Differences in electrochemical response of prospective anticancer drugs IPBD and Cl-IPBD, doxorubicin and Vitamin C at plasmid modified glassy carbon.

For the comparison of the DNA interactions with drugs, two newly synthesized prospective anticancer drugs, 6-(1H-imidazo[4,5-b]phenasine-2-yl)benzene-1,3-diol (IPBD) and, its -Cl derivative (Cl-IPBD) have been compared with doxorubicin, a drug widely used in medicine, and with Vitamin C. These compounds were accumulated at a supercoiled scpUC19 plasmid layer formed on a glassy carbon electrode (GCE). Stability of the drug-plasmid/GCE layer was achieved by initial plasmid accumulation using prolonged potential cycling for ca. 200 min. from highly diluted scpUC19 solutions (8 pg/mL), followed by accumulation of the drugs from 1 µM - 50 µM. Electrochemical properties in terms of the redox potentials of the compounds and capacitative/resistive characteristics of the layers have been tested using, in sequence, four voltammetric methods: Square Wave (SWV), Differential Pulse (DPV) and Alternating Current (ACV) with phase detection 0° and 90°. Importantly, with progressive drug accumulation in the plasmid, for Cl-IPBD, but not for IPBD, an increase in peak (I) at -0.42 V vs. SCE was observed, while biological tests revealed a higher cytotoxic activity for Cl-IPBD vs. IPBD. Moreover, an additional redox signal of Cl-IPBD was observed with the compound reductive accumulation at the plasmid layer in the presence of Vitamin C.

Molecular Organization of Dipalmitoylphosphatidylcholine Bilayers Containing Bioactive Compounds 4-(5-Heptyl-1,3,4-thiadiazol-2-yl) Benzene-1,3-diol and 4-(5-Methyl-1,3,4-thiadiazol-2-yl) Benzene-1,3-diols.

This article presents the results of spectroscopic studies of two compounds from the 1,3,4-thiadiazole group, that is, 4-(5-methyl-1,3,4-thiadiazole-2-yl)benzene-1,3-diol (C1) and 4-(5-heptyl-1,3,4-thiadiazole-2-yl)benzene-1,3-diol (C7), present at different molar concentrations in 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) liposome systems. In the case of both investigated compounds, fluorescence measurements revealed the presence of several emission bands, whose appearance is related to the molecular organization induced by changes in the phase transition in DPPC. On the basis of the interpretation of Fourier transform infrared spectra, we determined the molecular organization of the analyzed compounds in multilayers formed from DPPC and the 1,3,4-thiadiazoles. It was found that the compound with a longer alkyl substituent both occupied the lipid polar head region in the lipid multilayer and interacted with lipid hydrocarbon chains. In turn, the compound with a shorter alkyl substituent interacted more strongly with the membrane polar region. On the basis of the knowledge from previous investigations conducted using different solvents, the fluorescence effects observed were related to the phenomenon of molecular aggregation. The effects were strongly influenced by the structure of the compound and, primarily, by the type of the alkyl substituent used in the molecule. The substantial shortening of fluorescence lifetimes associated with the effect of long-wave emission (with a maximum at 505 nm) decay also confirms the model of aggregation effects in the analyzed systems. Similar effects can be very easily distinguished and associated with respective forms of the compounds in biologically relevant samples.

New derivative of 2-(2,4-dihydroxyphenyl)thieno-1,3-thiazin-4-one (BChTT) elicits antiproliferative effect via p38-mediated cell cycle arrest in cancer cells.

2-(2,4-Dihydroxyphenyl)thieno-1,3-thiazin-4-ones are a group of new compounds with potential anticancer activity. This type of derivatives was poorly investigated in the area of synthesis and biological activities. In the present study the antiproliferative action of the most active derivative BChTT was described. The aim of biological evaluation was to investigate the ability of the compound to inhibit cancer cell proliferation and identify mechanism involved in its action on the molecular level. BChTT inhibited the proliferation of lung cancer A549, colon cancer HT-29 and glioma C6 cells in the concentration-dependent manner. It was not toxic to normal cells including skin fibroblasts, hepatocytes and oligodendrocytes in the antiproliferative concentrations. BChTT decreased the DNA synthesis in the treated cancer cells and induced cell cycle arrest in the G0/G1 phase. Moreover, the ability of the compound to activate p38 kinase and decrease cyclin D1 expression was estimated. Participation of p38 kinase in the antiproliferative action of the compound was confirmed by the analysis of BChTT activity in the cells with the p38 silenced gene. The obtained results may suggest the ability of the tested derivative to inhibit cancer cells proliferation by induction of p38-mediated cyclin D1 downregulation.

Synthesis, characterization, and pharmacological evaluation of novel azolo- and azinothiazinones containing 2,4-dihydroxyphenyl substituent as anticancer agents.

ABSTRACT: We reported the synthesis and characterization of a series of azolo- and azino[1,3]thiazinones containing the 2,4-dihydroxyphenyl substituent. The compounds were prepared by a new one-step reaction of aryl-modified sulfinylbis[(2,4-dihydroxyphenyl)methanethione]s and the corresponding aminoazolo(azino)carboxamides. Their chemical structures were confirmed by IR, NMR: 1H, 13C, HSQC, and EI-MS spectral data. The compounds inhibited proliferation and viability of lung cancer A549, colon cancer HT-29, and glioma C6 cells in a structure- and concentration-dependent manner. The activity of some analogues was below 10 µmol dm-3 (IC50). Glioma C6 cells were the most sensitive to tested compounds. Generally, the derivatives were not toxic for the skin fibroblast HSF culture. Moreover, some of them exerted a protective effect on the treated normal cells. Evaluation of compound properties in silico showed that they possess significant drug-like characteristics and most of them display a low toxicity.

