Dendritic Molecular Baskets for Selective Binding of Toxic Methotrexate.

We describe the preparation, assembly, recognition characteristics, and bioactivity of dendritic basket 6. This novel cavitand has a deep aromatic pocket with three (S)-glutamic acid dendrons at the rim to amplify water solubility and prevent self-association. H NMR spectroscopy, calorimetry (ITC), and mass spectrometry (ESI-MS) measurements validate the formation of an inclusion complex between 6 and anticancer drug methotrexate (MTX) in water (K=9.

Molecular bowls for inclusion complexation of toxic anticancer drug methotrexate.

We describe the preparation and study of novel cavitands, molecular bowls 1 and 2, as good binders of the anticancer drug methotrexate (MTX). Molecular bowls are comprised of a curved tribenzotriquinacene (TBTQ) core conjugated to three macrocyclic pyridinium units at the top. The cavitands are easily accessible two synthetic steps from hexabromo-tribenzotriquinacene in 25% yield.

Molecular baskets form inclusion complexes with phenethylamine drugs in water.

Molecular basket 1 comprising a nonpolar cavity and an anionic nest of six carboxylates at its rim was found to form inclusion complexes with (1, 2)-ephedrine, (1, 2)-pseudoephedrine, and (1, 2)-tranylcypromine. Experimental results (NMR) and theory (MM/DFT) suggest the basket encapsulates phenethylamines in unique and predictable fashion.

Dynamic and Assembly Characteristics of Deep-Cavity Basket Acting as a Host for Inclusion Complexation of Mitoxantrone in Biotic and Abiotic Systems.

We describe the preparation, dynamic, assembly characteristics of vase-shaped basket 1 along with its ability to form an inclusion complex with anticancer drug mitoxantrone in abiotic and biotic systems. This novel cavitand has a deep nonpolar pocket consisting of three naphthalimide sides fused to a bicyclic platform at the bottom while carrying polar glycines at the top. The results of H Nuclear Magnetic Resonance (NMR), H NMR Chemical Exchange Saturation Transfer (CEST), Calorimetry, Hybrid Replica Exchange Molecular Dynamics (REMD), and Microcrystal Electron Diffraction (MicroED) measurements are in line with 1 forming dimer [1 ] , to be in equilibrium with monomers 1 (relaxed) and 1 (squeezed).

Crystalline Nanoparticles of Water-Soluble Covalent Basket Cages (CBCs) for Encapsulation of Anticancer Drugs.

We herein describe the preparation, assembly, recognition characteristics, and biocompatibility of novel covalent basket cage CBC-11, composed of four molecular baskets linked to four trivalent aromatic amines through amide groups. The cage is tetrahedral in shape and similar in size to small proteins (M =8637 g/mol) with a spacious nonpolar interior for accommodating multiple guests. While 24 carboxylates at the outer surface of CBC-11 render it soluble in aqueous phosphate buffer (PBS) at pH=7.

Rapid Access to Chiral and Tripodal Cavitands from β-Pinene.

We report Pd-catalyzed cyclotrimerization of (+)-α-bromoenone, obtained from monoterpene β-pinene, into an enantiopure cyclotrimer. This C symmetric compound has three bicyclo[3.1.

Closed Aromatic Tubes-Capsularenes.

In this study, we describe a synthetic method for incorporating arenes into closed tubes that we name capsularenes. First, we prepared vase-shaped molecular baskets 4-7. The baskets comprise a benzene base fused to three bicycle[2.

Dissipative Formation of Covalent Basket Cages.

Living systems use chemical fuels to transiently assemble functional structures. As a step toward constructing abiotic mimics of such structures, we herein describe dissipative formation of covalent basket cage CBC 5 by reversible imine condensation of cup-shaped aldehyde 2 (i.e.

A double-decker cage for allosteric encapsulation of ATP.

In this work, we describe the preparation of double-decker cage [1-H] comprising two binding pockets, each with three ammonium and three amide hydrogen bonding sites. This novel host possesses a high affinity for trapping two molecules of ATP in an allosteric fashion, with both experiments and theory suggesting the synergistic action of charged hydrogen bonds and π-π stacking in the encapsulation.

Picking on Carbonate: Kinetic Selectivity in the Encapsulation of Anions.

