Unsymmetric Chiral Ligands for Large Metallo-Macrocycles: Selectivity of Orientational Self-Sorting.

Nature uses various chiral and unsymmetric building blocks to form substantial and complex supramolecular assemblies. In contrary, majority of organic ligands used in metallosupramolecular chemistry are symmetric and achiral. Here we extend on the group of unsymmetric chiral bile acids used as a scaffold for organic bispyridyl ligands employing the chenodeoxycholic acid (CDCA), epimer of previously used ursodeoxycholic acid (UDCA). Ligands' epimerism, flexibility, and bulkiness leads to large structural differences of coordination products upon reaction with Pd(NO3)2. The UDCA-bispyridyl ligand self-assembles quantitatively into a single crown-like Pd3L6 complex, whereas the CDCA-ligand provides a mixture of coordination complexes of general formula PdnL2n, i.e., Pd2L4, Pd3L6, Pd4L8, Pd5L10, and even Pd6L12 containing impressive 120 chiral centers. The coordination products were studied by a combination of analytical methods, where the ion mobility-mass spectrometry (IM-MS) provided valuable details on their structure and allowed an effective separation of m/z 1461 to individual signals according to arrival time distribution, revealing four different ions of [Pd3L6(NO3)3]3+, [Pd4L8(NO3)4]4+, [Pd5L10(NO3)5]5+, and [Pd6L12(NO3)6]6+. The structures of all complexes were modelled using DFT calculations. Finally, challenges and conclusions in determination of specific structural identity of these unsymmetric species are discussed.

Diterpenes Isolated from Three Different Plectranthus Sensu Lato Species and Their Antiproliferative Activities against Gynecological and Glioblastoma Cancer Cells.

Fourteen diterpenes were isolated from methanol extracts of the aerial parts ofColeus comosus,Coleus forsteri "Marginatus", and Plectranthus ciliatus. The compounds belong to the abietane (1-4, 9-11, and 13), ent-clerodane (5-8), and ent-kaurane (14, 15) classes. Three new compounds were isolated from C. comosus, including 3-O-acetylornatin G (2), 3,12-di-O-acetylornatin G (3), ornatin B methyl ester (5), and ornatin F (4), for which we proposed a revised structure. The structures of the compounds were determined by comprehensive spectroscopic data analysis. The isolated diterpenes were examined in silico for their physicochemical and early ADME properties. Their antiproliferative effects were determined in vitro using human breast (MDA-MB-231 and MCF-7), cervical (HeLa), and glioblastoma (U-87 MG) cancer cell lines. The royleanone- and hydroquinone-type abietane diterpenes (9-13)exhibited the most potent antiproliferative activity against all cancer cell lines tested, particularly against glioblastoma cells, with IC50 values ranging from 1.1 to 15.6 µM.

Dibenzocyclooctadiene Lignans from Schisandra chinensis with Anti-Inflammatory Effects.

Schisandra chinensis (Schisandraceae) is a medicinal plant widely used in traditional Chinese medicine. Under the name Wu Wei Zi, it is used to treat many diseases, especially as a stimulant, adaptogen, and hepatoprotective. Dibenzocyclooctadiene lignans are the main compounds responsible for the effect of S. chinensis. As a part of ongoing studies to identify and evaluate anti-inflammatory natural compounds, we isolated a series of dibenzocyclooctadiene lignans and evaluated their biological activity. Furthermore, we isolated new sesquiterpene 7,7-dimethyl-11-methylidenespiro[5.5]undec-2-ene-3-carboxylic acid. Selected dibenzocyclooctadiene lignans were tested to assess their anti-inflammatory potential in LPS-stimulated monocytes by monitoring their anti-NF-κB activity, antioxidant activity in CAA assay, and their effect on gap junction intercellular communication in WB-ras cells. Some S. chinensis lignans showed antioxidant activity in CAA mode and affected the gap junction intercellular communication. The anti-inflammatory activity was proven for (-)-gomisin N, (+)-γ-schisandrin, rubrisandrin A, and (-)-gomisin J.

Bile Acids Transporters of Enterohepatic Circulation for Targeted Drug Delivery.

