Development of Potent Microtubule Targeting Agent by Structural Simplification of Natural Diazonamide.

The marine metabolite diazonamide A exerts low nanomolar cytotoxicity against a range of tumor cell lines; however, its highly complex molecular architecture undermines the therapeutic potential of the natural product. We demonstrate that truncation of heteroaromatic macrocycle in natural diazonamide A, combined with the replacement of the challenging-to-synthesize tetracyclic hemiaminal subunit by oxindole moiety leads to considerably less complex analogues with improved drug-like properties and nanomolar antiproliferative potency. The structurally simplified macrocycles are accessible in 12 steps from readily available indolin-2-one and tert-leucine with excellent diastereoselectivity (99:1 dr) in the key macrocyclization step. The most potent macrocycle acts as a tubulin assembly inhibitor and exerts similar effects on A2058 cell cycle progression and induction of apoptosis as does marketed microtubule-targeting agent vinorelbine.

Mechanochemical Birch Reduction with Low Reactive Alkaline Earth Metals.

Birch reduction and similar dissolved metal-type transformations hold significant importance in the organic synthesis toolbox. Historically, the field has been dominated by alkali metal reductants. In this study, we report that largely neglected, low-reactive alkaline earth metals can become powerful and affordable reductants when used in a ball mill under essentially solvent-free conditions, in the presence of ethylenediamine and THF as liquid additives. Calcium can reduce both electron-deficient and electron-rich arenes, with yields of products similar to those obtained with lithium metal. Magnesium reveals enhanced reducing power, enabling the reduction of benzoic acids while keeping electron-rich aromatic moieties intact and allows for chemoselective transformations. The developed mechanochemical approach uses readily available and safer-to-handle metals, operates under air and ambient temperature conditions, and can be used for gram-scale preparations. Finally, we demonstrate that the developed conditions can be used for other dissolved metal-type reductive transformations, including reductive amination, deoxygenation, dehalogenation, alkene and alkyne reductions.

Porphyrin-Based Hybrid Nanohelices: Cooperative Effect between Molecular and Supramolecular Chirality on Amplified Optical Activity.

The development of chiral receptors for discriminating the configuration of the analyte of interest is increasingly urgent in view of monitoring pollution in water and waste liquids. Here, we investigate an easy protocol to immobilize the desired non-water-soluble receptors inside a water-dispersible chiral nanoplatform made of silica. This approach induces chirality in the receptors and Here, we investigate an easy protocol to immobilize the desired non-water-soluble receptors inside a water-dispersible chiral nanoplatform made of silica. This approach induces chirality in the receptors and makes the dye@nanohelix system disperse in a suspension of water without aggregation. We noted strong induction and amplification of chiroptical activity in both achiral and chiral (proline-based or hemicucurbituril-based) porphyrin derivatives with and without zinc ions once confined and organized in nanometer silica helices. The results clearly demonstrated that the organization-induced chirality amplification of porphyrins dominates the molecular chirality, and the amplification is more efficient for more flexible porphyrins (especially free-base and achiral).

Natural pigments (anthocyanins and chlorophyll) and antioxidants profiling of European red and green gooseberry (Ribes uva-crispa L.) extracted using green techniques (UAE-citric acid-mediated extraction).

