Design, synthesis and antiviral evaluation of novel conjugates of the 1,7,7-trimethylbicyclo[2.2.1]heptane scaffold and saturated N-heterocycles via 1,2,3-triazole linker.

A new series of heterocyclic derivatives with a 1,7,7-trimethylbicyclo[2.2.1]heptane fragment was designed, synthesised and biologically evaluated. Synthesis of the target compounds was performed using the Cu(I) catalysed cycloaddition reaction. The key starting substances in the click reaction were an alkyne containing a 1,7,7-trimethylbicyclo[2.2.1]heptane fragment and a series of azides with saturated nitrogen-containing heterocycles. Some of the derivatives were found to exhibit strong antiviral activity against Marburg and Ebola pseudotype viruses. Lysosomal trapping assays revealed the derivatives to possess lysosomotropic properties. The molecular modelling study demonstrated the binding affinity between the compounds investigated and the possible active site to be mainly due to hydrophobic interactions. Thus, combining a natural hydrophobic structural fragment and a lysosome-targetable heterocycle may be an effective strategy for designing antiviral agents.

Design of Conjugates Based on Sesquiterpene Lactones with Polyalkoxybenzenes by "Click" Chemistry to Create Potential Anticancer Agents.

Using the methodology of "click" chemistry, a singular method has been developed for the synthesis of unique conjugates based on sesquiterpene lactones: dehydrocostuslactone and alantolactone with polyalkoxybenzenes. To expand the structural range of the resulting conjugates, the length of the 1,2,3-triazole spacer was varied. For all synthesized compounds, the cytotoxic profile was determined on the cell lines of tumor origin (SH-SY5Y, HeLa, Hep-2, A549) and normal Hek 293 cells. It was found that the compounds based on alantolactone 7a-d with a long spacer and substances containing dehydrocostuslactone 10a-d with a short spacer have the greatest toxic effect. The decrease in cell survival under the action of these conjugates may be due to their ability to cause dissipation of the transmembrane potential of mitochondria and inhibit the process of glycolysis, leading to cell death. The obtained results confirm the assumption that the development of conjugates based on sesquiterpene lactones and polyalkoxybenzenes can be considered as a promising strategy for the search for potential antitumor agents.

New Approach toward Dual-Emissive Organic-Inorganic Hybrids by Integrating Mn(II) and Cu(I) Emission Centers in Ionic Crystals.

Inorganic-organic hybrid luminescent materials have received great attention for their potential applications in a wide range of clean/renewable energy-related areas, including photovoltaics and solid-state lighting. Herein, we present a unique and general "Mn + Cu" approach by blending two earth-abundant luminogenic metals, manganese and copper, within a single ionic structure to construct a remarkable family of low-cost and multifunctional hybrid materials featuring dual emission, as well as triboluminescence and second-harmonic generation response. The novel hybrid materials are made of diphosphine dioxide-chelated [Mn(O∧O)3]2+ cations and various anionic [CuxIy](y-x)- clusters, ensuring manifestation of dual phosphorescence streamed from octahedral Mn2+ ions (605-648 nm) and iodocuprate anions (480-728 nm). Noteworthily, the relative ratio of the emission bands, and hence a resulting emission chromaticity, can be tuned in a wide range through modification of cluster [CuxIy](y-x)- modules. The structural diversity, enhanced robustness, and up to 100% luminescence quantum yield make the designed materials promising phosphors for lighting and sensing applications.

Parahydrogen-Induced Hyperpolarization of Unsaturated Phosphoric Acid Derivatives.

Parahydrogen-induced nuclear polarization offers a significant increase in the sensitivity of NMR spectroscopy to create new probes for medical diagnostics by magnetic resonance imaging. As precursors of the biocompatible hyperpolarized probes, unsaturated derivatives of phosphoric acid, propargyl and allyl phosphates, are proposed. The polarization transfer to 1H and 31P nuclei of the products of their hydrogenation by parahydrogen under the ALTADENA and PASADENA conditions, and by the PH-ECHO-INEPT+ pulse sequence of NMR spectroscopy, resulted in a very high signal amplification, which is among the largest for parahydrogen-induced nuclear polarization transfer to the 31P nucleus.

Synthesis and biological evaluation of indolylglyoxylamide bisphosphonates, antimitotic microtubule-targeting derivatives of indibulin with improved aqueous solubility.

Indibulin (D-24851) derivatives with bisphosphonate fragment connected to the N1 atom of imidazole ring were synthesized by alkylation of (indolyl-3)methylglyoxylates with ethylenebisphosphonate. Biological evaluation of targeted compounds 4a-d using the phenotypic sea urchin embryo assay provided evidence that replacing of p-chlorobenzene ring in indibulin by bisphosphonate group did not eliminate antimitotic microtubule destabilizing activity. The most active molecule, tetraacid 5a, at physiological pH formed tetrasodium salt 6a with aqueous solubility value of at least 10 mg/mL. Molecule 5a was more potent in the sea urchin embryo assay than the parent indibulin. This compound also exhibited pronounced cytotoxicity against A549 lung carcinoma and A375 melanoma cell lines.

Synthesis of Camphecene and Cytisine Conjugates Using Click Chemistry Methodology and Study of Their Antiviral Activity.

