SYNTHESIS AND BIOLOGICAL EVALUATION OF A SERIES OF TYRPHOSTINS CONTAINING NITROTHIOPHENE MOIETIES AS POSSIBLE EPIDERMAL GROWTH-FACTOR RECEPTOR TYROSINE KINASE INHIBITORS

A series of 36 nitrothiophene tyrphostins were synthesized, 32 of whic h were novel structures. Their ability to inhibit the epidermal growth factor (EGF) receptor tyrosine kinase was assessed in a cell-free ass ay. Compounds containing a dinitrile, 2-aminoethene-1,1-dinitrile or a thioamide group were good inhibitors of the receptor tyrosine kinase. Although anti-proliferative and cytotoxic activity was seen, no evide nce of inhibition of EGF receptor autophosphorylation in intact cells was observed. The compounds showed no preferential inhibition of EGF-d ependent proliferation of fibroblasts transfected with the EGF recepto r. Furthermore, in a panel of squamous cell carcinoma cell lines with varying levels of EGF receptor expression, there was no selective cell kill of lines with the highest EGF receptor expression. The 2-nitro-5 -substituted-thiophenes and the 2-nitro-3-substituted-thiophenes showe d reduction potentials falling within the range likely to be reduced b y cellular reducing agents, while the 2-nitro-4-substituted-thiophenes and 4-nitro-2-substituted-thiophenes did not. Compounds from the 2-ni tro-5-substituted-thiophene series were shown to induce DNA damage, wh ile no evidence of DNA damage was demonstrated with compounds from the 2-nitro-4-substituted-thiophene series. The 2-nitro-5-substituted-thi ophene compound 4 showed significant tumour-type selectivity in the US National Cancer Institute human tumour cell line panel. The leukaemia cell lines were particularly sensitive to the compound, as were the m ajority of the colon cancer, melanoma and breast cancer cell lines, wh ile the central nervous system-derived lines and the non-small cell lu ng cancer lines were particularly resistant. Further work is required to determine the precise mechanisms involved in these effects.