We report for the first time cyclic phosphine-free “head to tail” N,N,N pincer-like (pincer complexes mimicking) N-(pyrimidin-2-yl)-1,2-azole-3-carboxamide Pd(II) complexes with deprotonated amide ...groups as high-turnover catalysts (TON up to 106, TOF up to 1.2 × 107 h–1) for cross-coupling reactions on the background of up to quantitative yields under Green Chemistry conditions. The potency of the described catalyst family representatives was demonstrated in Suzuki–Miyaura, Mizoroki–Heck, and Sonogashira reactions on industrially practical examples. Corresponding ligands could be synthesized based on readily available reagents through simple chemical transformations. Within the complex structures, a highly unusual 1,3,5,7-tetraza-2,6-dipalladocane frame could be observed.
Mixed-ligand copper(II) complexes with 4,5-dichloro-isothiazole-3-carboxylic acid and heterocyclic N-donor ligands as potential anticancer agents.
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•Mixed-ligand Cu(II) polypyridine ...complexes with isothiazole derivative were prepared.•SC-XRD revealed square bipyramid and square pyramidal geometry of complexes.•Formation of Cu(L)(polypyridine)(H2O)+ clusters was revealed in aqueous solution.•Dose-dependent cytotoxicity of 3–5 was shown against Hep-2 and MCF-7 tumor cells.•Cu(dmphen)L2 possessed highest cytotoxicity on Hep-2 cells (IC50 = 0.97 ± 0.03 µM).
Mixed-ligand copper(II) complexes based on 1,10-phenanthroline and related compounds are of interest to scientists due to their promising anticancer properties. In this study, four new water-soluble copper(II) complexes Cu(dmbipy)L2, Cu(phen)(H2O)L2, Cu(dmphen)L2 and Cu2(bipy)2L4, where HL – 4,5-dichloro-isothiazole-3-carboxylic acid, bipy – 2,2′-bipyridine, dmbipy – 2,2′-bi-4-picoline, phen – 1,10-phenanthroline, dmphen – 4,7-dimethyl-1,10-phenanthroline are reported. All complexes have been characterized by elemental and powder X-ray diffraction analysis, EPR and IR-spectroscopy. Molecular structures of the reported complexes have been determined by single crystal X–ray diffraction. Copper(II) ion, HL and heterocyclic N-donor ligands have been found to form 1:2:1 complexes that possess square bipyramid or square pyramidal geometry. The UV–vis spectroscopy and mass spectrometry have been applied to show the behavior of the compounds in solution. All complexes have been screened in vitro for their cytotoxic activity against Hep-2 and MCF-7 cell lines. They exhibit significant dose-dependent cytotoxic effect and Cu(dmphen)L2 is found to be the most cytotoxic (IC50 = 0.97 ± 0.03 µM when compared to IC50 = 9.2 ± 0.5 µM for control, cisplatin – Hep-2 cell line). The investigation of DNA binding ability by UV–vis titration technique indicates that complexes obtained exhibit moderate binding affinity toward calf thymus DNA. Effect of Cu(dmbipy)L2 and Cu(dmphen)L2 on activity of drug-metabolizing enzymes cytochromes P450 has also been investigated. The addition of complexes to the hepatic microsomes of 3-MC or PB-treated rat, lead to a dose-dependent decrease of CYP’s activities. The data obtained indicate that Cu(dmphen)L2 and Cu(phen)(H2O)L2 can be potential anticancer agents.
One-pot synthesis of tetrahydro-β-carbolines, fused with an isoindole core, was proposed starting from maleic anhydride and azomethines easily available from tryptamines and 3-(hetaryl)acroleins. ...This sequence includes four key steps: an acylation of the aldimine with maleic anhydride, a Pictet–Spengler cyclization, an intramolecular Diels–Alder reaction, and a concluding 1,3-H shift. As a result, six- or seven-nuclear alkaloid-like heterocyclic systems, containing a benzo1,2indolizino8,7-bindole fragment annulated with furan, thiophene, or pyrrole, are formed in a diastereoselective manner.
A series of N-acyl derivatives of anabasine and cytisine were prepared, to discover novel, natural product-based medicinal agents. All synthesized compounds were tested for antimicrobial, antifungal, ...antiviral and analgesic activity. The most pronounced antibacterial activity was shown by the compounds with isoxazole fragments, while the adamantane derivatives showed the greatest antiviral effect. It was found that the majority of anabasine derivatives showed significant analgesic activity, reducing the pain response of animals to the irritating effect of acetic acid. The presence of a high level of antimicrobial and antiviral activity in newly synthesized compounds makes it possible to consider them promising for further study of their pharmacological properties.
An efficient method of producing quinine derivatives via reaction of acylation with 4,5-dichloroisothiazole-3-, 5-arylisoxazole-3-, adamantane- and hydrochlorides of pyridine-3- and ...pyridine-4-carbonyl chlorides was developed. All synthesized compounds were tested for antiviral, antimicrobial and analgesic activity. The most pronounced antibacterial activity was shown by the compounds
,
,
and
with isoxazole and pyridine fragments. It was found that most of the tested compounds showed significant analgesic activity reducing the pain response of animals to the irritating effect of acetic acid.
