The development of powerful methods for living covalent polymerization has been a key driver of progress in organic materials science. While there have been remarkable reports on living supramolecular polymerization recently, the scope of monomers is still narrow and a simple solution to the problem is elusive. Here we report a minimalistic molecular platform for living supramolecular polymerization that is based on the unique structure of all-cis 1,2,3,4,5,6-hexafluorocyclohexane, the most polar aliphatic compound reported to date. We use this large dipole moment (6.2 Debye) not only to thermodynamically drive the self-assembly of supramolecular polymers, but also to generate kinetically trapped monomeric states. Upon addition of well-defined seeds, we observed that the dormant monomers engage in a kinetically controlled supramolecular polymerization. The obtained nanofibers have an unusual double helical structure and their length can be controlled by the ratio between seeds and monomers. The successful preparation of supramolecular block copolymers demonstrates the versatility of the approach.

Depending on the substitution pattern and stereochemistry, 1,3-dioxanes 1 with an aminoethyl moiety in 4-position represent potent σ1 receptor antagonists. In order to increase the stability, a cyclohexane ring first replaced the acetalic 1, 3-dioxane ring of 1. A large set of aminoethyl substituted cyclohexane derivatives was prepared in a six-step synthesis. All enantiomers and diastereomers were separated by chiral HPLC at the stage of the primary alcohol 7, and their absolute configuration was determined by CD spectroscopy. Neither the relative nor the absolute configuration had a large impact on the σ1 affinity. The highest σ1 affinity was found for cis-configured benzylamines (1R,3S)-11 (Ki = 0.61 nM) and (1S,3R)-11 (Ki = 1.3 nM). Molecular dynamics simulations showed that binding of (1R,3S)-11 at the σ1 receptor is stabilized by the typical polar interaction of the protonated amino moiety with the carboxy group of E172 which is optimally oriented by an H-bond interaction with Y103. The lipophilic interaction of I124 with the N-substituent also contributes to the high σ1 affinity of the benzylamines. The antagonistic activity was determined in a Ca2+ influx assay in retinal ganglion cells. The enantiomeric cis-configured benzylamines (1R,3S)-11 and (1S,3R)-11 were able to inhibit the growth of DU145 cells, a highly aggressive human prostate tumor cell line. Moreover, cis-11 could also inhibit the growth of further human tumor cells expressing σ1 receptors. The experimentally determined logD7.4 value of 3.13 for (1R,3S)-11 is in a promising range regarding membrane penetration. After incubation with mouse liver microsomes and NADPH for 90 min, 43% of the parent (1R,3S)-11 remained unchanged, indicating intermediate metabolic stability. Altogether, nine metabolites including one glutathione adduct were detected by means of LC-MS analysis.

1,3-Dioxanes 1 and cyclohexanes 2 bearing a phenyl ring and an aminoethyl moiety in 1,3-relationship to each other represent highly potent σ1 receptor antagonists. In order to increase the chemical stability of the acetalic 1,3-dioxanes 1 and the polarity of the cyclohexanes 2, tetrahydropyran derivatives 3 equipped with the same substituents were designed, synthesized and pharmacologically evaluated. The key step of the synthesis was a lipase-catalyzed enantioselective acetylation of the alcohol (R)-5 leading finally to enantiomerically pure test compounds 3a-g. With respect to σ1 receptor affinity and selectivity over a broad range of related (σ2, PCP binding site) and further targets, the enantiomeric benzylamines 3a and cyclohexylmethylamines 3b represent the most promising drug candidates of this series. However, the eudismic ratio for σ1 binding is only in the range of 2.5-3.3. Classical molecular dynamics (MD) simulations confirmed the same binding pose for both the tetrahydropyran 3 and cyclohexane derivatives 2 at the σ1 receptor, according to which: i) the protonated amino moiety of (2S,6R)-3a engages the same key polar interactions with Glu172 (ionic) and Phe107 (π-cation), ii) the lipophilic parts of (2S,6R)-3a are hosted in three hydrophobic regions of the σ1 receptor, and iii) the O-atom of the tetrahydropyran derivatives 3 does not show a relevant interaction with the σ1 receptor. Further in silico evidences obtained by the application of free energy perturbation and steered MD techniques fully supported the experimentally observed difference in receptor/ligand affinities. Tetrahydropyrans 3 require a lower dissociative force peak than cyclohexane analogs 2. Enantiomeric benzylamines 3a and cyclohexylmethylamines 3b were able to inhibit the growth of the androgen negative human prostate cancer cell line DU145. The cyclohexylmethylamine (2S,6R)-3b showed the highest σ1 affinity (Ki(σ1) = 0.95 nM) and the highest analgesic activity in vivo (67%).

