Molecular clip and tweezer introduce new mechanisms of enzyme inhibition

Artificial molecular clips and tweezers, designed for cofactor and amino acid recognition, are able to inhibit the enzymatic activity of alcohol dehydrogenase (ADH). IC50 values and kinetic investigations point to two different new mechanisms of interference with the NAD(+)-dependent oxidoreductase: While the clip seems to pull the cofactor out of its cleft, the tweezer docks onto lysine residues around the active site. Both modes of action can be reverted to some extent, by appropriate additives. However, while cofactor depletion by clip 1 was in part restored by subsequent NAD(+) addition, the tweezer (2) inhibition requires the competitive action of lysine derivatives. Lineweaver-Burk plots indicate a competitive mechanism for the clip, with respect to both substrate and cofactor, while the tweezer clearly follows a noncompetitive mechanism. Conformational analysis by CD spectroscopy demonstrates significant ADH denaturation in both cases. However, only the latter case (tweezer-lysine) is reversible, in full agreement with the above-detailed enzyme switch experiments. The complexes of ADH with clips or tweezer can be visualized in a nondenaturing gel electrophoresis, where the complexes migrate toward the anode, in contrast to the pure enzyme which approaches the cathode. Supramolecular chemistry has thus been employed as a means to control protein function with the specificity of artificial hosts opening new avenues for this endeavor.     

Guest-dependent complexation of triptycene-based macrotricyclic host with paraquat derivatives and secondary ammonium salts: a chemically controlled complexation process

The triptycene-based macrotricyclic host containing two dibenzo-[24]-crown-8 moieties has been found to form stable 1:1 or 1:2 complexes in different complexation modes with different functional paraquat derivatives and secondary ammonium salts in solution and in the solid state. Consequently, the alkyl-substituted paraquat derivatives thread the lateral crown cavities of the host to form 1:1 complexes. It was interestingly found that the paraquat derivatives containing two beta-hydroxyethyl or gamma-hydroxypropyl groups form 1:2 complexes, in which two guests thread the central cavity of the host. Other paraquat derivatives containing terminal hydroxy, methoxy, 9-anthracylmethyl, and amide groups were included in the cavity of the host to form 1:1 complexes. Moreover, the host also forms a 1:2 complex with two 9-anthracylmethylbenzylammonium salts, in which the 9-anthracyl groups were selectively positioned outside the lateral crown cavities. The competition complexation process between the host and two different guests (the propyl-substituted paraquat derivative and a dibenzylammonium salt) could be chemically controlled.     

2,3,10,11‐Tetrahydroxytetraphenylene and Its Application in Molecular Recognition

A rationally designed 2,3,10,11‐tetrahydroxytetraphenylene ( 1 ) has been synthesized. Employing 1 as a building block, a structurally novel tweezer‐like host 2 containing dibenzo‐24‐crown‐8 moieties has been prepared. Host 2 showed excellent molecular‐recognition ability toward paraquat (=1,1′‐dimethyl‐4,4′‐bipyridinium dichloride) derivative 3a to form a 1 : 1 stable complex in solution.     

Absolute Stereochemical Determination of Chiral Carboxylates Using an Achiral Molecular Tweezer

A new type of molecular tweezer ( 1 ) has been synthesized for the direct determination of the absolute configuration of chiral carboxylates without analyte derivatization. Upon the addition of diamine and anionic guests, 1 exhibited shifts in its absorption spectrum with clear isosbestic points. The continuous variation method indicated that both the diamine and anionic guests form 1:1 host–guest complexes with 1 with very high binding affinity. When Boc‐L ‐Ala (BLA) as a form of tetrabutylammonium salt was added to 1 , a weak negative CD signal was observed. This weak CD signal was dramatically changed to a strong positive CD couplet upon addition of achiral 1,12‐diaminododecane. Such a positive CD couplet was observed for all of the tested L ‐amino acid derivatives, while the D ‐amino acid derivatives gave the opposite signals. As a result of these unique characteristics of 1 , it can be utilized as a highly sensitive probe for the absolute stereochemical determination of chiral carboxylates.     