In this study, Ni(II) and Co(II) complexes Co(H
2
O)
2
L
2
(
1
), Ni(H
2
O)
2
L
2
(
2
), Co(phen)L
2
(
3
), Ni(phen)L
2
·2H
2
O·EtOH (
4·2H
2
O
), and Ni(phen)
2
(H
2
O)L·L·2H
2
O (
5
), where ...L—4,5-dichloro-isothiazole-3-carboxylate anion and phen—1,10-phenanthroline are reported. All complexes have been characterized by physicochemical and spectroscopic methods. Mass spectrometry and UV–Vis spectroscopy have been used to show the behavior of complexes in ethanol solution and phosphate buffer saline. Crystal structures of mononuclear complexes
1
,
4
and
5
have been determined by single-crystal X-ray diffraction. In the structure of
4
, mononuclear units have been found to form infinite zigzag chains due to the presence of Cl•••Cl non-covalent interactions which can be regarded as halogen bonding. All complexes have been screened in vitro for their cytotoxic activity against Hep2 cancer cell line. The complexes obtained showed no activity (IC
50
> 50 µM) in comparison with structurally related Cu(II) complex Cu(phen)(H
2
O)L
2
exhibiting dose-dependent toxicity comparable to that of cisplatin (IC
50
= 3.06 ± 0.07 µM (Cu(II) complex), IC
50
= 9.2 ± 0.5 µM (cisplatin)). DNA binding constants were determined using absorption titration: Cu(II), Ni(II) and Co(II) complexes possessed similar DNA binding efficacy (K
b
~ 10
4
).
Despite significant progress made over the past two decades in the treatment of chronic myeloid leukemia (CML), there is still an unmet need for effective and safe agents to treat patients with ...resistance and intolerance to the drugs used in clinic. In this work, we designed 2-arylaminopyrimidine amides of isoxazole-3-carboxylic acid, assessed
in silico
their inhibitory potential against Bcr-Abl tyrosine kinase, and determined their antitumor activity in K562 (CML), HL-60 (acute promyelocytic leukemia), and HeLa (cervical cancer) cells. Based on the analysis of computational and experimental data, three compounds with the antitumor activity against K562 and HL-60 cells were identified. The lead compound efficiently suppressed the growth of these cells, as evidenced by the low IC
50
values of 2.8 ± 0.8 μM (K562) and 3.5 ± 0.2 μM (HL-60). The obtained compounds represent promising basic structures for the design of novel, effective, and safe anticancer drugs able to inhibit the catalytic activity of Bcr-Abl kinase by blocking the ATP-binding site of the enzyme.
Multicomponent condensation of 5-phenyl(
p
-tolyl)isoxazole-3-carbaldehydes, cyclohexane-1,3-dione (or dimedone), ethyl acetoacetate (or acetylacetone), and ammonium acetate was used to synthesize ...polysubstituted derivatives of 1,4-dihydropyridines with an isoxazole fragment. As a result of oxidation of the obtained compounds with sodium nitrite, the corresponding substituted pyridine derivatives were formed. Biological testing revealed that some of the obtained compounds exhibited cytotoxic activity against LS174T colorectal cancer cells, as well as antibacterial activity against susceptible strains of
Escherichia coli
(C600) and
Staphylococcus aureus
(ATCC-25923).
Neuroepithelial tumor cells were cultured in vitro. The biopsy material was taken from 93 children at removal of the brain tumors during neurosurgical operations. The individual features of the cells ...sensitivity of primary cultures in respect to protocol-approved chemotherapy drugs and changes in the Interleukin-6 (Il-6) level in the culture medium after the application of chemotherapy were established. The initial level of Il-6 exceeded 600.0 pg/ml in the cultural medium with histologically verified pilomyxoid astrocytoma cells, and ranged from 100.0 to 200.0 pg/ml in the medium at cultivation of ganglioneuroblastoma and pilocytic astrocytoma. A decrease in the Il-6 level in the medium culture of primary tumors cells was observed after the application of chemotherapeutic agents on the cells of pilomyxoid astrocytoma, astrocytomas, and pilocytic desmoplastic/nodular medulloblastoma. The production of Il-6 increased after application of cytostatic drugs on the cells of oligoastrocytomas. A decrease in Il-6 level after application of Cisplatin and Methotrexate and a 5-10 fold increase in the level of Il-6 after application of Etoposide, Carboplatin, Cytarabine, and Gemcitabine were registered in the medium with ganglioneuroblastoma. To improve the cytotoxic action of chemotherapeutic agents, the combined application of cytostatics with heterocyclic compounds was carried out. A computer modeling of ligand-protein complexes of carbamide using the Dock 6.4 and USF Chimera program packages was performed with molecular mechanics method. Special attention was drawn to the ability of several isoxazole heterocycles and isothiazolyl to inhibit the tyrosine kinase. It was proved in vitro that the joint application of chemotherapeutic agents and heterocyclic compounds could reduce the concentration of the cytostatic factor by 10 or more times, having maintained the maximum cytotoxic effect. It was assumed that the target amplification of cytotoxic action of chemotherapeutic agents had prospects for reducing toxic side effects of chemotherapy in vivo, which would be carried out only after the preclinical studies.
