Novel 2-Thienyl- and 2-Benzothienyl-Substituted 6-(2-Imidazolinyl)Benzothiazoles: Synthesis; in vitro Evaluation of Antitumor Effects and Assessment of Mitochondrial Toxicity.

BACKGROUND: Differently substituted thiophenes are largely studied due to their diverse pharmacological properties, especially anticancer activity. Recent studies have reported on interesting benzothiophene compounds antitumor properties and we also recently reported on the synthesis, strong antitumor activities and DNA binding features of substituted thieno[3',2':4,5]thieno- and benzo[b]thieno[2,3-c]quinolones, containing different substituents, mostly amidino- or substituted amidino- groups. OBJECTIVE: The objective of presented paper was to prepare a series of novel cationic 2-thiophene and 2- benzothiophene substituted 6-(2- imidazolinyl)benzothiazole derivatives and to test their antiproliferative activity against several human cancer cell lines. METHOD: Synthesis of 2-thiophene and 2-benzothiophene substituted 6-(2-imidazolinyl)benzothiazole derivatives was carried out by condensation reaction of 2-amino-5-(2-imidazolinium)benzenethiolate with aldehydes or carbonyl chloride derivatives followed by two simple acid-base reaction steps was used for their conversion into targeted mesylates. Evaluation of antiproliferative effects and cell death was done by use of MTT assay and annexin-V test, while expression of sphingosine kinase 1 was studied by Western blot and gluthatione intracellular levels were measured by use of a luminescence-based assay. RESULTS: Preparation of water soluble mesylate salts 3a-3j was successfully achieved. In general, all compounds showed pronounced anticancer activities in vitro. Compound 3f showed strong and selective cytostatic activity in cervical carcinoma cells (HeLa) with moderate toxicity on normal fibroblasts. Similar to all other tested compounds, 3f cannot be considered a mitochondrial toxicant. One of the major mechanisms accounting for observed cytostatic effects of 3f was induction of apoptosis, probably due to specific inhibition of acid ceramidase activity. Compound 3h negatively regulated activity of sphingosine kinase 1 in HeLa cells. CONCLUSION: Design of novel inhibitors targeting enzymes that regulate sphingolipid biosynthesis and turnover could change the landscape for the development of new anticancer drugs.

Efficient and economical access to substituted benzothiazoles: copper-catalyzed coupling of 2-haloanilides with metal sulfides and subsequent condensation.

Don't tell azole: The first metal-catalyzed direct coupling of metal sulfides with aryl halides and subsequent intramolecular condensation provided substituted benzothiazoles (see scheme). A wide range of functional groups are tolerated under the reaction conditions.

Synthesis of 2-aminobenzothiazole via copper(I)-catalyzed tandem reaction of 2-iodobenzenamine with isothiocyanate.

Copper(I)-catalyzed tandem reaction of 2-iodobenzenamine with isothiocyanate under mild conditions is described, which provides an efficient and practical route for the synthesis of 2-aminobenzothiazole.

A simple, versatile, low-cost and remotely operated apparatus for [11C]acetate, [11C]choline, [11C]methionine and [11C]PIB synthesis.

A simple, efficient and remotely operated synthesis apparatus for carrying out routine [(11)C]carboxylation, on-column and bubbling [(11)C]methylation was essential for reliable, day-to-day production of [(11)C]-labelled PET radiopharmaceuticals. We developed an in-house apparatus specifically applied to the synthesis of [(11)C]acetate, [(11)C]choline, [(11)C]methionine and 2-(4'-N-[(11)C]methylaminophenyl)-6-hydroxybenzothiazole ([(11)C]PIB), where high radiochemical purity (>or= 97%) and moderate radiochemical yields (18% for [(11)C]PIB, 41-55% for the others) could be achieved. These findings provided evidence that this was a fast, versatile and reliable apparatus suitable for a PET/CT centre with limited financial budget and hot cell space for synthesis of [(11)C]-labelled radiopharmaceuticals.