Synthesis and selected immunological properties of substituted quino[3,2-b]benzo[1,4]thiazines

A new type of azaphenothiazines – tetracyclic quino[3,2-b]benzo[1,4]thiazines, possessing common substituents (H, CH3, Cl, Br, F, CF3, SCH3) in positions 8–10 and pharmacophoric aminoalkyl substituents in position 6, were obtained from diquinodithiin and 2,2′-dichloro-3,3′-diquinolinyl disulfide in several-step syntheses. Sixty one compounds, grouped as the 6H, 6-dialkylaminoalkyl, 6-acylaminoalkyl and sulfonylaminoalkyl derivatives, were tested for cytotoxicity, their effects on phytohemagglutin A (PHA)-induced proliferative response of human peripheral blood mononuclear cells (PBMC) and lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-α) production by these cells. The compounds exhibited differential inhibitory activities in these tests and significantly varied in terms of cytotoxicity. The most promising compounds were tested for growth inhibition of leukemia L-1210 cells, colon cancer SV-948 cells and epidermal carcinoma A-341 cells. The most active compounds exhibited anticancer activity against these cell lines comparable to that of cisplatin. The structure–activity relationship of the compounds were discussed.

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► The studied tricyclic phenothiazines are modified with the quinoline ring.
► The new type of azaphenothiazines contains a linearly fused tetracyclic ring system.
► The quinobenzothiazines show potent antiproliferative and anticancer activities.
► The most active ligands are acetylaminoalkyl and chlororoethylureidoalkyl groups.
► Several compounds exhibit anticancer activity comparable to that of cisplatin.