Green techniques to extract natural pigments are gaining prominence among consumers and food industries. This trend is predominantly due to the harmful effects imparted by commonly used synthetic dyes and the unwarranted stress created on our ecosystem. The objectives of this study were to obtain natural pigments (anthocyanins and chlorophyll) from Estonian-gown European green and red gooseberries by ultrasonic-assisted citric acid-mediated extraction method and perform antioxidant profiling (quantification via HPLC analysis). Green gooseberry extracts showed lower content of targeted compounds, with low concentrations of rutin (0.7-1.2 mg/L) and quercetin 3-glucoside (0.9-1.3 mg/L), while in the red gooseberry extracts, the amount was slightly higher (1.4-6.9 and 1.0-1.3 mg/L, respectively) with 0.6-6.8 mg/L cyanidin 3-glucoside and 0.32-0.35 mg/L peonidin 3 glucoside recorded. Further, the yield of anthocyanins ranged between 1.14-1.79 and 1.86-3.63 mg/100 g in green and red gooseberries, respectively. Total phenols ranged between 162-392 and 263-987 mg GAE/100 g in green and red gooseberry extracts, respectively. The DPPH free radicals scavenging activity showed 73-86% and 87-91% inhibition in both green and red gooseberry, respectively. Results showed significant improvements in pigment extraction with higher values obtained for targeted antioxidant compounds using conventional and UAE extraction (aqueous extract), thus confirming that green extractions are a reliable technique to obtain pigments of interest from natural sources. The results support consumers' demand and open up the avenue to explore pigments as natural colourants in food and cosmetics applications.

Mechanochemistry-Amended Barbier Reaction as an Expedient Alternative to Grignard Synthesis.

Organomagnesium halides (Grignard reagents) are essential carbanionic building blocks widely used in carbon-carbon and carbon-heteroatom bond-forming reactions with various electrophiles. In the Barbier variant of the Grignard synthesis, the generation of air- and moisture-sensitive Grignard reagents occurs concurrently with their reaction with an electrophile. Although operationally simpler, the classic Barbier approach suffers from low yields due to multiple side reactions, thereby limiting the scope of its application. Here, we report a mechanochemical adaptation of the Mg-mediated Barbier reaction, which overcomes these limitations and facilitates the coupling of versatile organic halides (e.g., allylic, vinylic, aromatic, aliphatic) with a diverse range of electrophilic substrates (e.g., aromatic aldehydes, ketones, esters, amides, O-benzoyl hydroxylamine, chlorosilane, borate ester) to assemble C-C, C-N, C-Si, and C-B bonds. The mechanochemical approach has the advantage of being essentially solvent-free, operationally simple, immune to air, and surprisingly tolerant to water and some weak Brønsted acids. Notably, solid ammonium chloride was found to improve yields in the reactions of ketones. Mechanistic studies have clarified the role of mechanochemistry in the process, indicating the generation of transient organometallics facilitated by improved mass transfer and activation of the surface of magnesium metal.

Chiral Recognition by Supramolecular Porphyrin-Hemicucurbit[8]uril-Functionalized Gravimetric Sensors.

Enantiorecognition of a chiral analyte usually requires the ability to respond with high specificity to one of the two enantiomers of a chiral compound. However, in most cases, chiral sensors have chemical sensitivity toward both enantiomers, showing differences only in the intensity of responses. Furthermore, specific chiral receptors are obtained with high synthetic efforts and have limited structural versatility. These facts hinder the implementation of chiral sensors in many potential applications. Here, we utilize the presence of both enantiomers of each receptor to introduce a novel normalization that allows the enantio-recognition of compounds even when single sensors are not specific for one enantiomer of a target analyte. For this purpose, a novel protocol that permits the fabrication of a large set of enantiomeric receptor pairs with low synthetic efforts by combining metalloporphyrins with (R,R)- and (S,S)-cyclohexanohemicucurbit[8]uril is developed. The potentialities of this approach are investigated by an array of four pairs of enantiomeric sensors fabricated using quartz microbalances since gravimetric sensors are intrinsically non-selective toward the mechanism of interaction of analytes and receptors. Albeit the weak enantioselectivity of single sensors toward limonene and 1-phenylethylamine, the normalization allows the correct identification of these enantiomers in the vapor phase indifferent to their concentration. Remarkably, the achiral metalloporphyrin choice influences the enantioselective properties, opening the way to easily obtain a large library of chiral receptors that can be implemented in actual sensor arrays. These enantioselective electronic noses and tongues may have a potential striking impact in many medical, agrochemical, and environmental fields.

Solution- and gas-phase study of binding of ammonium and bisammonium hydrocarbons to oxacalix[4]arene carboxylate.

