6-Substituted 9-fluoroquino[3,2-b]benzo[1,4]thiazines display strong antiproliferative and antitumor properties
PBN-AR
Instytucja
Instytut Immunologii i Terapii Doświadczalnej im. Ludwika Hirszfelda Polskiej Akademii Nauk
Źródłowe zdarzenia ewaluacyjne
Informacje podstawowe
Główny język publikacji
EN
Czasopismo
European journal of medicinal chemistry.
ISSN
0223-5234
EISSN
1768-3254
Wydawca
Paris : Editions Scientifiques Elsevier
Rok publikacji
2015
Numer zeszytu
Strony od-do
411-420
Numer tomu
89
Identyfikator DOI
Liczba arkuszy
1,5
Słowa kluczowe
EN
Phenothiazines
Azaphenothiazines
Antiproliferative activity
Anticancer activity
Thiazine ring formation
Streszczenia
Język
EN
Treść
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.
Cechy publikacji
artykuł oryginalny
Inne
System-identifier
PX-56b48bcb8106eb71826f81ec
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