Synthesis of 2-(2,4-dihydroxyphenyl)thieno-1,3-thiazin-4-ones, their lipophilicity and anticancer activity in vitro.

A new one-step synthesis of novel biologically active 2-substituted 2,4-dihydroxyphenyl-4[Formula: see text]-thieno[3,2-[Formula: see text]][1,3]thiazin-4-ones and 4[Formula: see text]-thieno[2,3-[Formula: see text]][1,3]thiazin-4-ones has been elaborated and described. The compounds were prepared by the reaction of aryl-modified sulfinylbis [(2,4-dihydroxyphenyl)methanethione]s and the corresponding aminothiophenecarboxamides. The derivatives showed anticancer activity in vitro. These compounds inhibited the proliferation and viability of lung cancer A549, colon cancer HT-29 and glioma C6 cells in a concentration-dependent manner. Some of the derivatives had no influence on normal skin fibroblasts culture viability. Moreover, one compound (1b) showed the ability to inhibit DNA synthesis in cancer cells, especially in C6 cells, and was not toxic for normal oligodendrocytes and hepatocytes. Using reversed phase RP 18 HPLC and immobilised artificial membrane (IAM) chromatography the phase affinity of the compounds was determined. The influence of lipophilicity on the activity of compounds has been discussed.

Synthesis and anticholinesterase activities of novel 1,3,4-thiadiazole based compounds.

In the present study, new (1,3,4-thiadiazol-2-yl)benzene-1,3-diol based compounds have been synthesized and their potential anticholinesterases properties have been investigated using the modified of Ellman's spectrophotometric method. The compounds were obtained by the reaction of hydrazides or thiosemicarbazides with aryl-modified sulfinylbis[(2,4-dihydroxyphenyl)methanethione]s. Their chemical structures were elucidated by IR, (1)H-NMR, (13)C-NMR and EI-MS spectral data and elemental analyses. Most of the compounds acted as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors in vitro, with IC50 values ranging from >500 to 0.053 µM and from >500 to 0.105 µM, respectively. The most potent compound 9 (IC50 = 0.053 µM) proved to be selective toward AChE, exhibiting selectivity ratios versus BuChE of ca. 950. The kinetic studies showed that it is a mixed-type of AChE inhibitor. Another compound (2) was active against both enzymes with IC50 values in the low nM range. The structure-activity relationships (SARs) of the compounds under consideration were discussed.

One-pot synthesis of new (1,3-thiazolo[5,4-b]pyridin-2-yl)benzenediols and their antiproliferative activities against human cancer cell lines.

A one-pot synthesis of new 4-(1,3-thiazolo[5,4-b]pyridin-2-yl)benzene-1,3-diols has been described. The compounds were prepared by the reaction of sulfinylbis[(2,4-dihydroxyphenyl)methanethione] derivatives, with various substituents in the aryl rings, with 2-chloropyridin-3-amines. Their structures were deduced from IR and, (1) H- and (13) C-NMR spectroscopic, mass spectrometric, and elemental analyses. The antiproliferative properties of some of the products against human cancer cell lines were comparable to those of cisplatin. Structure-activity analysis showed that the presence of hydrophobic substituents in both heterocyclic fused and phenyl rings of the compounds improves their biological effects. Further, an additional OH group in the resorcinol moiety reduced the antiproliferative activity.

Synthesis and antibacterial activity of novel fused 1,3-thiazoles and 1,3-thiazines incorporating a 2,4-dihydroxyphenyl residue.

In an attempt to find a new class of antimicrobial agents, a series of benzothiazoles, 1,3-thiazolo[5,4-b]pyridines, 4H-3,1-benzothiazines, naphtho[2,3-d][1,3]thiazole-4,9-diones and other related compounds containing a 2,4-dihydroxyphenyl moiety were prepared. They were obtained via the reaction of aryl-modified sulfinyl[bis(2,4-dihydroxyphenylmethanethione)]s with appropriate commercial chemical reagents in the endocyclization processes. The MIC values of the compounds towards eight reference bacterial strains were assessed by the two-fold serial micro-dilution broth method. They exhibited inhibitory effects against the Gram-positive strains tested opposite to Gram-negative ones. Some compounds were more effective than the reference drug. 4-(6-Chloro-4H-3,1-benzothiazin-2-yl)-6-methylbenzene-1,3-diol (5b) due to its very good activity (MIC from 1.56 to 3.13 µg/mL) and low cytotoxicity (IC(50) > 50 µg/mL) may be regarded as a promising precursor for the development of novel antibacterial agents.

Synthesis and anticancer activity of new 2-aryl-4h-3,1-benzothiazines.

New compounds of 2-aryl-4H-3,1-benzothiazine set were synthesized and tested for their antiproliferative activity as part of our research in the antitumor field. The title compounds were obtained by the reaction of aryl-modified sulfinylbis((2,4-dihydroxyphenyl)methanethione) with 2-aminobenzyl alcohols. The reaction proceeded through thiobenzanilide intermediates, which were converted to the 4H-3,1-benzothiazine fused ring by an endocyclization process. The structures of compounds were identified from elemental, IR, (1) H-NMR, (13) C-NMR, and MS spectra analyses. The cytotoxicity in vitro against four human cancer cell lines was determined. The antiproliferative properties of some compounds were more beneficial than cisplatin studied comparatively.