Hydrogen bonding-driven elastic bis(zinc)porphyrin receptors for neutral and cationic electron-deficient guests with a sandwich-styled complexing pattern

This Letter reports the design and synthesis of a new type of hydrogen bonding-mediated foldamer-derived tweezer receptors that are incorporated with two peripheral (zinc)porphyrin units. Due to the existence of four intramolecular hydrogen bonds, the (zinc)porphyrin units are forced to approach and stack with each other. ¹H NMR and fluorescent studies revealed that the new receptors could form 1:1 complexes with planar electron-deficient molecules such as naphthalene and benzene diimides and paraquat through a unique sandwich-styled binding pattern. The association constants of the new complexes have been evaluated by the ¹H NMR or fluorescent titration methods.     

Efficient syntheses of bis(m-phenylene)-26-crown-8-based cryptand/paraquat derivative [2]rotaxanes by immediate solvent evaporation method

A novel bis(m-phenylene)-26-crown-8-based cryptand has been synthesized. It has been used to prepare two 1:1 complexes with two paraquat derivatives with high association constants (6.5×10⁵ and 4.0×10⁵ M⁻¹) in acetone. In the solid state the cryptand forms a 2:1 threaded structure with paraquat and an interesting supramolecular poly[2]pseudorotaxane threaded structure with a dihydroxyethyl-substituted paraquat derivative, respectively. It has been further used to prepare cryptand/paraquat derivative [2]rotaxanes efficiently by the immediate solvent evaporation method using easily available 3,5-dimethylphenyl groups as the stoppers.     

Dynamic Assembly Inclusion Complexes of Tweezer‐type Bis(zinc porphyrin) with 5,15‐Di(4‐pyridyl)porphyrin Derivatives

Dynamic assembly inclusion complexes of tweezer-type bis(zinc porphyrin) (1) with di(4-pyridyl)porphyrin derivatives have been designed and constructed. The complexes are induced by Zn-N coordination, and the weak binding allows the large-size di(4-pyridyl)porphyrin guests in random rotation. Dynamic characteristics of these assemblies, such as ligand exchange and dynamic fluorescence quenching, have been investigated by 1H NMR, UV-Vis and fluorescence spectra. The stability of such assembly has pronounced dependence on the size-matching effect and thermal effect.     

Bis(m-phenylene)-32-crown-10-based cryptands, powerful hosts for paraquat derivatives

Four new bis(m-phenylene)-32-crown-10-based cryptands with different third bridges were prepared. Their complexes with paraquat derivatives were studied by proton NMR spectroscopy, mass spectrometry, and X-ray analysis. It was found that these cryptands bind paraquat derivatives very strongly. Specifically, a diester cryptand with a pyridyl nitrogen atom located at a site occupied by either water or a PF(6) anion in analogous complexes exhibited the highest association constant K(a) = 5.0 x 10(6) M(-1) in acetone with paraquat, 9000 times greater than the crown ether system. X-ray structures of this and analogous complexes demonstrate that improved complexation with this host is a consequence of preorganization, adequate ring size for occupation by the guest, and the proper location of the pyridyl N-atom for binding to the beta-pyridinium hydrogens of the paraquat guests. This readily accessible cryptand is one of the most powerful hosts reported for paraquats.     

Synthesis of triptycene-derived macrotricyclic host containing two dibenzo-[18]-crown-6 moieties and its complexation with paraquat derivatives: Li(+)-ion-controlled binding and release of the guests in the complexes

A new triptycene-derived macrotricyclic host containing two dibenzo-[18]-crown-6 moieties was synthesized and shown to form 1:1 complexes with paraquat derivatives in solution, in which the guests all thread the central cavity of the host. However, it was interestingly found that, depending on the paraquat derivatives with different functional groups, the host can form stable 1:1 or 1:2 complexes in different complexation modes in the solid state, which is significantly different from those of the macrotricyclic host containing two dibenzo-[24]-crown-8 moieties. The formation of the complexes was also proved by the ESI MS and electrochemical experiments. Moreover, it was found that the binding and release of the guests in the complexes could be easily controlled by the addition and removal of lithium ions.     

Chiral recognition by CD-sensitive dimeric zinc porphyrin host. 2. Structural studies of host-guest complexes with chiral alcohol and monoamine conjugates.

