Investigation of radiation protective features of azadispiro derivatives and their genotoxic potential with Ames/Salmonella test system.

PURPOSE: Five different types of synthesized azadispiro derivatives have been analyzed for radiation absorption capacity and determined their potential to be exploited as substances for a drug to be developed against radiation has been investigated. MATERIAL AND METHODS: Fast neutron attenuation parameters like the effective mean free path, half-value layer (HVL), removal cross-sections, and neutron transmission number were found with the Monte Carlo simulation Geometry And Tracking (GEANT4) code. Gamma radiation absorption parameters, such as effective atom number (Zeff), mean free path (MFP), mass attenuation coefficient (MAC), and half-value layer (HVL) were theoretically determined with WinXCom software. Besides, the exposure build-up factor (EBF) was calculated by using GP fitting parameters. Neutron absorption dose rate was experimentally calculated with 241Am-Be fast neutron source which has 4.5 MeV of energy, 74 GBq activity, and portative BF3 neutron detector. Ames/Salmonella test systems were used for the genotoxic potentials of the azadispiro derivatives. RESULTS AND CONCLUSIONS: Experimental and theoretical results were checked with paraffin and High-Density Polyethylene. The results showed that Azadispiro derivatives have neutron radiation absorption capability close to paraffin and High-Density Polyethylene. The gamma radiation absorption properties for azadispiro derivatives have been investigated, and it has been observed that these materials can absorb gamma radiation. Ames/Salmonella assay was used to examine whether the derivatives had a genotoxic effect probability or not. The results showed that these derivatives were genotoxic and safe at test doses (up to 5 mM). Consequently, it has been understood that these azadispiro derivatives can be used as active and genotoxic safety ingredients in the production of a protective drug against both neutrons and gamma rays.

Synthesis, molecular modeling, and biological evaluation of novel imatinib derivatives as anticancer agents.

Different derivatives of imatinib were synthesized by a 3-step reaction method. The structures of the new compounds were characterized by spectroscopic methods. For quantitative evaluation of the biological activity of the compounds, MTT assays were performed, where four BCR-ABL negative leukemic cell lines (Jurkat, Reh, Nalm-6 and Molt-4), one BCR-ABL positive cell line (K562), and one non-leukemic cell line (Hek293T) were incubated with various concentrations of the derivatives. Although imatinib was specifically designed for the BCR-ABL protein, our results showed that it was also effective on BCR-ABL negative cell lines except for Reh cell line. Compound 9 showed lowest IC50 values against Nalm-6 cells as 1.639 µM, also the values of Compound 10 for each cell were very close to imatinib. Molecular docking simulations suggest that except for compound 6, the compounds prefer a DFG-out conformation of the ABL kinase domain. Among them, compound 10 has the highest affinity for ABL kinase domain that is close to the affinity of imatinib. The common rings between compound 10 and imatinib adopt exactly the same conformation and same type of interactions in the ATP binding site with the ABL kinase domain.

Investigation of neutron and gamma radiation protective characteristics of synthesized quinoline derivatives.

PURPOSE: Quinoline is formed by various natural compounds, such as alkaloids from the cinchona plant, which exhibit various biological activities, and is an important building material for the development of new drugs. Quinoline can be used in anti-radiation drug development but radiation interaction properties must be determined. MATERIAL AND METHODS: In this study, six types of synthesized quinoline derivatives were used. Fast neutron removal cross-section, mean free path, half value layer and transmission number were theoretically determined by using GEometry ANd Tracking 4 and FLUktuierende KAskade simulation codes for neutron shielding. Neutron dose absorption rates were determined using the 241Am-Be fast neutron source and the Canberra NP series portable BF3 gas proportional neutron detector. Gamma radiation shielding parameters were determined by using WinXCom and PSY-X/PSD software. Additionally, the genotoxic potentials of the derivatives were assessed by using the Ames/Salmonella bacterial reversion assay. RESULTS AND CONCLUSIONS: Neutron shielding parameters such as removal cross-section, mean free path, half value layer and transmission number were theoretically determined for fast neutrons. To determine neutron absorption capacity of quinoline derivatives, neutron absorption, experiments were conducted. In addition, gamma radiation shielding parameters were calculated such as the mean free path (MFP), mass attenuation coefficient (µt), half value thickness layer (HVL) and effective atomic number (Zeff) in the energy range of 0.015-15 MeV. The results of the all quinoline derivatives have excellent fast neutron shielding power compared to ordinary concrete. In addition, all quinoline derivatives have been found to have the capacity to attenuate gamma radiation. Moreover, they absorb well in both types of radiation, do not cause secondary radiation, and they are genotoxically safe at the tested concentrations. This study has demonstrated that these products can be used as active ingredients for a drug to be developed against radiation.

Novel benzo[b]xanthene derivatives: Bismuth(III) triflate-catalyzed one-pot synthesis, characterization, and acetylcholinesterase, glutathione S-transferase, and butyrylcholinesterase inhibitory properties.