Bile acids (BAs) are important steroidal molecules with a rapidly growing span of applications across a variety of fields such as supramolecular chemistry, pharmacy, and biomedicine. This work provides a systematic review on their transport processes within the enterohepatic circulation and related processes. The focus is laid on the description of specific or less-specific BA transport proteins and their localization. Initially, the reader is provided with essential information about BAs' properties, their systemic flow, metabolism, and functions. Later, the transport processes are described in detail and schematically illustrated, moving step by step from the liver via bile ducts to the gallbladder, small intestine, and colon; this description is accompanied by descriptions of major proteins known to be involved in BA transport. Spillage of BAs into systemic circulation and urine excretion are also discussed. Finally, the review also points out some of the less-studied areas of the enterohepatic circulation, which can be crucial for the development of BA-related drugs, prodrugs, and drug carrier systems.

Anion Recognition by a Bioactive Diureidodecalin Anionophore: Solid-State, Solution, and Computational Studies.

Recent work has identified a bis-(p-nitrophenyl)ureidodecalin anion carrier as a promising candidate for biomedical applications, showing good activity for chloride transport in cells yet almost no cytotoxicity. To underpin further development of this and related compounds, a detailed structural and binding investigation is reported. Crystal structures of the transporter as five solvates confirm the diaxial positioning of urea groups while revealing a degree of conformational flexibility. Structures of complexes with Cl- , Br- , NO3- , SO42- and AcO- , supported by computational studies, show how the binding site can adapt to accommodate these anions. 1 H NMR binding studies revealed exceptionally high affinities for anions in DMSO, decreasing in the order SO42- >H2 PO4- ≈HCO3- ≈AcO- ≫HSO4- >Cl- >Br- >NO3- >I- . Analysis of the binding results suggests that selectivity is determined mainly by the H-bond acceptor strength of different anions, but is also modulated by receptor geometry.

Solution and Solid-State Studies on the Halide Binding Affinity of Perfluorophenyl-Armed Uranyl-Salophen Receptors Enhanced by Anion-π Interactions.

The enhancement of the binding between halide anions and a Lewis acidic uranyl-salophen receptor has been achieved by the introduction of pendant electron-deficient arene units into the receptor skeleton. The association and the occurrence of the elusive anion-π interaction with halide anions (as tetrabutylammonium salts) have been demonstrated in solution and in the solid state, providing unambiguous evidence on the interplay of the concerted interactions responsible for the anion binding.

Very strong (-)N-X(+)(-)O-N(+) halogen bonds.

A new (-)N-X(+)(-)O-N(+) paradigm for halogen bonding is established by using an oxygen atom as an unusual halogen bond acceptor. The strategy yielded extremely strong halogen bonded complexes with very high association constants characterized in either CDCl3 or acetone-d6 solution by (1)H NMR titrations and in the solid-state by single crystal X-ray analysis. The obtained halogen bond interactions, RXB, in the solid-state are found to be in the order of strong hydrogen bonds, viz. RXB ≈ RHB.

Efficient, non-toxic anion transport by synthetic carriers in cells and epithelia.

Transmembrane anion transporters (anionophores) have potential for new modes of biological activity, including therapeutic applications. In particular they might replace the activity of defective anion channels in conditions such as cystic fibrosis. However, data on the biological effects of anionophores are scarce, and it remains uncertain whether such molecules are fundamentally toxic. Here, we report a biological study of an extensive series of powerful anion carriers. Fifteen anionophores were assayed in single cells by monitoring anion transport in real time through fluorescence emission from halide-sensitive yellow fluorescent protein. A bis-(p-nitrophenyl)ureidodecalin shows especially promising activity, including deliverability, potency and persistence. Electrophysiological tests show strong effects in epithelia, close to those of natural anion channels. Toxicity assays yield negative results in three cell lines, suggesting that promotion of anion transport may not be deleterious to cells. We therefore conclude that synthetic anion carriers are realistic candidates for further investigation as treatments for cystic fibrosis.

Superchiral Pd3 L6 Coordination Complex and Its Reversible Structural Conversion into Pd3 L3 Cl6 Metallocycles.