A structural study of complexes formed between a dimeric zinc porphyrin tweezer (host) and chiral monoalcohols and monoamines derivatized by a bidentate carrier molecule (guest) confirmed that their CD couplets arise from the preferred porphyrin helicity of 1:1 host-guest complexes. NMR experiments and molecular modeling of selected tweezer complexes revealed that the preferred conformation is the one in which the L (larger) group protrudes from the porphyrin sandwich; this preferred helicity of the complex determines the CD of the complexes. It was found that the porphyrin ring-current induced (1)H chemical shifts and molecular modeling studies of the complex lead to the assignments of relative steric size of the L (large)/M (medium) substituents attached to the stereogenic center. The assignments, in turn, are correlated with the sign of the CD exciton couplet that establishes the absolute configuration at the stereogenic center. Variable-temperature NMR experiments proved that the observed increase in CD amplitude at lower temperatures derives from conformational changes in the preferred offset geometry between two porphyrin rings.     

A triptycene-based bis(crown ether) host: complexation with both paraquat derivatives and dibenzylammonium salts

[reaction: see text] A novel triptycene-based bis(crown ether) host (1) incorporating two dibenzo-24-crown-8 ether moieties has been synthesized. It can form not only a new bis[2]pseudorotaxane with dibenzylammonium salts but also stable clip-shaped complexes with paraquat derivatives. Moreover, the complexation process between 1 and the two classes of guests can be chemically controlled.     

Drug release by pH‐responsive molecular tweezers: Atomistic details from molecular modeling

pH‐responsive molecular tweezers have been proposed as an approach for targeting drug‐delivery to tumors, which tend to have a lower pH than normal cells. We performed a computational study of a pH‐responsive molecular tweezer using ab initio quantum chemistry in the gas‐phase and molecular dynamics (MD) simulations in solution. The binding free energy in solution was calculated using steered MD. We observe, in atomistic detail, the pH‐induced conformational switch of the tweezer and the resulting release of the drug molecule. Even when the tweezer opens, the drug molecule remains near a hydrophobic arm of the molecular tweezer. Drug release cannot occur, it seems, unless the tweezer is in a hydrophobic environment with low pH. © 2014 Wiley Periodicals, Inc.     

Simultaneous enhancement of phosphorescence and chirality by host–guest recognition of molecular tweezers

A novel type of host–guest recognition systems have been developed on the basis of a Au(III) molecular tweezer receptor and chiral Pt(II) guests. The complementary host–guest motifs display high non-covalent binding affinity (K_a: ～10⁴ L/mol) due to the participation of two-fold intermolecular π–π stacking interactions. Both phosphorescence and chirality signals of the Pt(II) guests strengthen in the resulting host–guest complexes, because of the cooperative rigidifying and shielding effects rendered by the tweezer receptor. Their intensities can be reversibly switched toward pH changes, by taking advantage of the electronic repulsion effect between the protonated form of tweezer receptor and the positive-charged guests in acidic environments. Overall, the current study demonstrates the feasibility to enhance and modulate phosphorescence and chirality signals simultaneously via molecular tweezer-based host–guest recognition.     

Di-(R,R)-1-[10-(1-hydroxy-2,2,2-trifluoroethyl)-9-anthryl]-2,2,2-trifluoroethyl muconate: a highly chiral cavity for enantiodiscrimination by NMR

A new chiral molecular tweezer, di-(R,R)-1-[10-(1-hydroxy-2,2,2-trifluoroethyl)-9-anthryl]-2,2,2-trifluoroethyl muconate 2, was synthesized in enantiopure form, and its geometry was studied using NMR and molecular mechanics. The effectiveness of 2 as a chiral solvating agent for determining the enantiomeric composition of chiral compounds using NMR was demonstrated, improving the results obtained with other methods. The stoichiometry and the association constant of the resulting diastereomeric complexes were studied, and their geometry was analyzed by NOE and 1H NMR.     

A hyodeoxycholic acid-based molecular tweezer: a highly selective fluoride anion receptor

A new molecular tweezer receptor Hc1 based on hyodeoxycholic acid has been synthesized and its binding properties were accessed by ¹H NMR and isothermal titration calorimetry experiments. Molecular tweezer Hc1 shows a high selectivity toward F⁻ over Cl⁻, Br⁻, I⁻, and H₂PO₄⁻.     