In this study, 3,4-dihydro-12-aryl-1H-benzo[b]xanthene-1,6,11-(2H,12H)trione compounds were obtained through one-pot condensation of various substituted aromatic aldehydes, 2-hydroxy-1,4-naphthoquinone, and dimedone in the presence of Bi(OTf)3 as a green and reusable catalyst. The structural characterization of these novel substituted benzo[b]xanthenes was performed by spectroscopic methods, and their inhibitory actions against butyrylcholinesterase (BChE), acetylcholinesterase (AChE), and glutathione S-transferase (GST) were investigated. GST is an enzyme responsible for removing toxic molecules during Phase II reactions in the detoxification mechanism. The AChE and BChE enzymes, which are called cholinesterases, are among the enzymes that occur especially during dementia such as brain damage or Alzheimer's disease. Inhibition effects of the benzo[b]xanthene derivatives on AChE, BChE, and GST were found at the millimolar level. The best inhibitor for GST is compound 4a (31.18 ± 6.13 mM), for AChE, it is compound 4d (28.16 ± 3.46 mM), and for BChE, it is compound 4f (36.24 ± 3.19 mM). Compound 4a inhibited the dimerization of GST subunits, and compounds 4d and 4f directly inhibited the catalytic activity by interacting with the catalytic active site or a related site of the AChE and BChE enzymes, respectively.

Cholinesterases, α-glycosidase, and carbonic anhydrase inhibition properties of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives: Synthetic analogues for the treatment of Alzheimer's disease and diabetes mellitus.

In this study, using the Cu(OTf)2 catalyst, 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivative molecules were carried out in one step and with high yield (86-91%). The previously synthesized 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives, carbonic anhydrase I and II isozymes (hCA I and II), acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and α-glycosidase (α-Gly) enzymes with Ki values in the range of 4.88-15.94 nM for hCA I, 7.04-20.83 nM for hCA II, 68.25-158.27 for AChE, 60.17-91.27 for BChE and 0.36-2.36 nM for α-Gly, respectively. In silico studies were performed on the molecules inhibiting hCA I, hCA II, AChE, BChE and α-Gly receptors. When we evaluated the data obtained in this work, we determined the inhibition type of the 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives at the receptors. Reference inhibitors were used for all enzymes.

Ultrasonic synthesis, characterization of ß-aminoketones by bismuth(III) triflate and determination of antigenotoxic properties.

Direct-type catalytic Mannich reaction for the synthesis of ß-aminoketones from cyclohexanone, substituted aromatic amines and aromatic or hetero-aromatic aldehydes has been applied in water with bismuth triflate under ultrasound. Good yields of the expected ß-aminoketones were obtained from available substrates, at room temperature in 1-2 hours. This study was designed to evaluate the mutagenic and antimutagenic potential of synthesized ß-aminoketones compounds using Ames/Salmonella and Escherichia coli WP2 bacterial reverse mutation assay systems.

One-pot synthesis of indenonaphthopyrans catalyzed by copper(II) triflate: a comparative study of reflux and ultrasound methods.

An effective and environment-friendly protocol for the synthesis of indenonaphthopyrans has been developed by one-pot reaction of 2-naphthol, various aromatic aldehydes and 1,3-indandione, in the presence of copper(II) triflate as the catalyst while using reflux (Method A) and ultrasound (Method B). The Method B approach offers the advantages of a simple reaction method, short reaction time, excellent yield, and showcases the economic importance of the catalysts for such processes.

Three-component aza-Diels-Alder reactions using Yb(OTf)3 catalyst under conventional/ultrasonic techniques.

The Yb(OTf)3 catalyzed formal aza-Diels-Alder (or Povarov) reaction of cyclopentadiene and 1,3-cyclohexadiene with in situ-generated N-arylimines under conventional/ultrasonic techniques is herein described. This kind of three-component Povarov reaction results in quinoline and phenanthridine derivatives, which are important biological compounds.

Inhibition of the mutagenic effects of N-methyl-N'-nitro-N-nitrosoguanidine and 9-aminoacridine by indenopyridines in the Salmonella typhimurium tester strain 1537 and E. coli.

The goal of the present research was to determine the protective potential of five newly synthesized indenopyridine derivatives against N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and 9-aminoacridine (9-AA) induced mutagenesis. MNNG sensitive Escherichia coli WP2uvrA and 9-AA sensitive Salmonella typhimurium TA1537 were chosen as the bacterial tester strains. All of the test compounds showed significant antimutagenic activity at various tested concentrations. The inhibition rates ranged from 25.6% (Compound 2 - 1 mM/plate) to 68.2% (Compound 1 - 2.5 mM/plate) for MNNG and from 25.7% (Compound 4 - 1 mM/plate) to 76.1% (Compound 3 - 2.5 mM/plate) for 9-AA genotoxicity. Moreover, the mutagenicity of the test compounds was investigated by using the same strains. None of the test compounds has mutagenic properties on the bacterial strains at the highest concentration of 2.5 mM. Thus, the findings of the present study give valuable clues to develop new strategies for chemical prevention from MNNG and 9-AA genotoxicity by using synthetic indenopyridine derivatives.