A series of camphecene and quinolizidine alkaloid (-)-cytisine conjugates has been obtained for the first time using 'click' chemistry methodology. The cytotoxicity and virus-inhibiting activity of compounds were determined against MDCK cells and influenza virus A/Puerto Rico/8/34 (H1N1), correspondingly, in in vitro tests. Based on the results obtained, values of 50 % cytotoxic dose (CC50 ), 50 % inhibition dose (IC50 ) and selectivity index (SI) were determined for each compound. It has been shown that the antiviral activity is affected by the length and nature of linkers between cytisine and camphor units. Conjugate 13 ((1R,5S)-3-(6-{4-[(2-{(E)-[(1R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene]amino}ethoxy)methyl]-1H-1,2,3-triazol-1-yl}hexyl)-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one), which contains cytisine fragment separated from triazole ring by -C6 H12 - aliphatic linker, showed the highest activity at relatively low toxicity (CC50 =168 µmol, IC50 =8 µmol, SI=20). Its selectivity index appeared higher than that of reference compound, rimantadine. According to theoretical calculations, the antiviral activity of the lead compound 13 can be explained by its influence on the functioning of neuraminidase.

Synthesis and antitumor activity of daunorubicin conjugates with of 3,4-methylendioxybenzaldehyde.

The design of hybrid (chimeric) molecules containing two different pharmacophores connected via a spacer (linker) is a promising approach to the functionalization of natural compounds and potentially of drug molecules. These are important examples for the use of this approach with anthracycline antibiotics. The use of this methodology may help to eliminate some of the drawbacks of anthracycline drugs, e.g., high cardiotoxicity and MDR development.

Synthesis of camphecene derivatives using click chemistry methodology and study of their antiviral activity.

A series of seventeen tetrazole derivatives of 1,7,7-trimethyl-[2.2.1]bicycloheptane were synthesized using click chemistry methodology and characterized by spectral data. Studies of cytotoxicity and in vitro antiviral activity against influenza virus A/Puerto Rico/8/34 (H1N1) in MDCK cells of the compounds obtained were performed. The structure-activity relationship analysis suggests that to possess virus-inhibiting activity, the compounds of this group should bear oxygen atom with a short linker (C2-C4), either as a hydroxyl group (18, 19, 29), keto-group (21) or as a part of a heterocycle (24). These compounds demonstrated low cytotoxicity along with high anti-viral activity.

Clathrochelates meet phosphorus. New thio- and phosphorylation reactions of an iron(II) dichloroclathrochelate precursor and preparation of its first phosphorus(III)-containing macrobicyclic derivative.

Phosphorylation reactions of an iron(II) dichloroclathrochelate FeBd2(Cl2Gm)(BF)2 (where Bd(2-) and Cl2Gm(2-) are α-benzildioxime and dichloroglyoxime dianions, respectively) with diphenylphosphine oxide and diethyl thiophosphite were performed under phase-transfer conditions. In the case of diethyl thiophosphite as a P-nucleophile, the best yields were obtained in the dichloromethane-50% NaOH aqueous solution-5 mol% triethylbenzylammonium chloride (TEBAC) system. The use of different molar ratios of a macrobicycle precursor and this thiophosphorylating agent allowed us to obtain both the mono- and the diphosphorylated cage complexes. Nucleophilic substitution with diphenylphosphine oxide was performed in the K2CO3-acetonitrile-5 mol% TEBAC system, giving only the corresponding monophosphorylated iron(II) complex in high yield even in the presence of an excess of this P-nucleophile. The phosphorus(v)-containing clathrochelate product was reduced with an excess of silicoform to give an iron(II) macrobicycle with an inherent diphenylphosphine group in an almost quantitative yield, which was then characterized by (31)P{(1)H} NMR and single-crystal X-ray diffraction; it easily undergoes re-oxidation to the initial clathrochelate. The synthesized phosphorus(v)-containing cage complexes were characterized using elemental analysis, MALDI-TOF mass, IR, UV-Vis, (1)H, (11)B, (13)C{(1)H}, (19)F{(1)H} and (31)P{(1)H} NMR spectra, and by single-crystal X-ray diffraction.

Clathrochelates meet phosphorus: thiophosphorylation of Fe(II) dichloroclathrochelate precursor, synthesis of N,S-donor macrobicyclic ligands and their Pd(II) complexes as potent catalysts of Suzuki cross-coupling reaction.

Nucleophilic substitution of an iron(ii) dichloroclathrochelate with diphenylphosphine sulfide under PTC afforded a monophosphorylated cage complex. This precursor undergoes further nucleophilic substitution with mono- and diamines giving P,N-substituted mono- and bis-clathrochelates; those with thiophosphoryl and pyridyl groups were used as N,S-donor macrobicyclic ligands toward the palladium(ii) ion. In the resulting Pd,Fe-binuclear 1 : 1 complexes, the clathrochelate moieties retain the geometry, characteristic of low-spin iron(ii) complexes, with a minor distortion caused by intramolecular interactions. The Pd(2+) ion has a twisted square-planar N2SCl-environment. The complexes thus obtained proved to be efficient catalysts of the Suzuki cross-coupling reaction.

o-Semiquinonic PCP-pincer nickel complexes with alkyl substituents: versatile coordination sphere dynamics.

o-Semiquinonic nickel pincer complexes (R2PCP)Ni(SQ) show a versatile coordination sphere dynamics via "swing" or "fan" oscillations depending on the steric properties of the phosphorus substituents.