Supramolecular hosts bind to inorganic anions at a fast rate and select them in proportion with thermodynamic stability of the corresponding [anion⊂host] complexes, forming in a reversible manner. In this study, we describe the action of hexapodal capsule 1 and its remarkable ability to select anions based on a large span of rates by which they enter this host. The thermodynamic affinity of 1 toward eighteen anions extends over eight orders of magnitude (0 View Article and Find Full Text PDF

A computational study of competing conformational selection and induced fit in an abiotic system.

Host-guest complexations can be described by two competing mechanisms, conformational selection (CS) and induced fit (IF). In this work, we used a combination of nudged elastic band (NEB), adaptive steered molecular dynamics (ASMD), and density functional theory (DFT, with a correction for dispersion) to study the dynamics of the pathways (IF/CS) by which two conformers of basket B(+) and B(-) interconvert and trap CX guests (X = Cl and Br). While the results from NEB/DFT studies disclosed host-guest noncovalent contacts reducing the basket's conformational dynamics, ASMD methodology suggested an associative mechanism for the guest complexation.

Enantioselective Construction of Modular and Asymmetric Baskets.

The precise positioning of functional groups about the inner space of abiotic hosts is a challenging task and of interest for developing more effective receptors and catalysts akin to those found in nature. To address it, we herein report a synthetic methodology for preparing basket-like cavitands comprised of three different aromatics as side arms with orthogonal esters at the rim for further functionalization. First, enantioenriched A (borochloronorbornene), B (iodobromonorbornene), and C (boronorbornene) building blocks were obtained by stereoselective syntheses.

Molecular Recognition of Nerve Agents and Their Organophosphorus Surrogates: Toward Supramolecular Scavengers and Catalysts.

Nerve agents are tetrahedral organophosphorus compounds (OPs) that were developed in the last century to irreversibly inhibit acetylcholinesterase (AChE) and therefore impede neurological signaling in living organisms. Exposure to OPs leads to a rapid development of symptoms from excessive salivation, nasal congestion and chest pain to convulsion and asphyxiation which if left untreated may lead to death. These potent toxins are prepared on a large scale from inexpensive staring materials, making it feasible for terrorist groups or states to use them against military and civilians.

From Selection to Instruction and Back: Competing Conformational Selection and Induced Fit Pathways in Abiotic Hosts.

Two limiting cases of molecular recognition, induced fit (IF) and conformational selection (CS), play a central role in allosteric regulation of natural systems. The IF paradigm states that a substrate "instructs" the host to change its shape after complexation, while CS asserts that a guest "selects" the optimal fit from an ensemble of preexisting host conformations. With no studies that quantitatively address the interplay of two limiting pathways in abiotic systems, we herein and for the first time describe the way by which twisted capsule M-1, encompassing two conformers M-1(+) and M-1(-), trap CX (X=Cl, Br) to give CX ⊂M-1(+) and CX ⊂M-1(-), with all four states being in thermal equilibrium.

A Hexapodal Capsule for the Recognition of Anions.

We herein describe the preparation, characterization, and recognition characteristics of novel hexapodal capsule composed of two benzenes joined by six hydrogen bonding (HB) groups to encircle space. This barrel-shaped host was obtained by reversible imine condensation of hexakis-aldehyde and hexakis-amine in the presence of oxyanions or halides acting as templates. Fascinatingly, capsule includes 18 HB donating (C-H and N-H) and 12 HB accepting groups (C═O and C═N) surrounding a binding pocket (78 Å).

A highly diastereoselective synthesis of deep molecular baskets.

We describe a preparative method for directing Mizoroki-Heck cyclotrimerization of enantioenriched bromonorbornenes into molecular baskets having increasingly deeper and extendable aromatic cavities. Such diastereoselective cyclotrimerizations of the bromo-olefinic substrates resulted from prevalent β migratory insertions without the formation of palladacycle intermediate(s). The facile access to multigram quantity of a new series of basket-like hosts clears the way for creating novel supramolecular materials for storage, sequestration and catalysis.

A Molecular Capsule with Revolving Doors Partitioning Its Inner Space.

Covalent capsule 1 was designed to include two molecular baskets linked with three mobile pyridines tucked into its inner space. On the basis of both theory (DFT) and experiments (NMR and X-ray crystallography), we found that the pyridine "doors" split the chamber (380 Å ) of 1 so that two equally sizeable compartments (190 Å ) became joined through a conformationally flexible aromatic barrier. The compartments of such unique host could be populated with CCl (88 Å ; PC=46 %), CBr (106 Å ; 56 %) or their combination CCl /CBr (PC=51 %), with thermodynamic stabilities ΔG° tracking the values of packing coefficients (PC).

