurbit[n ]uril (CB[n ]) congener 1 towards seven local anaesthetic drugs (2–8) are reported. Job plots constructed from 1H NMR experiments confirm the 1:1 host:guest nature of these complexes, whereas the changes in chemical shift observed upon complex formation (Dd values) provide information about the geometry of the host–guest complexes. For complexes between host 1 and guests 2–5 and 8, a single geometry was preferred, whereas for guests 6 and 7 a mixture of two diastereomeric complexes was indicated. The Ka values for complexes between 1 and 2–8 fall in the range of 103–108M21 as determined by UV–vis and 1H NMR competition experiments. The results further
establish that acyclic CB[n ]-type receptor 1 is preorganised into the C-shape required for binding and that its aromatic o-xylylene walls endow it with a potency towards aromatic ammonium ions. The Ka values reported in this paper constitute a blind data-set used in the SAMPL3 challenge aimed at testing computational methods relevant to proteinzligand systems. The work thus highlights the great potential of CB[n ] receptors as model systems to promote synergy between the supramolecular and computational chemistry communities
Supramolecular Chemistry 01/2012; 24:325. · 2.14 Impact Factor
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ABSTRACT: The solubility characteristics of 40–70% of new drug candidates are so poor that they cannot be formulated on their own, so new methods for increasing drug solubility are highly prized. Here, we describe a new class of general-purpose solubilizing agents—acyclic cucurbituril-type containers—which increase the solubility of ten insoluble drugs by a factor of between 23 and 2,750 by forming container–drug complexes. The containers exhibit low in vitro toxicity in human liver, kidney and monocyte cell lines, and outbred Swiss Webster mice tolerate high doses of the container without sickness or weight loss. Paclitaxel solubilized by the acyclic cucurbituril-type containers kills cervical and ovarian cancer cells more efficiently than paclitaxel alone. The acyclic cucurbituril-type containers preferentially bind cationic and aromatic drugs, but also solubilize neutral drugs such as paclitaxel, and represent an attractive extension of cyclodextrin-based technology for drug solubilization and delivery.
Nature Chemistry 01/2012; 4(6):503-510. · 20.52 Impact Factor
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ABSTRACT: We report that the p-xylylenediammonium ion (11) acts as a template in the cucurbit[n]uril forming reaction that biases the reaction toward the production of methylene bridged glycoluril hexamer (6C) and bis-nor-seco-CB[10]. Hexamer 6C is readily available on the gram scale by a one step synthetic procedure that avoids chromatography. Hexamer 6C undergoes macrocylization with (substituted) phthalaldehydes 12, 14, 15, and 18-in 9 M H(2)SO(4) or concd HCl at room temperature to deliver monofunctionalized CB[6] derivatives 13, 16, 17, and 19-that are poised for further functionalization reactions. The kinetics of the macrocyclization reaction between hexamer and formaldehyde or phthalaldehyde depends on the presence and identity of ammonium ions as templates. p-Xylylenediammonium ion (11) which barely fits inside CB[6] sized cavities acts as a negative template which slows down transformation of 6C and paraformaldehyde into CB[6]. In contrast, 11 and hexanediammonium ion (20) act as a positive template that promotes the macrocyclization reaction between 6C and 12 to deliver (±)-21 as a key intermediate along the mechanistic pathway to CB[6] derivatives. Naphthalene-CB[6] derivative 19 which contains both fluorophore and ureidyl C═O metal-ion (e.g., Eu(3+)) binding sites forms the basis for a fluorescence turn-on assay for suitable ammonium ions (e.g., hexanediammonium ion and histamine).
Journal of the American Chemical Society 11/2011; 133(44):17966-76. · 9.91 Impact Factor
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ABSTRACT: This paper describes the synthesis of host 1 by the double bridging reaction of bis-ns-CB[10] with 2 under acidic conditions. Host 1 functions as a double cavity host for aliphatic and aromatic ammonium ions (3-17) in water. Conducting the bridging reaction in the presence of guest 4 delivers [3]rotaxane 1·4(2) by a clipping process.
Chemical Communications 09/2011; 47(33):9420-2. · 6.17 Impact Factor
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ABSTRACT: The fragmentation reaction of bis-nor-seco-CB[10] with 3,5-dimethylphenol (3) delivers methylene bridged glycoluril pentamer 5 in 81% yield. The host-guest recognition properties of the previously known tetramer 4 and those of pentamer 5 and hexamer 6 toward cationic guests in water are used to delineate some important features of the binding of acyclic CB[n]-type receptors.
