Acyclic cucurbituril congener binds to local anaesthetics

Ma, Da; Glassenberg, Raymond; Ghosh, Soumyadip; Zavalij, Peter Y.; Isaacs, Lyle

doi:10.1080/10610278.2012.658394

Cited by 24 publications

(13 citation statements)

References 31 publications

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“…At present, it has been shown that calabadion 1, like his ancestor CB [7], forms stable hostguest complexes with local anesthetics in aqueous solution in vitro. 37,45 If these findings are relevant in vivo, a second application of the calabadions may relate to treatment of local anesthetic-induced toxicity. In light of the application explored in current study, it is important to investigate in a future study whether systemic local anesthetic administration or systemic distribution may result in reparalysis after calabadion 1-induced reversal of neuromuscular block.…”

Section: Discussionmentioning

confidence: 99%

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Calabadion

et al. 2013

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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 1 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

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Section: Discussionmentioning

confidence: 99%

“…Isaacs et al have synthesized acyclic CB[n]-type receptors-calabadionsand studied their molecular recognition properties. 24,[37][38][39] Based on the acyclic structure, calabadions are able to flex Arterial blood gas parameters measured before and after the administration of calabadion 1. Data shown as mean ± SD.…”

Section: Discussionmentioning

confidence: 99%

Calabadion

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“…[9,11] In related synergistic interactions between experimentalists and computational chemists, our group has participated in the SAMPL challenges. [12–15] In the SAMPL challenges, experimentalists measure and computational chemists compute the ΔG values of unknown host•guest complexes; the results are mutually revealed at the SAMPL conference which allows computational chemists to assess and subsequently refine their methodology. [13,16] CB[7]•guest complexes were featured prominently in the SAMPL4 challenge.…”

Section: Introductionmentioning

confidence: 99%

Glycoluril‐Derived Molecular Clips are Potent and Selective Receptors for Cationic Dyes in Water

She

Moncelet

Gilberg

et al. 2016

Chemistry A European J

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Molecular clip 1 remains monomeric in water and engages in host•guest recognition processes with suitable guests. We report the Ka values for 32 1•guest complexes measured by 1H NMR, UV/Vis, and fluorescence titrations. The cavity of 1 is shaped by aromatic surfaces of negative electrostatic potential and therefore displays high affinity and selectivity for planar and cationic aromatic guests which distinguishes it from CB[n] receptors that prefer aliphatic over aromatic guests. Electrostatic effects play a dominant role in the recognition process whereby ion-dipole interactions may occur between ammonium ions and the C=O groups of 1, between the SO3− groups of 1 and pendant cationic groups on the guest, and within the cavity of 1 by cation-π interactions. Host 1 displays high affinity toward dicationic guests with large planar aromatic surfaces (e.g. naphthalene diimide NDI+ and perylene diimide PDI+) and cationic dyes derived from acridine (e.g. methylene blue and azure A). The critical importance of cation-π interactions was ascertained by a comparison of analogous neutral and cationic guests (e.g. methylene violet vs. methylene blue; quinoline vs. N-methylquinolinium; acridine vs. N-methylacridinium; neutral red vs. neutral red H+) whose affinities differ by up to 380-fold. We demonstrate that the high affinity of 1 toward methylene blue (Ka = 3.92 × 107 M−1; Kd = 25 nM) allows for the selective sequestration and destaining of U87 cells stained with methylene blue.

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“…The upfield nature of the changes in chemical shift is indicative of guest 6 binding within the cavity of 2h and 2a as observed previously for (acyclic) CB[n]-type receptors. 13,44,46,52,53 The larger upfield shift observed for protons H b , H c and H d within the mixture of negative host 2a (figure 2d) and guest 6 relative to neutral host 2h and guest 6 (Figure 4c) indicates that the negatively charged host 2a binds the dicationic guest significantly stronger than the neutral host 2h . It was also observed that the resonances for protons H a on the aromatic sidewalls of hosts 2h and 2a undergo a downfield shift upon complexation with guest 6 .…”

Section: Resultsmentioning

confidence: 95%

Acyclic CB[n]-type molecular containers: effect of solubilizing group on their function as solubilizing excipients

2014

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We report the synthesis and x-ray crystal structures of three acyclic CB[n]-type molecular containers (2a, 2h, 2f) that differ in the charge on their solubilizing groups (SO3−, OH, NH3+). The x-ray crystal structures of compounds 2h and 2f reveal a self-folding of the ArOCH2CH2X wall into the cavity driven by π–π interactions, H-bonds and ion-dipole interactions. The need to reverse this self-folding phenomenon upon guest binding decreases the affinity of 2h and 2f toward cationic guests in water relative to 2a as revealed by direct 1H NMR and UV/Vis titrations as well as UV/Vis competition experiments. We determined the pKa of 6-aminocoumarin 7 (pKa = 3.6) on its own and in the presence anionic, neutral, and cationic hosts (2a: pKa = 4.9; 2h: pKa = 4.1; 2f, pKa = 3.4) which reflect in part the relevance of direct ion-ion interactions between the arms of the host and the guest toward the recognition properties of acyclic CB[n]-type containers. Finally, we showed that the weaker binding affinities measured for neutral and positively charged hosts 2h and 2f compared to anionic 2a results in a decreased ability to act as solubilizing agents for either cationic (tamoxifen), neutral (17α–ethynylestradiol), or anionic (indomethacin) drugs in water. The results establish that acyclic CB[n] compounds that bear anionic solubilizing groups are most suitable for development as general purpose solubilizing excipients for insoluble pharmaceutical agents.

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Acyclic cucurbituril congener binds to local anaesthetics

Cited by 24 publications

References 31 publications

Calabadion

Calabadion

Glycoluril‐Derived Molecular Clips are Potent and Selective Receptors for Cationic Dyes in Water

Acyclic CB[n]-type molecular containers: effect of solubilizing group on their function as solubilizing excipients

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