In orderto synthesize new pyridazine derivatives anellated with different nitrogen heterocyclic moieties, spiro[cycloalkane]pyridazinones were transformed into the corresponding thioxo derivatives via a reaction with phosphorus pentasulfide. The reaction of the formed 2,3-diazaspiro[5.5] undec-3-ene-1-thiones with hydrazine provided the corresponding 1-hydrazono-2,3-diazaspiro[5.5] undec-3-ene, whose diazotization led to the desired spiro[cyclohexane-1,8'-tetrazolo[1,5-b]pyridazines. The reaction of dihydropyridazinethiones with benzhydrazide afforded the corresponding 7H-spiro[[1,2,4]triazolo[4,3-b]pyridazin-8,1'-cyclohexanes]. As a result of our work, seven new pyridazinethione intermediates were prepared, which served as starting materials for the synthesis of two kinds of new ring systems: tetrazolo-pyridazines and triazolo-pyridazines. The six new annulated derivatives were characterized by physicochemical parameters. The new N-heterocycles are valuable members of the large family of pyridazines.

The presence of strong stereoelectronic interactions involving the substituents in cis-2-substituted cyclohexanes may lead to results different from those expected. In this work, we studied the conformational behavior of cis-2-fluoro- (F), cis-2-chloro- (Cl), cis-2-bromo- (Br) and cis-2-iodocyclohexylamine (I) by dynamic NMR and theoretical calculations. The experimental data pointed to an equilibrium strongly shifted toward the ea conformer (equatorial amine group and axial halogen), with populations greater than 90% for F, Cl and Br in both dichloromethane-d 2 and methanol-d 4. Theoretical calculations (M06-2X/6-311++G(2df,2p)) were in agreement with the experimental, with no influence of the solvent or the halogen on the equilibrium. A principal component analysis of natural bond orbital energies pointed to the σ*C-X and σC-H orbitals and the halogen lone pairs (LPX) as the most significant for the hyperconjugative interactions that influenced the equilibrium. The σC-H → σ*C-X hyperconjugation and the interactions involving the LPX counterbalance each other, explaining the non-influence of the halogen on the conformational equilibrium. These interactions are responsible for the strong preference for the ea conformer in cis-2-halocyclohexylamines, being strong enough to restrain the shift in the equilibrium due to other factors such as steric repulsion or solvent effects.