Large, non-symmetrical, inherently chiral bispyridyl ligand L derived from natural ursodeoxycholic bile acid was used for square-planar coordination of tetravalent Pd(II) , yielding the cationic single enantiomer of superchiral coordination complex 1 Pd3 L6 containing 60 well-defined chiral centers in its flower-like structure. Complex 1 can readily be transformed by addition of chloride into a smaller enantiomerically pure cyclic trimer 2 Pd3 L3 Cl6 containing 30 chiral centers. This transformation is reversible and can be restored by the addition of silver cations. Furthermore, a mixture of two constitutional isomers of trimer, 2 and 2', and dimer, 3 and 3', can be obtained directly from L by its coordination to trans- or cis-N-pyridyl-coordinating Pd(II) . These intriguing, water-resistant, stable supramolecular assemblies have been thoroughly described by (1) H DOSY NMR, mass spectrometry, circular dichroism, molecular modelling, and drift tube ion-mobility mass spectrometry.

Spontaneous Resolution of an Electron-Deficient Tetrahedral Fe4L4 cage.

A highly electron-deficient C3-symmetric tris(bipyridyl) ligand was prepared in four steps and used for the coordination of Fe(OTf)2, thereby resulting in the homochiral assembly of a new family of robust tetrahedral M4L4 cages. This homochiral T-symmetric cage containing a relatively large cavity of 330 Å(3) is capable of encapsulating an anionic guest, as was determined by mass spectrometry, (19)F NMR spectroscopy, and finally shown from its crystal structure. Moreover, crystallization of the cage from CH3CN led to crystals containing both (ΔΔΔΔ and ΛΛΛΛ) enantiomers, while crystallization from CH3 OH resulted in crystals containing only the right-handed (ΔΔΔΔ) cage. The difference in the crystal packing of the two crystal structures is discussed and a feasible explanation for the unique phenomenon among supramolecular cages--spontaneous resolution--is given.

Sterically geared tris-thioureas; transmembrane chloride transporters with unusual activity and accessibility.

Tris-N-arylthioureas derived in one step from 1,3,5-tris(aminomethyl)-2,4,6-triethylbenzene are remarkably effective anion carriers. With optimised aryl substituents their activities come close to the best currently known, suggesting that they might find use as readily available standards in anion transport research.

A zinc-salophen/bile-acid conjugate receptor solubilized by CTABr micelles binds phosphate in water.

Receptor 1, composed of two deoxycholic acid moieties appended to a Zn-salophen complex, was prepared, characterized and tested for anion binding by (1)H NMR and UV-vis spectroscopic techniques. While in polar DMSO, 1 is able to bind phosphate (K = ∼700 M(-1)), the addition of water severely diminishes the association. In a 1 : 9 water-DMSO mixture, the binding constant K is only ca. 20 M(-1). Notably, in an aqueous solution of CTABr micelles (CTABr 10 mM, cmc = ∼1 mM), the zinc-salophen conjugate 1, due to its two non-polar bile-acid moieties, becomes solubilized and, most importantly, it almost completely recovers its binding ability towards phosphate, displaying a remarkable affinity (K = ∼450 M(-1)) in water.

Crystallization, spectral, crystallographical, and thermoanalytical studies of succinobucol polymorphism.

Four different polymorphs, A, C, D, and E, of succinobucol were isolated and characterized by means of solid-state nuclear magnetic resonance spectroscopy, single crystal and powder X-ray diffraction, differential scanning calorimetry, thermogravimetry, and attenuated total reflection-infrared spectroscopy. From a number of experiments, the same polymorphs (C, D, and E) and an equilibrium phase mixture B consisting of polymorphs C and D were repeatedly gained using different solvents or their mixtures. Although polymorph A was obtained directly from recrystallization only on few occasions, polymorphs C, D, and E proved to be metastable kinetic polymorphs, which slowly transform to a thermodynamically more stable form A during long-term storage. The single-crystal structures of polymorph C and D were determined by X-ray single-crystal diffraction.

Succinobucol's new coat--conjugation with steroids to alter its drug effect and bioavailability.