One-Pot Aldol Cascade for the Preparation of Isospiropyrans, Flavylium Salts, and bis-Spiropyrans.

We probed tandem aldol condensations of sixteen -hydroxyacetophenones, carrying electron-withdrawing and -donating groups at positions 4 and 5, using five molar equivalents of SiCl in anhydrous ethanol. Substrates carrying electron-withdrawing groups (EWGs) (0 < ∑σ > 0.63) populated the equilibria with isospiropyrans (12-74% yield), while those carrying electron-donating groups (EDGs) (∑σ < -0.

Photoinduced interruption of interannular cooperativity for delivery of cationic guests in water.

The synergy among twelve carboxylates from two hexavalent baskets 16- assisted the encapsulation of one divalent diammonium guest 32+-62+ and the formation of ternary [3-6⊂12]10-. The reduction of basket's multivalency, by photoinduced α-decarboxylation of 16- to give 23-, intercepted the interannular cooperativity operating in the stabilization of capsulpex [3-6⊂12]10- to dramatically diminish the binding affinity towards diammonium guests. As a result, the cationic guests were released into bulk water with 23- assembling into nanoparticles.

Tuning the allosteric sequestration of anticancer drugs for developing cooperative nano-antidotes.

A dual-cavity basket 1, holding six γ-aminobutyric acids at its termini, encapsulates variously sized aromatics 2-7, including four anthracyclines (8-11), driven by the hydrophobic effect and hydrogen bonding (HB). In particular, the formation of stable (K = 10 M) anthracycline complexes [(8-11)⊂1], assembled into nanoparticles, occurred with positive homotropic cooperativity (α = 4K/K = 1.1 ± 0.

Twist-Turn-Twist Motif Chaperoned Inside Molecular Baskets.

Two molecular baskets , each with three ()glutamic acids at its rim, were found (NMR, ITC) to complex diammonium alkanes (HN(CH)NH, = 710) giving ternary [-⊂] assemblies ( = 1010 M). From the magnetic perturbation of proton nuclei (H NMR, NICS), we deduced that each guest assumed a U shape within the binary complex, [-⊂]. Two ammonium groups were bound in the "anionic nest" at the top of , while the hydrocarbon chain resided in its nonpolar cavity.

An easily accessible isospiropyran switch.

In the presence of SiCl4, three molecules of 5'-bromo-2'-hydroxyacetophenone underwent an unexpected tandem aldol condensation to give a novel isospiropyran switch (69%), with X-ray crystallography confirming its structure. The strong Brønsted acid CH3SO3H turned the colorless isospiropyran into its protonated and open form possessing red color. This process was reversed using the Et3N base, with the acid/base toggling repeatable for at least six times (UV-Vis).

On the encapsulation and assembly of anticancer drugs in a cooperative fashion.

In this study, we report the remarkable recognition and assembly characteristics of symmetric basket containing two adjoining and nonpolar cavities with six biocompatible GABA residues at their northern and southern termini. From the results of experimental (H NMR, fluorescence and UV-Vis spectroscopies) and computational (MM-MC/OPLS3e) investigations, we deduced that hexaanionic captured two molecules of anticancer drug doxorubicin in water and accommodated them in its two deep cavities. The formation of stable ⊂ ( = 3 × 10 M) was accompanied by the exceptional homotopic cooperativity ( = 4 / = 112) in which = 3.

Multivalent C-H⋅⋅⋅Cl/Br-C Interactions Directing the Resolution of Dynamic and Twisted Capsules.

In this work, we report a mechanism by which stereoisomeric and twisted capsules P/M-1 direct their dynamic chirality in the presence of haloalkane guests. The capsule comprises a static, but twisted, cage that is linked to a dynamic tris(2-pyridylmethyl)amine (TPA) lid at its top. From the results of experimental (NMR spectroscopy and X-ray crystallography) and computational (DFT) studies, the TPA lid was shown to assume clockwise (+) and counterclockwise (-) folds with diastereomeric (but racemic) capsules M-1(+) and M-1(-) interconverting at a rapid rate (ΔG =9.

Stackable molecular chairs.

We describe the design, preparation and assembly of chair-shaped molecules, comprising a tris-bicyclo[2.2.1]heptane hub that extends into three phthalimides carrying amino acids or short peptides.