The health of key species in the Baltic region has been impaired by exposure to anthropogenic hazardous substances (AHSs), which accumulate in organisms and are transferred through food chains. There is, thus, a need for comprehensive characterization of the occurrence and accumulation of AHSs in the ecosystem. In this study, we use a non-target screening (NTS) approach for this purpose. A major challenge in NTS of biological samples is the removal of matrix components such as lipids that may interfere with the detection and identification of compounds of interest. Here, we combine gel permeation chromatography with Florisil® column fractionation to achieve sufficient lipid removal for gas chromatography-high-resolution mass spectrometry analysis using electron ionization (EI) and electron capture negative ion chemical ionization (ECNI). In addition, we present new data processing workflows designed to systematically find and identify frequently occurring and biomagnifying AHSs, including known, emerging, and new contaminants. Using these workflows, we discovered a wide range of contaminants in tissue samples from blue mussels, fish, and marine mammals, and calculated their biomagnification factors (BMFs). Compounds with BMFs above 1 for herring and at least one marine mammal included legacy chlorinated pollutants (polychlorinated biphenyls, DDTs, chloro-benzenes/cyclohexanes, chlordanes, toxaphenes, dieldrin), polybrominated diphenyl ethers (PBDEs), and brominated biphenyls. However, there were also several halogenated natural products (halogenated methoxylated brominated diphenyl ethers, 1'-methyl-1,2'-bipyrroles, 1,1'-dimethyl-2,2'-bipyrroles, and the halogenated monoterpene mixed halogenated compound 1) as well as the novel flame retardant Dechlorane 602 and several polycyclic aromatic hydrocarbons, terpenoids, and steroids. The legacy pollutants exhibited the expected biomagnification behavior, demonstrating the utility of the unguided data processing workflow. Graphical abstract.

Human pancreatic tumor cells have an intrinsic ability to tolerate nutrition starvation and survive in the hypovascular tumor microenvironment, the phenomenon termed as "austerity". Searching for an agent that inhibits such tolerance to nutrient starvation and kills the pancreatic cancer cells preferentially in nutrient-starvation is a unique anti-austerity strategy in anti-cancer drug discovery. In this strategy, plant extracts and compounds are tested against PANC-1 human pancreatic cancer cell line under the conditions of nutrient-deprived medium (NDM) and nutrient-rich medium (DMEM), to discover the compounds that show selective cytotoxicity in NDM. Screening of twenty-five Thai indigenous medicinal plant extracts for their anti-austerity activity against the PANC-1 human pancreatic cancer cell line in nutrient deprived medium (NDM) resulted in the identification of four active plants, Derris scandens, Boesenbergia pandurata, Citrus hystrix, and Kaempferia parviflora, with PC50 values 0.5-8.9 µg/mL. K. parviflora extract also inhibited PANC-1 cancer cell colony formation. Phytochemical investigation of K. parviflora extract led to the isolation of fourteen compounds, including two polyoxygenated cyclohexanes (1 and 2), eleven flavonoids (3-13), and β-sitosterol (14). Stereochemical assignment of compound 1 was confirmed through X-ray analysis. All isolated compounds were tested for their preferential cytotoxicity against PANC-1 cells. Among them, 5-hydroxy-7-methoxyflavone (3) displayed the most potent activity with a PC50 value of 0.8 µM. Mechanistically, it was found to induce apoptosis in PANC-1 cell death in NDM as evident by caspase cleavage. It was also found to inhibit PANC-1 cancer cell colony formation in DMEM. Therefore, compound 3 can be considered as a potential lead compound for the anticancer drug development based on the anti-austerity strategy.

The ortho-substituted phenyl ring is a basic structural element in chemistry. It is found in more than three hundred drugs and agrochemicals. During the past decade, scientists have tried to replace the phenyl ring in bioactive compounds with saturated bioisosteres to obtain novel patentable structures. However, most of the research in this area has been devoted to the replacement of the para-substituted phenyl ring. Here we have developed saturated bioisosteres of the ortho-substituted phenyl ring with improved physicochemical properties: 2-oxabicyclo[2.1.1]hexanes. Crystallographic analysis revealed that these structures and the ortho-substituted phenyl ring indeed have similar geometric properties. Replacement of the phenyl ring in marketed agrochemicals fluxapyroxad (BASF) and boscalid (BASF) with 2-oxabicyclo[2.1.1]hexanes dramatically improved their water solubility, reduced lipophilicity and most importantly retained bioactivity. This work suggests an opportunity for chemists to replace the ortho-substituted phenyl ring in bioactive compounds with saturated bioisosteres in medicinal chemistry and agrochemistry.