Analytical calculation of the electrostatic interaction energy within the CNDO framework

This work analyses the adequacy of an analytical electrostatic energy formulation within the CNDO framework to predict the stable conformations of large molecular complexes. Comparisons are made with abinitio results for small systems such as water-formamide, methanol-water-imidazole, or guanine-cytosine and with AM 1 results for two large systems: a molecular tweezer + the 9-methyladenine complex and a model active site of the α-chymotrypsin and its ligand complex. This approach is efficient in providing reliable confromers for large molecular systems in a very fast way. © 1993 John Wiley & Sons, Inc.     

A Modular Phosphorylated Glycoluril-Derived Molecular Tweezer for Potent Binding of Aliphatic Diamines

A molecular tweezer based on a glycoluril-derived framework bearing four phosphate groups was synthesized and shown to be capable of binding organic amines in aqueous solution. This work reports the K_a values for 30 complexes of this molecular tweezer and amine guests, determined by means of ¹H NMR titrations. Both the hydrophobic cavity and the phosphate groups contribute to the binding. Bulkier molecules and molecules bearing negatively charged groups like carboxylates in amino acids bind less tightly due to a steric clash and coulombic repulsion. The narrow cavity and the strong ionic interactions of the phosphate groups with ammonium guests favor binding of aliphatic diamines. These binding properties clearly distinguish this system from structurally related molecular clips and tweezers.     

Molecular complexes of paraquat with anilines

The U V-VIS spectra of molecular complexes of paraquat with ring and N-substituted anilines have been recorded in methanol and 50% v/v aqueous methanol. All the complexes exhibited well-resolved charge transfer bands in the wavelength region where neither of the components have any absorption. The energies of charge transfer bands of the substituted aniline-paraquat complexes bear linear relationships with the ionization potentials obtained from the substituted aniline-TCNE complexes, indicating π - π interaction between paraquat and the donors. Both ring and N-substituents have effects on the positions of the CT bands as well as on the stabilities of the complexes. The positions of the CT bands are shifted to shorter wavelengths and the stabilities of the complexes decrease on going from methanol to aqueous. methanol.     

Metalla-Assembled Electron-Rich Tweezers: Redox-Controlled Guest Release Through Supramolecular Dimerization

Developing methodologies for on-demand control of the release of a molecular guest requires the rational design of stimuli-responsive hosts with functional cavities. While a substantial number of responsive metallacages have already been described, the case of coordination-tweezers has been less explored. Herein, we report the first example of a redox-triggered guest release from a metalla-assembled tweezer. This tweezer incorporates two redox-active panels constructed from the electron-rich 9-(1,3-dithiol-2-ylidene)fluorene unit that are facing each other. It dimerizes spontaneously in solution and the resulting interpenetrated supramolecular structure can dissociate in the presence of an electron-poor planar unit, forming a 1:1 host–guest complex. This complex dissociates upon tweezer oxidation/dimerization, offering an original redox-triggered molecular delivery pathway.     

Sterically controlled recognition of macromolecular sequence information by molecular tweezers

Sequence-specific binding is demonstrated between pyrene-based tweezer molecules and soluble, high molar mass copolyimides. The binding involves complementary pi-pi stacking interactions, polymer chain-folding, and hydrogen bonding and is extremely sensitive to the steric environment around the pyromellitimide binding-site. A detailed picture of the intermolecular interactions involved has been obtained through single-crystal X-ray studies of tweezer complexes with model diimides. Ring-current magnetic shielding of polyimide protons by the pyrene "arms" of the tweezer molecule induces large complexation shifts of the corresponding 1H NMR resonances, enabling specific triplet sequences to be identified by their complexation shifts. Extended comonomer sequences (triplets of triplets in which the monomer residues differ only by the presence or absence of a methyl group) can be "read" by a mechanism which involves multiple binding of tweezer molecules to adjacent diimide residues within the copolymer chain. The adjacent-binding model for sequence recognition has been validated by two conceptually different sets of tweezer binding experiments. One approach compares sequence-recognition events for copolyimides having either restricted or unrestricted triple-triplet sequences, and the other makes use of copolymers containing both strongly binding and completely nonbinding diimide residues. In all cases the nature and relative proportions of triple-triplet sequences predicted by the adjacent-binding model are fully consistent with the observed 1H NMR data.