Organic Letters 08/2011; 13(15):4112-5. · 5.86 Impact Factor
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ABSTRACT: We report herein a five-component self-sorted system comprising molecular clips that form heterodimers 1·4 and 8·11, and homodimer 14·14 in C(6)D(5)CD(3)/CDCl(3). The three component self-sorting mixture comprising 1·1, 8·8, and 14·14 undergoes triggered reassembly self-sorting upon addition of 4·4 and 11·11.
Chemical Communications 07/2011; 47(30):8548-50. · 6.17 Impact Factor
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Lyle Isaacs
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ABSTRACT: This article begins by describing the synthesis and recognition properties of the cucurbit[n]uril homologues CB[5], CB[6], CB[7], CB[8], and CB[10]. Subsequently, we describe the state-of-the-art in understanding the mechanism of CB[n] formation. We describe the experiments that establish that glycoluril (1 H) undergoes condensation with formaldehyde by a combination of chain-growth and step-growth polymerization processes. Chain-growth processes deliver methylene bridged glycoluril oligomers 2 C–8 C as intermediates that may undergo macrocyclization to nor-seco-CB[n] when the oligomer is long enough (5 C–8 C) and subsequently form CB[n]. Step-growth processes allow oligomers to condense to give longer oligomers connected by a single CH2-bridge that undergo macrocyclization to deliver (±)-bis-nor-seco-CB[6] and bis-nor-seco-CB[10]. Lastly, we describe some of the exciting new recognition processes of the newly formed members of the CB[n] family. For example, bis-nor-seco-CB[10] undergoes homotropic allostery during ternary complex formation, (±)-bis-nor-seco-CB[6] exhibits moderately diastereoselective recognition processes (d.r. up to 88 : 12) with chiral ammonium ions in water, and nor-seco-CB[6] functions as an aldehyde reactive CB[n] synthon that can control the folding of alkanediammonium ions into a backfolded conformation in water.
Israel Journal of Chemistry. 04/2011; 51(5‐6):578 - 591.
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ABSTRACT: We present the design, synthesis via methylene bridged glycoluril tetramer building blocks, and charaterization of acyclic cucurbit[n]uril congeners that function as hosts for a wide variety of ammonium ions in water. The X-ray crystallographic characterization of the free host and its complexes with p-xylylenediamine and spermine establish the flexibility of the methylene bridged backbone of the acyclic cucurbit[n]uril congeners that allow them to adapt to the structural features of the guest. We find that the acyclic cucurbit[n]uril congeners-with their four contiguous methylene bridged glycoluril units and two aromatic o-xylylene walls bearing CO(2)H substituents-bind to ammonium ions in buffered water with values of K(a) ranging from approximately 10(5) M(-1) to greater than 10(9) M(-1). Similar to the cucurbit[n]uril family of hosts, we find that increasing the concentration of metal cations in the buffer reduces the affinity of the acyclic cucurbit[n]uril congener toward guests by competitive binding at the ureidyl C horizontal lineO portals. Although the acyclic cucurbit[n]uril congeners retain the ability to bind to ammonium ions with high affinity, they do so with lower selectivity than cucurbit[n]urils presumably do to the structural flexibility of the hosts. A methylene bridged glycoluril tetramer model compound that lacks the substituted o-xylylene walls is a much lower affinity host, which establishes the importance of these rings on the overall recognition behavior of the acyclic cucurbit[n]uril congeners. Overall, the results in this paper establish that acyclic cucurbit[n]uril receptors that contain four or more contiguous methylene bridged glycoluril units retain many of the excellent recognition properties of the cucurbit[n]uril family.
The Journal of Organic Chemistry 07/2010; 75(14):4786-95. · 4.45 Impact Factor
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ABSTRACT: A noncovalent macrocycle-within-noncovalent macrocycle assembly is formed from twelve molecules of (+/-)-1 and twelve molecules of MeOH in the solid state. The H-bonded (MeOH)(12) cyclododecamer assumes a crown-shaped geometry that has not previously been predicted theoretically or found experimentally.
Chemical Communications 07/2010; 46(25):4508-10. · 6.17 Impact Factor
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ABSTRACT: We report the synthesis of two-faced inhibitors 1-5 that contain both enzyme inhibitor and cucurbit[n]uril binding domains. The enzyme binding domains of 1-5 bind to the active sites of bovine carbonic anhydrase (BCA) or acetylcholinesterase (AChE) and inhibit their catalytic activities. Addition of CB[7] to BCA*1 and BCA*2 results in the transient formation of the BCA*1*CB[7] and BCA*2*CB[7] ternary complexes that undergo rapid dissociation to form free catalytically active BCA along with CB[7]*1 and CB[7]*2. The on-off cycle can be performed repetitively by the sequential addition of competitive guest 8 and CB[7]. The detailed origins of this on-off switching of the catalytic activity of BCA is delineated by the combined inference of UV/vis catalytic assays, fluorescence displacement assays, (1)H NMR, along with measurement of the fundamental values of K(a), k(on), and k(off) for the various complexes involved. In contrast, addition of CB[7] to AChE*4(4) and AChE*5(4) results in the formation of thermodynamically stable ternary complexes AChE*4(4)*CB[7](4) and AChE*5(4)*CB[7](4) that are catalytically inactive. We highlight some of the advantages and disadvantages of the strategy, based on the direct competition between two receptors (e.g., enzyme and CB[7]) for a common inhibitor, used in this paper to control enzyme catalytic activity compared to the strategy employed by Nature involving the binding of an allosteric small molecule remote from the enzyme active site.
