title: 6-Substituted 9-fluoroquino[3,2-b]benzo[1,4]thiazines display strong antiproliferative and antitumor properties.
abstract: 6-Substituted 9-fluoroquino[3,2-b]benzo[1,4]thiazines - a new type of tetracyclic azaphenothiazines-were obtained from of 6H-9-fluoroquinobenzothiazine by the introduction of appropriate substituents to the thiazine nitrogen atom (alkyl, aminoalkyl, amidoalkyl, sulfonamidoalkyl and nitrogen half-mustard groups). The compounds displayed differential cytotoxic as well as antiproliferative actions against human peripheral blood mononuclear cells (PBMC) stimulated with phytohemagglutinin A (PHA). In addition, they suppressed lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-α) production by whole blood human cell cultures. Two compounds (4 and 15, with the propargyl and methanesulfonamidopropyl groups) were selected for further experiments because of lack of cytotoxicity and strong antiproliferative actions. Compound 4 showed strong suppressive actions on growth of L1210, SW948, A-431 and CX-1 tumor cell lines which were close to those of cisplatin, the reference drug (e.g. GI50 of 2.28 μg/mL vs. 1.86 μg/mL for L1210 cells). Further, the compound appeared to be equally effective as cyclosporine A (CsA) in the inhibition of human two-way mixed lymphocyte reaction (MLR). The compound did not significantly inhibit interleukin 2 (IL-2)-induced growth of CTLL-2 cell line. In addition, inhibition of prostaglandin (PG) synthesis by indomethacin or block of PG receptors did not interfere with the inhibitory effect of the compound on PHA-induced cell proliferation. Therefore, it is likely that the compound acts by inhibiting cell cycle as proposed for other phenothiazines. Further studies are required for the elucidation of the mechanism of action and therapeutic utility of these compounds in more advanced in vivo models.
authors.affiliation: The Medical University of Silesia, School of Pharmacy with the Division of Laboratory Medicine, Department of Organic Chemistry, Jagiellońska 4, 41-200 Sosnowiec, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Jeleń
authors.affiliation: The Medical University of Silesia, School of Pharmacy with the Division of Laboratory Medicine, Department of Organic Chemistry, Jagiellońska 4, 41-200 Sosnowiec, Poland. Electronic address: pluta@sum.edu.pl.
authors.forename: Krystian
authors.initials: K
authors.lastname: Pluta
authors.affiliation: Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Department of Experimental Therapy, R. Weigla 12, 53-114 Wrocław, Poland.
authors.forename: Michał
authors.initials: M
authors.lastname: Zimecki
authors.affiliation: The Medical University of Silesia, School of Pharmacy with the Division of Laboratory Medicine, Department of Organic Chemistry, Jagiellońska 4, 41-200 Sosnowiec, Poland.
authors.forename: Beata
authors.initials: B
authors.lastname: Morak-Młodawska
authors.affiliation: Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Department of Experimental Therapy, R. Weigla 12, 53-114 Wrocław, Poland.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Artym
authors.affiliation: Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Department of Experimental Therapy, R. Weigla 12, 53-114 Wrocław, Poland.
authors.forename: Maja
authors.initials: M
authors.lastname: Kocięba
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D024841:Fluoroquinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000473:pathology; D015394:Molecular Structure; D010640:Phenothiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D000970:Antineoplastic Agents; D024841:Fluoroquinolones; D010640:Phenothiazines; D014409:Tumor Necrosis Factor-alpha
keywords: Anticancer activity; Antiproliferative activity; Azaphenothiazines; Phenothiazines; Thiazine ring formation