Oxacalixarenes represent a distinctive class of macrocyclic compounds, which are closely related to the parent calixarene family, offering binding motifs characteristic of calixarenes and crown ethers. Nevertheless, they still lack extensive characterization in terms of molecular recognition properties and the subsequent practical applicability. We present here the results of binding studies of an oxacalix[4]arene carboxylate macrocycle toward a variety of organic ammonium cationic species. Our results show that the substituents attached to the guest ammonium compound largely influence the binding strengths of the host. Furthermore, we show that the characteristic binding pattern changes upon transition from the gas phase to solution in terms of the governing intermolecular interactions. We identify the key factors affecting host-guest binding efficacy and suggest rules for the important molecular structural motifs of the interacting parts of ammonium guest species and the macrocycle to facilitate sensing of ammonium cations.

Carbonyl hypoiodites from pivalic and trimesic acid and their silver(I) intermediates.

The first tris(O-I-N) carbonyl hypoiodites have been synthesised based on trimesic acid and pyridine or 4-methylpyridine, with their structures definitively confirmed by single crystal X-ray diffraction (SCXRD). The more soluble carbonyl hypoiodites based on pivalic acid have also been studied via NMR, SCXRD, and computational analyses, enabling the study of the direct silver(I) precursor and intermediates of the resulting carbonyl hypoiodites generated using a range of substituted pyridines.

Self-Assembly of Chiral Cyclohexanohemicucurbit[n]urils with Bis(Zn Porphyrin): Size, Shape, and Time-Dependent Binding.

In order to investigate the ability of bis(zinc octaethylporphyrin) (bis-ZnOEP) to discriminate cyclohexanohemicucurbit[n]urils (cycHC[n]) of different shapes and sizes, the self-assembly of barrel-shaped chiral cycHC[n] with bis-ZnOEP was studied by various spectroscopic methods (absorption, fluorescence, circular dichroism (CD), and NMR). While the binding of 6-membered cycHC[6] induced a tweezer-like conformation followed by the formation of anti-form of bis-ZnOEP upon further addition of cycHC[6], the interaction of 8-membered cycHC[8] is more complex and proceeds through the featured syn-to-anti conformational change of bis-ZnOEP and further intermolecular self-assembly via multiple noncovalent associations between cycHC[8] and bis-ZnOEP. Whilst bis-porphyrins are known to be effective chemical sensors able to differentiate various guests based on their chirality via induced CD, their ability to sense small differences in the shape and size of relatively large macrocycles, such as chiral cycHC[6] and cycHC[8], is scarcely examined. Both studied complexes exhibited characteristic induced CD signals in the region of porphyrin absorption upon complexation.

Mechanochemical Nucleophilic Substitution of Alcohols via Isouronium Intermediates.

An expansion of the solvent-free synthetic toolbox is essential for advances in the sustainable chemical industry. Mechanochemical reactions offer a superior safety profile and reduced amount of waste compared to conventional solvent-based synthesis. Herein a new mechanochemical method was developed for nucleophilic substitution of alcohols using fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TFFH) and K2 HPO4 as an alcohol-activating reagent and a base, respectively. Alcohol activation and reaction with a nucleophile were performed in one milling jar via reactive isouronium intermediates. Nucleophilic substitution with amines afforded alkylated amines in 31-91 % yields. The complete stereoinversion occurred for the SN 2 reaction of (R)- and (S)-ethyl lactates. Substitution with halide anions (F- , Br- , I- ) and oxygen-centered (CH3 OH, PhO- ) nucleophiles was also tested. Application of the method to the synthesis of active pharmaceutical ingredients has been demonstrated.

Cyclohexanohemicucurbit[8]uril Inclusion Complexes With Heterocycles and Selective Extraction of Sulfur Compounds From Water.

Solid-phase extraction that utilizes selective macrocyclic receptors can serve as a useful tool for removal of chemical wastes. Hemicucurbiturils are known to form inclusion complexes with suitably sized anions; however, their use in selective binding of non-charged species is still very limited. In this study, we found that cyclohexanohemicucurbit[8]uril encapsulates five- and six-membered sulfur- and oxygen-containing unsubstituted heterocycles, which is investigated by single-crystal X-ray diffraction, NMR spectroscopy, isothermal titration calorimetry, and thermogravimetry. The macrocycle acts as a promising selective sorption material for the extraction of sulfur heterocycles, such as 1,3-dithiolane and α-lipoic acid, from water.

