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.