title: Synthesis, in vitro and in vivo cytotoxicity, and prediction of the intestinal absorption of substituted 2-ethoxycarbonyl-imidazo[2,1-b]benzothiazoles.
abstract: The imidazobenzothiazole compounds 3-17 together with the imidazobenzoxazole 18, and the imidazobenzoimidazole 19 were prepared and their cytotoxic activity evaluated at the National Cancer Institute (NCI) for testing against a panel of approximately 60 tumor cell lines. Compounds 5, 7, 8, and 16 exhibited interesting in vitro cytotoxic activity. The most active imidazobenzothiazole derivative 8 was further evaluated as a cytotoxic agent in the hollow fiber assay and showed a score greater than the minimum values for xenograft testing together with a net cell kill. Comparison with the results displayed in the in vivo assay by standard antitumor drugs in clinical use revealed a significant in vivo activity of the benzothiazole compound. COMPARE analyses for compounds 4-19 against the NCI's standard agent database show poor or no correlation, and it might suggest for these compounds a mechanism of action unrelated to that of any known drug. Furthermore, the benzothiazole 8 did not show significant antitumor activity in a panel of two xenotransplanted tumors (i.e. colon and non-small cell lung tumors). By computing the polar surface area of compounds 3-19 with the MAREA computer program it was established that the most active compounds 5, 7, 8, and 16 should experience good intestinal permeability.
authors.affiliation: Dipartimento Farmaco-Chimico, Facoltà di Farmacia, Università degli Studi di Bari, Via Orabona 4, 70125, Bari, Italy. trapani@farmchim.uniba.it
authors.forename: G
authors.initials: G
authors.lastname: Trapani
authors.forename: M
authors.initials: M
authors.lastname: Franco
authors.forename: A
authors.initials: A
authors.lastname: Latrofa
authors.forename: A
authors.initials: A
authors.lastname: Reho
authors.forename: G
authors.initials: G
authors.lastname: Liso
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D052160:Benzothiazoles; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D003110:Colonic Neoplasms / Q000188:drug therapy; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007408:Intestinal Absorption; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D012984:Software; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: C111133:2-(4-aminophenyl)benzothiazole; D000970:Antineoplastic Agents; D052160:Benzothiazoles; D013844:Thiazoles