Synthesis, detailed structural characterization (X-ray, NMR, MS, IR, elemental analysis), and studies of toxicity, antioxidant activity and bioavailability of unique potent anti-atherosclerotic succinobucol-steroid conjugates are reported. The conjugates consist of, on one side, the therapeutically important drug succinobucol ([4-{2,6-di-tert-butyl-4-[(1-{[3-tert-butyl-4-hydroxy-5-(propan-2-yl)phenyl]sulfanyl}ethyl)sulfanyl]phenoxy}-4-oxo-butanoic acid]) possessing an antioxidant and anti-inflammatory activity, and on the other side, plant stanol/sterols (stigmastanol, ß-sitosterol and stigmasterol) possessing an ability to lower the blood cholesterol level. A cholesterol-succinobucol prodrug was also prepared in order to enhance the absorption of succinobucol through the intestinal membrane into the organism and to target the drug into the place of lipid metabolism-The enterohepatic circulation system. Their low toxicity towards mice fibroblasts at maximal concentrations, their antioxidant activity, comparable or even higher than that of ascorbic acid as determined by direct quenching of the DPPH radical, and their potential for significantly altering total and LDL cholesterol levels, suggest that these conjugates merit further studies in the treatment of cardiovascular or other related diseases. A brief discussion of succinobucol's ability to quench the radicals, supported with a computational model of the electrostatic potential mapped on the electron density surface of the drug, is also presented.

Novel juvenogens (insect hormonogenic agents): preparation and biological tests on Neobellieria bullata.

The development of new types of environmentally safe insecticides has been advantageous to replace toxic and persistent insecticides, which have adverse effects on animals and humans. Our effort in this field was aimed at the synthesis of insect juvenile hormone analogues, juvenoids, nontoxic for warm-blooded animals and fish, which can become advanced compounds in regulating many aspects in insect physiology. Structure modification of juvenoids via juvenogen derivatives (hormonogenic substances) plays an important role in controlling the juvenoid liberation rate in the insect digestive system and can also play an important role in the mode of action toward different arthropod groups, with focus on insect pest species. For that reason, juvenoids were esterified with hexadecanoic, butanoic, and 3-methylbut-2-enoic acids. A total of 12 new compounds with potential insecticidal activity were synthesized and characterized, and the results of biological screening tests on blowflies Neobellieria (Sarcophaga) bullata were presented. Results of the inhibitory activity of the tested compounds on the reproduction of the blowflies were also presented.

Preparation and preliminary biological screening of cholic acid-juvenoid conjugates.

Steroidal compounds have been utilized as carriers and for modification of physico-chemical properties of model biologically active secondary alcohols - juvenoids. Juvenoids are juvenile hormone analogues - environmentally safe insecticides, possessing significant biological activity towards different arthropods groups in focus on insect pest species. Structure modification of juvenoids plays important role to control the rate of liberation and decomposition of juvenoid in digestive system and can also play important role in the mode of action towards selected insect. This study presents an approach to the synthesis of steroidal monomers and dimers carrying one and two molecules of a juvenoid in their structures. The prepared compounds were tested for their inhibition activity on reproduction of the blowfly Neobellieria (Sarcophaga) bullata. These steroid-juvenoid conjugates showed promising possibilities in synthesis of new unique biochemical insecticides. Preliminary biological test results of prepared compounds are presented.

Insect pest management agents: hormonogen esters (juvenogens).

The chemical part of this investigation focused on designing structures and synthesizing a series of six new esters (juvenogens), derived from biologically active insect juvenile hormone bioanalogues (juvenoids, JHAs) and unsaturated short-chain linear and branched fatty acids for possible application as biochemically targeted insect hormonogen agents. The structures of the new compounds were assigned on the basis of a detailed NMR analysis of their (1)H and (13)C NMR spectra. The biological part of this investigation focused on introductory biological screening tests with these compounds against the red firebug (Pyrrhocoris apterus), termites (Reticulitermes santonensis and Prorhinotermes simplex), and the blowfly (Neobellieria bullata). The biological activity of the juvenogens was studied in relation to the fatty acid functionality in the structures. Notable biological activity in topical tests and medium activity in peroral tests was found for the juvenogens 3 and 7 with P. apterus. The compounds 6 and 8 showed the lowest activity in both topical and oral assays with P. apterus. Considerable effect of all tested juvenogens was observed in P. simplex; however, the juvenogens 5 and 6 (derivatives of the only branched short-chain fatty acid) showed no activity against R. santonensis. The effect of the compounds 3-8 on larval hatching of N. bullata was only moderate (larval hatching 80-90%); however, the proliferation effect caused by 5, 6, and 8 is more pronounced than the effect caused by 3, 4, and 7.