Genotoxic and antigenotoxic assessment of four newly synthesized dihydropyridine derivatives.

The current study aims to determine the genotoxic and antigenotoxic potential of four newly synthesized dihydropyridine derivatives using Escherichia coli WP2 and Ames/Salmonella bacterial reversion assay systems. The bacterial mutant tester strains, E. coli WP2uvrA with a point mutation and Salmonella typhimurium TA1537 with a frameshift mutation, were used to determine genotoxic potentials of the test compounds. To determine antigenotoxic potentials of the test compounds, the same strains were also used together with positive mutagens N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) for E. coli WP2uvrA and 9-aminoacridine (9-AA) for S. typhimurium TA1537. According to the results, neither of the test compounds showed significant genotoxic activity on both tester strains at the tested concentrations. However, except compound 4, all the test compounds showed significant antigenotoxic activity on MNNG- or/and 9-AA-induced mutations. The inhibition rates of mutagenesis ranged from 27.0% (compound 2: 2.5 mM/plate) to 65.0% (compound 2: 0.5 mM/plate) for MNNG and from 30.6% (compound 2: 2 mM/plate) to 58.5% (compound 1: 1 mM/plate) for 9-AA genotoxicity. According to these results, it is concluded that all the test compounds do not have a mutagenic potential on the bacterial strains at the tested concentrations, and some of them have antigenotoxic potentials against MNNG- and 9-AA-induced mutagenesis.

Antigenotoxic properties of two newly synthesized ß-aminoketones against N-methyl-N'-nitro-N-nitrosoguanidine and 9-aminoacridine-induced mutagenesis.

The aim of this study was to determine the antigenotoxic potential of two newly synthesized ß-aminoketones against N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and 9-aminoacridine (9-AA)-induced mutagenesis. The mutant bacterial tester strains were MNNG-sensitive Escherichia coli WP2 uvrA and 9-AA-sensitive Salmonella typhimurium TA1537. Both test compounds showed significant antimutagenic activity at various tested concentrations. The inhibition rates ranged from 29.5% (compound 1: 2 mM/plate) to 47.5% (compound 2: 1.5 mM/plate) for MNNG and from 25.0% (compound 2: 1 mM/plate) to 52.1% (compound 2: 2.5 mM/plate) for 9-AA genotoxicity. Moreover, the mutagenicity of the test compounds was investigated by using the same strains. Neither test compound has mutagenic properties on the bacterial strains at the tested concentrations. Thus, the findings of the present study give valuable information about chemical prevention from MNNG and 9-AA genotoxicity by using synthetic ß-aminoketones.

Protective properties of five newly synthesized cyclic compounds against sodium azide and N-methyl-N'-nitro-N-nitrosoguanidine genotoxicity.

The current study aims to determine the antimutagenic potential of five newly synthesized cyclic compounds against the genotoxic agents sodium azide (NaN3) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). The mutant bacterial tester strains were NaN3-sensitive Salmonella typhimurium TA1535 and MNNG-sensitive Escherichia coli WP2uvrA. According to the results, all the test compounds showed significant antimutagenic activity. The inhibition rates ranged from 26.05% (Compound 4-1 µg/plate) to 68.54% (Compound 5-0.01 µg/plate) for NaN3 and from 32.44% (Compound 3-1 µg/plate) to 60.77% (Compound 5-1 µg/plate) for MNNG genotoxicity. Moreover, the mutagenic potential of the test compounds was investigated using the same strains. The results showed that all the test compounds do not have mutagenic potential on the bacterial strains at the tested concentrations. Thus, the findings of the present study give valuable information about chemical prevention from NaN3 and MNNG genotoxicity.

1,3-Di-3-pyridyl-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazine.

In the crystal structure of the title compound, C(22)H(17)N(3)O, the oxazine ring has a half-chair conformation. The dihedral angles between the best least-squares plane through the pyridine rings and the planar part (O-C-C-C-N) of the oxazine ring are 72.14 (6) and 35.44 (7)°, the smaller angle involving the pyridine ring adjacent to the oxazine O atom. The mol-ecule has two stereogenic centers at the oxazine carbons, RS and SR. The crystal packing reveals that symmetry-related mol-ecules are linked by inter-molecular N-H⋯N hydrogen bonds to form chains parallel to the b axis.

Synthesis of new pyrazolothiazole derivatives from 4-thiazolidinones.

The synthesis of new 2,3,5,6-aryl substituted tetrahydro-2H-pyrazolo[3,4-d]- thiazoles 4a-j as potential biologically active compounds by the cyclocondensation of phenyl hydrazine with new 5-arylidene derivatives 2a-j of 2,3-disubstituted-1,3- thiazolidin-4-ones 1a-e is reported.

Synthesis of new 1,3-disubstituted-2,3-dihydro-1H-naphth[1,2e][1,3]oxazines.

1,3-Disubstituted-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazines were prepared through the ring-closure reactions of the aminobenzylnaphthols with substituted aryl- and heteroarylaldehydes.