Acyclic Cucurbit[n]uril-Type Receptors: Optimization of Electrostatic Interactions for Dicationic Guests.
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ABSTRACT:
SUBMITTER: Lu X
PROVIDER: S-EPMC7576436 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We report the synthesis of three new triazole functionalized acyclic CB[n]-type receptors (2-4) by click chemistry. The compounds have good solubility in water (≥8 mM) and do not undergo strong self-association (Ks ≤ 903 M-1). We measured the binding constants of 2-4 toward guests 9-24 and compared the results to those obtained for the prototypical acyclic CB[n]-type receptor 1. The X-ray crystal structure of 4 is also described.
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Project description:Two acyclic CB[n]-type hosts (1 and 2) which possess four 2° or 3° amide arms are reported; 1 and 2 are slightly soluble in water and do not self-associate. Host 2 has four 3° amide arms that exist as a mixture of E- and Z-isomers. 1H NMR was used to qualitatively investigate the binding properties of 1 and 2 which indicates they retain the essential binding features of macrocyclic CB[n] hosts (e.g. cavity binding of hydrophobic residues and portal binding of cationic groups). We measured the Ka values of 1 and 2 toward guests 6 - 12, methamphetamine, and fentanyl by ITC to evaluate their potential as in vivo sequestration agents. Neutral hosts 1 and 2 bind less tightly than tetraanionic hosts M1, ACB1, and ACB2. We attribute the lower Ka values to the absence of secondary ion-ion (ammonium•••sulfonate or ammonium•••carboxylate) electrostatic interactions for host•guest complexes of 1 and 2. The secondary amide functionality on 1 decreases affinity by formation of intramolecular NH•••O=C H-bonds. Tertiary amide host 2 binds even more weakly than 1 due to backfolding of the amide N-CH3-groups of 2 into its own cavity. The x-ray crystal structure of 2 supports this conclusion.
| S-EPMC7531588 | biostudies-literature
Project description:The synthesis of acyclic cucurbit[n]uril dendrimers G1-G3 that bear four dendrons on their aromatic sidewalls via thiolate S(N)2 chemistry is reported. G1-G3 are polycationic and can bind to pEGFP plasmid DNA as shown by dynamic light scattering (DLS), gel electrophoresis, and scanning electron microscopy (SEM). The gene delivery ability of G1-G3 is presented.
| S-EPMC4670575 | biostudies-literature
Project description:Acyclic cucurbit[n]uril molecular containers 1 and 2C3 have previously been shown to strongly bind to the neuromuscular blocking agents rocuronium, vecuronium, pancuronium, and cisatracurium in vitro by optical methods and to reverse neuromuscular block in vivo in rats. In this paper we study the in vitro binding of a panel of acyclic CB[n]-type receptors toward the four neuromuscular blocking agents and acetylcholine to develop structure-binding affinity relationships. The selected variants include those with different aromatic sidewalls (e.g. 1Me4 with dimethyl o-xylylene walls; 3 with 1,8-linked naphthalene walls), with different glycoluril oligomer lengths (e.g. 4 and 5 based on glycoluril trimer), and with different linker lengths between aromatic wall and SO3 - solubilizing group (e.g. 2C2 - 2C4). Based on the analysis of complexation induced changes in 1H NMR chemical shift we conclude that the hydrophobic regions of the guests bind in the hydrophobic cavity of the hosts with the cationic moieties of the guest binding at the ureidyl C=O portals by ion-dipole and ion-ion interactions. The thermodynamic parameters of binding were determined by direct and competition isothermal titration calorimetry experiments. We find that hosts 4 and 5 based on glycoluril trimer form significantly weaker complexes with the streroidal NMBAs than with the analogues hosts based on glycoluril tetramer (1 and 2C3). Similarly, hosts 1Me4 and 3 with different length and height aromatic walls do not exhibit the extreme binding constants displayed by 2C3 but rather behave similarly to 1. Finally, we find that hosts 2C2 and 2C4 bind only slightly more weakly to the NMBAs than 2C3, but retain the ability to discriminate against acetylcholine, and possess higher inherent water solubility than 2C3. Host 2C4, in particular, holds potential for future in vivo applications.
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Project description:We report the linear extension from M1 to M2 to anthracene walled M3 which adopts a helical conformation (X-ray) to avoid unfavorable interactions between sidewalls. M3 is water soluble (=30 mm) and displays enhanced optical properties (ϵ=1.28×105 m-1 cm-1 , λmax =370 nm) relative to M2. The binding properties of M3 toward guests 1-29 were examined by 1 H NMR and ITC. The M3⋅guest complexes are stronger than the analogous complexes of M2 and M1. The enhanced binding of M3 toward neuromuscular blockers 25, 27-29 suggests that M3 holds significant promise as an in vivo reversal agent. The changes in fluorescence observed for M3⋅guest complexes are a function of the relative orientation of the anthracene sidewalls, guest concentration, Ka , and guest electronics which rendered M3 a superb component of a fluorescence sensing array. The work establishes M3 as a next generation sequestering agent and a versatile component of fluorescence sensors.
