Structural Studies on Bioactive Compounds. 23. Synthesis of Polyhydroxylated 2-Phenylbenzothiazoles and a Comparison of their Cytotoxicities and Pharmacological Properties with Genistein and Quercetin

Abstract

A series of polyhydroxylated 2-phenylbenzothiazoles 3 has been prepared by demethylation of the precursor methoxylated 2-phenylbenzothiazoles 9. The key step in the construction of the benzothiazole nucleus involves a Jacobson cyclization of methoxylated thiobenzanilides 8. The target compounds inhibit WiDr human colon tumor cells and MCF-7 human mammary tumor cells in vitro with IC50 values in the low micromolar range, but the activity against MCF-7 cells is not related to estrogen receptor-binding affinity. None of the compounds showed selective cytotoxicity against Abelson virus-transformed ANN-1 cells encoded with the pp120gag-abl tyrosine kinase compared with the parental 3T3 line. Compounds 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)benzothiazole (3b) which has the same overall hydroxyl substitution pattern as genistein (1a). The compounds were weakly cytotoxic for an EGF receptor, overexpressing cell line HN5, but when tested for differential toxicity against the EGF receptor tyrosine kinase or the PDGF receptor tyrosine kinase in a standard mitogenesis assay utilizing human fibroblasts, no discrimination was observed. In this assay, the compounds inhibited DNA synthesis when added to cells during S phase. This suggests that inhibition could not be interpreted in terms of tyrosine kinase inactivation but more likely as a relatively broad specificity for the ATP-binding domain of other kinases such as thymidine kinase.

Inhibition of mitochondrial proton F0F1‐ATPase/ATP synthase by polyphenolic phytochemicals

“…However, several earlier studies indicated that the tyrosine kinase was not required for the inhibitory eect of genistein on tumour growth (Barnes & Peterson, 1995;Stevens et al, 1994;Shao et al, 1998), nor for biochanin A and daidzein. Other mechanisms have been Figure 5 Eects of resveratrol, genistein and quercetin on porcine cerebral cortex Na + /K + -ATPase.…”

2-(4-Aminophenyl)benzothiazoles: novel agents with selective profiles of in vitro anti-tumour activity

“…We have previously reported on the biological properties of polyhydroxylated 2-phenylbenzothiazoles (Stevens et al, 1994), which were originally designed as potential tyrosine kinase inhibitors modelled on structural comparisons with the flavone quercetin and isoflavone genistein (Yates et al, 1991). 2-(4-Aminophenyl)benzothiazole (CJM 126) (Figure 1), prepared as a synthetic intermediate in this programme, was found to elicit pronounced inhibitory effects against certain breast cancer cell lines in vitro with an intriguing biphasic dose-response relationship .…”

Influence of 2-(4-aminophenyl)benzothiazoles on growth of human ovarian carcinoma cells in vitro and in vivo

“…2-(4-Aminophenyl)benzothiazole (CJM 126, Figure 1) was originally prepared as a synthetic intermediate within a programme to design potential tyrosine kinase inhibitors modelled on structural comparisons with the flavone quercetin and isoflavone genistein (Yates et al, 1991;Stevens et al, 1994). It was found to elicit potent inhibitory effects against breast cancer cell lines in vitro, yielding biphasic dose-response profiles (Shi et al, 1996).…”