Prodrugs of the cancer cell selective anti-cancer agent (Z)-2-(1H-indol-3-yl)-3-(isoquinolin-5-yl)acrylonitrile (A131) are orally efficacious in a mouse model of resistant colon cancer

[Display omitted] •A131 possesses a unique cancer cell selective dual mechanism of action.•Prodrugs based on modification of the indole nitrogen of 1 undergo degradation to the parent drug in plasma.•Preferred prodrugs fully elicited the pharmacological effects of 1 in cells.•Preferred prodrugs and had high aqueous solubility suitable for oral administration.•In paclitaxel-resistant colon cancer xenograft model, 10 had 76% tumor growth inhibition when given orally at 80 mg/kg BID. A131 (1) possesses a unique cancer cell selective dual mechanism of action where cancer cells are killed but normal cells only undergo growth arrest and are able to regrow after removal of 1. SAR studies of 1 indicate that only the specific structure of 1 elicits the full pharmacological effect. However, application of 1 in mouse models of cancer has been hampered by its low solubility and stability when given orally. In this work we describe the study of various prodrugs based on modification of the indole nitrogen. A range of acyl analogues were prepared as prodrugs which were shown to undergo degradation to the parent drug in plasma. A preferred prodrug fully elicited the pharmacological effects of 1 in cells and led to high aqueous solubility suitable for oral administration. In a mouse model of paclitaxel-resistant colon cancer, compound 10, as a TFA salt, showed 76% tumor growth inhibition when administered at an oral dose of 80 mg/kg twice a day.