| S-EPMC7704778 | biostudies-literature
Project description:We report the synthesis of M2NH3 which is a tetracationic analogue of our prototypical acyclic CB[n]-type molecular container M2. Both M1NH3 and M2NH3 possess excellent solubility in D2O and do not undergo intermolecular self-association processes that would impinge on their molecular recognition properties. Compounds M1NH3 and M2NH3 do, however, undergo an intramolecular self-complexation process driven by ion-dipole interactions between the ureidyl C=O portals and the OCH2CH2NH3 arms along with inclusion of one aromatic wall in its own hydrophobic cavity. The Ka values for M1NH3 and M2NH3 toward seven nucleotides were determined by 1H NMR titration and found to be quite modest (Ka in the 102 - 103 M-1 range) although M2NH3 is slightly more potent. The more highly charged guests (e.g. ATP) form stronger complexes with M1NH3 and M2NH3 than the less highly charged guest (e.g. ADP, AMP). The work highlights the dominant influence of the ureidyl C=O portals on the molecular recognition behavior of acyclic CB[n]-type receptors and suggests routes (e.g. more highly charged arms) to enhance their recognition behavior toward anions.
| S-EPMC5063241 | biostudies-literature
Project description:High-affinity guests have been reported for the macrocyclic host cucurbit[7]uril (CB[7]), enabling widespread applications, but hindering CB[7] materials from being returned to their guest-free state for reuse. Here, we present polyhedral boron clusters (carboranes) as strongly binding, yet easily removable, guests for CB[7]. Aided by a Pd-catalyzed coupling of an azide anion, we prepared boron-functionalized 9-amino-ortho-carborane that binds to CB[7] with a Ka ≈ 1010 M-1. Upon basic treatment, ortho-carborane readily undergoes deboronation to yield anionic nido-carborane, a poor guest for CB[7], facilitating recovery of guest-free CB[7]. We showcase the utility of the modified ortho-carborane guest by recycling a CB[7]-functionalized resin. With this report, we introduce stimuli-responsive decomplexation as an additional consideration in the design of high-affinity host-guest complexes.
| S-EPMC8147132 | biostudies-literature
Project description:Two acyclic cucurbit[n]uril (CB[n])-type molecular containers that differ in the length of the (CH2 )n linker (M2C2: n=2, M2C4: n=4) between their aromatic sidewalls and sulfonate solubilizing groups were prepared and studied. The inherent solubilities of M2C2 (68 mm) and M2C4 (196 mm) are higher than the analogue with a (CH2 )3 linker (M2, 14 mm) studied previously. (1) H NMR dilution experiments show that M2C2 and M2C4 do not self-associate in water, which enables their use as solubilizing excipients. We used phase solubility diagrams (PSDs) to compare the solubilizing capacities of M2, M2C2, M2C4, hydroxypropyl-β-cyclodextrin (HP-β-CD), and sulfobutylether-β-cyclodextrin (SBE-β-CD) toward 15 insoluble drugs. We found that M2C2 and M2C4-as gauged by the slope of their PSDs-are less potent solubilizing agents than M2. However, the higher inherent solubility of M2C2 allows higher concentrations of drug to be formulated using M2C2 than with M2 in several cases. The solubilizing ability of M2C2 and SBE-β-CD were similar in many cases, with Krel values averaging 23 and 12, respectively, relative to HP-β-CD. In vitro cytotoxicity and in vivo maximum tolerated dose studies document the biocompatibility of M2C2.
| S-EPMC4861662 | biostudies-literature
Project description:The host-guest complexation of symmetrical α,α',δ,δ'-tetramethyl-cucurbit[6]uril (TMeQ[6]) and cucurbit[7]uril (Q[7]) with a series of aniline-containing guests has been investigated by various experimental techniques including NMR, ITC, and X-ray crystallography. Experimental results indicate that both TMeQ[6] and Q[7] hosts can encapsulate aniline-containing guests to form stable inclusion complexes. However, the oval cavity of TMeQ[6] is more complementary in size and shape to the aromatic ring of the guests than the spherical cavity of Q[7]. Shielding and deshielding effects of the aromatic ring on guests lead to the remarkable chemical shifts of the TMeQ[6] host protons. The rotational restriction of the guests in the oval cavity of TMeQ[6] results in the large negative values of entropy. The X-ray crystal structure of the 1:1 inclusion complex between TMeQ[6] and N,N'-diethyl-benzene-1,4-diamine unambiguously reveals that the aromatic ring of the guest resides in the oval cavity of TMeQ[6].
| S-EPMC5153640 | biostudies-literature
Project description:We present the synthesis of a series of six new glycoluril derived molecular clips and acyclic CB[n]-type molecular containers (1–3) that all feature SO3(?) solubilizing groups but differ in the number of glycoluril rings between the two terminal dialkoxyaromatic sidewalls. We report the X-ray crystal structure of 3b which shows that its dialkoxynaphthalene sidewalls actively define a hydrophobic cavity with high potential to engage in ?–? interactions with insoluble aromatic guests. Compounds 1–3 possess very good solubility characteristics (?38 mM) and undergo only very weak self-association (Ks < 92 M(?1)) in water. The weak self-association is attributed to unfavorable SO3(?)···SO3(?) electrostatic interactions in the putative dimers 12–42. Accordingly, we created phase solubility diagrams to study their ability to act as solubilizing agents for four water insoluble drugs (PBS-1086, camptothecin, ?-estradiol, and ziprasidone). We find that the containers 3a and 3b which feature three glycoluril rings between the terminal dialkoxy-o-xylylene and dialkoxynaphthalene sidewalls are less efficient solubilizing agents than 4a and 4b because of their smaller hydrophobic cavities. Containers 1 and 2 behave as molecular clip type receptors and therefore possess the ability to bind to and thereby solubilize aromatic drugs like camptothecin, ziprasidone, and PBS-1086.
| S-EPMC4366302 | biostudies-literature