Journal of the American Chemical Society 03/2010; 132(12):4445-54. · 9.91 Impact Factor
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ABSTRACT: The reaction of substituted glycolurils or a glycoluril dimer with a dialdehyde (o-phthalaldehyde) delivers S-shaped dimers and an S-shaped tetramer selectively. A combination of X-ray crystallography, PM3 calculations, and product resubmission experiments establish that the S-shaped isomers are thermodynamically more stable than the C-shaped diastereomers which we attribute to the conformational preferences of the newly formed benzo bicyclo[3.3.2]decane ring system. The preferential formation of S-shaped subunits is one reason why o-phthalaldehyde and possibly other aldehydes do not usually participate in CB[n] forming reactions. We also present evidence that points toward an equilibrium between glycoluril monomer + phthalaldehyde and S-shaped dimer + water that responds to concentration over the 1-50 mM range. This result suggests a second reason, insufficient reactivity (e.g., low equilibrium constant), why o-phthalaldehyde and possibly other aldehydes do not participate in CB[n] forming reactions. Delineation of the reasons why some aldehydes fail in these reactions is the first step toward devising methods to overcome these limitations.
The Journal of Organic Chemistry 03/2010; 75(9):2934-41. · 4.45 Impact Factor
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ABSTRACT: Many drug delivery systems are based on the ability of certain macrocyclic compounds - such as cyclodextrins (CDs) - to act as molecular containers for pharmaceutical agents in water. Indeed beta-CD and its derivatives have been widely used in the formulation of hydrophobic pharmaceuticals despite their poor abilities to act as a molecular container (e.g., weak binding (K(a)<10(4) M(-1)) and their challenges toward chemical functionalization. Cucurbit[n]urils (CB[n]) are a class of molecular containers that bind to a variety of cationic and neutral species with high affinity (K(a)>10(4) M(-1)) and therefore show great promise as a drug delivery system.
In this study we investigated the toxicology, uptake, and bioactivity of two cucurbit[n]urils (CB[5] and CB[7]) and three CB[n]-type containers (Pentamer 1, methyl hexamer 2, and phenyl hexamer 3). All five containers demonstrated high cell tolerance at concentrations of up to 1 mM in cell lines originating from kidney, liver or blood tissue using assays for metabolic activity and cytotoxicity. Furthermore, the CB[7] molecular container was efficiently internalized by macrophages indicating their potential for the intracellular delivery of drugs. Bioactivity assays showed that the first-line tuberculosis drug, ethambutol, was as efficient in treating mycobacteria infected macrophages when loaded into CB[7] as when given in the unbound form. This result suggests that CB[7]-bound drug molecules can be released from the container to find their intracellular target.
Our study reveals very low toxicity of five members of the cucurbit[n]uril family of nanocontainers. It demonstrates the uptake of containers by cells and intracellular release of container-loaded drugs. These results provide initial proof-of-concept towards the use of CB[n] molecular containers as an advanced drug delivery system.
PLoS ONE 01/2010; 5(5):e10514. · 4.09 Impact Factor
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Papers presented at the ... meeting. American Chemical Society. Division of Polymer Chemistry 01/2010; 51:154.
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ABSTRACT: Complexation of yellow diaminoazobenzenes 1 and 3 inside cucurbit[7]uril (CB[7]) results in the formation of purple-colored CB[7].cis-1.2H+ and CB[7].cis-3.2H+ complexes, respectively. The high binding affinity and selectivity displayed by CB[7] toward 1 and 3 pays the >10 kcal mol(-1) thermodynamic cost for this isomerization. We investigated the behavior of these complexes as a function of pH and observed large pK(a) shifts and high pH responsiveness, which are characteristic of cucurbit[n]uril molecular containers. The remarkable yellow to purple color change was utilized in the construction of an indicator displacement assay for biologically active amines 4-10. This indicator displacement assay is capable of quantifying the pseudoephedrine (5) content in Sudafed tablets over the 5-350 microM range.
Chemistry 09/2009; 15(43):11675-80. · 5.93 Impact Factor