Binding Between Cyclohexanohemicucurbit[n]urils and Polar Organic Guests.

Inherently chiral, barrel-shaped, macrocyclic hosts such as cyclohexanohemicucurbit[n]urils (cycHC[n]) bind zinc porphyrins and trifluoroacetic acid externally in halogenated solvents. In the current study, we tested a set of eighteen organic guests with various functional groups and polarity, namely, thiophenols, phenols, and carboxylic and sulfonic acids, to identify a preference toward hydrogen bond-donating molecules for homologous cycHC[6] and cycHC[8]. Guests were characterized by Hirshfeld partial charges on acidic hydrogens and their binding by 1H and 19F NMR titrations. Evaluation of association constants revealed the complexity of the system and indirectly proved an external binding with stoichiometry over 2:1 for both homologs. It was found that overall binding strength is influenced by the stoichiometry of the formed complexes, the partial atomic charge on the hydrogen atom of the hydrogen bond donor, and the bulkiness of the guest. Additionally, a study on the formation of complexes with halogen anions (Cl- and Br-) in methanol and chloroform, analyzed by 1H NMR, did not confirm complexation. The current study widens the scope of potential applications for host molecules by demonstrating the formation of hydrogen-bonded complexes with multisite hydrogen bond acceptors such as cycHC[6] and cycHC[8].

Chirogenesis in Zinc Porphyrins: Theoretical Evaluation of Electronic Transitions, Controlling Structural Factors and Axial Ligation.

In the present work, sixteen different zinc porphyrins (possessing different meso substituents) with and without a chiral guest were modelled using DFT and TD-DFT approaches in order to understand the influence of various controlling factors on electronic circular dichroism (ECD) spectra. Two major aspects are influenced by these factors: excitation energy of the electronic transitions and their intensity. In the case of excitation energy, the influence increases in the following order: orientation of the peripheral substituents

Dynamic chiral cyclohexanohemicucurbit[12]uril.

NMR spectroscopy and DFT modeling studies of chiral cyclohexanohemicucurbit[12]uril indicate that the macrocycle adopts a concave octagonal shape with two distinct conformational flexibilities in solution. Methylene bridge flipping occurs at temperatures above 265 K, while urea monomers rotate at temperatures above 308 K, resulting in the loss of confined space within the macrocycle.

Benchmarking computational methods and influence of guest conformation on chirogenesis in zinc porphyrin complexes.

Circular dichroism (CD) is a convenient and widely used tool for investigating structures of chiral molecules. However, the unambiguous simulation of CD spectra is not a trivial task, because the accuracy of theoretical calculations depends on the nature of the system. In the present work, the induced CD spectra of six zinc porphyrin complexes with chiral guests were simulated by using different DFT methods. The best agreement between theoretical and experimental results for the Soret (B) band absorption region was achieved with the ωB97X-D, CAM-B3LYP, and M06-2X functionals with implicit inclusion of solvent effects (SMD model). Also, a good correlation between the simulated and experimental spectra was obtained with the DZVP basis sets, however a more accurate simulation of the length- and velocity rotational strengths needed larger TZVP basis sets. Additionally, the conformation of the chiral guest influences the chirogenic mechanism.

Supramolecular chirogenesis in zinc porphyrins by enantiopure hemicucurbit[n]urils (n = 6, 8).

Chiral cyclohexanohemicucurbit[n]urils (n = 6, 8) (cycHCs) are able to bind guests through multiple "outer surface interactions", which in the case of planar zinc porphyrins leads to induction of chirality. Crystal structures of complexes of complementary sized hosts revealed social self-sorting, while in the solution phase one cycHC can accommodate up to three porphyrin molecules with log Ktotal 9.