STRUCTURAL STUDIES ON BIOACTIVE COMPOUNDS .23. SYNTHESIS OF POLYHYDROXYLATED 2-PHENYLBENZOTHIAZOLES AND A COMPARISON OF THEIR CYTOTOXICITIES AND PHARMACOLOGICAL PROPERTIES WITH GENISTEIN AND QUERCETIN

A series of polyhydroxylated 2-phenylbenzothiazoles 3 has been prepare d by demethylation of the precursor methoxylated 2-phenylbenzothiazole s 9. The key step in the construction of the benzothiazole nucleus inv olves a Jackson cyclization of methoxylated thiobenzanilides 8. The ta rget compounds inhibit WiDr human colon tumor cells and MCF-7 human ma mmary tumor cells in vitro with IC50 values in the low micromolar rang e, but the activity against MCF-7 cells is not related to estrogen rec eptor-binding affinity. None of the compounds showed selective cytotox icity against Abelson virus-transformed ANN-1 cells encoded with the p p120(gag-abl) tyrosine kinase compared with the parental 3T3 line. Com pounds were only marginally inhibitory to the EGF receptor-associated protein tyrosine kinase from a membrane preparation of A431 cells. The most active compound was 4,6-dihydroxy-2-(4-hydroxyphenyl)benzothiazo le (3b) which has the same overall hydroxyl substitution pattern as ge nistein (1a). The compounds were weakly cytotoxic for an EGF receptor, overexpressing cell line HN5, but when tested for differential toxici ty against the EGF receptor tyrosine kinase or the PDGF receptor tyros ine kinase in a standard mitogenesis assay utilizing human fibroblasts , no discrimination was observed. In this assay, the compounds inhibit ed DNA synthesis when added to cells during S phase. This suggests tha t inhibition could not be interpreted in terms of tyrosine kinase inac tivation but more likely as a relatively broad specificity for the ATP -binding domain of other kinases such as thymidine kinase.