title: Novel 2-Thienyl- and 2-Benzothienyl-Substituted 6-(2-Imidazolinyl)Benzothiazoles: Synthesis; in vitro Evaluation of Antitumor Effects and Assessment of Mitochondrial Toxicity.
abstract: 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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  Design of novel inhibitors targeting enzymes that regulate sphingolipid biosynthesis and turnover could change the landscape for the development of new anticancer drugs.
authors.forename: Livio
authors.initials: L
authors.lastname: Racané
authors.forename: Mirela
authors.initials: M
authors.lastname: Sedić
authors.forename: Nataša
authors.initials: N
authors.lastname: Ilić
authors.forename: Maja
authors.initials: M
authors.lastname: Aleksić
authors.affiliation: University of Rijeka, Department of Biotechnology, Centre for highthroughput technologies, 51000 Rijeka, Croatia.
authors.forename: Sandra Kraljević
authors.initials: SK
authors.lastname: Pavelić
authors.affiliation: Department of Organic chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, P. O. Box 177, HR-10000 Zagreb, Croatia.
authors.forename: Grace
authors.initials: G
authors.lastname: Karminski-Zamola
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000099157:Sphingosine Kinase
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; D017853:Phosphotransferases (Alcohol Group Acceptor); D013876:Thiophenes; D000099157:Sphingosine Kinase; C088015:benzothiophene