Biological Evaluation of a Potential Anticancer Agent Methyl N-[5-(3′-Iodobenzoyl)-1H-Benzimidazol-2-yl]Carbamate

Background: Resistance of cancer to chemo-and radiotherapy remains a major clinical problem. This study contributes to the ongoing search for agents that can bypass this resistance by developing a novel antimitotic theranostic. Materials and Methods: Methyl N-[5-(3′-iodobenzoyl)-1H-benzimidazol-2-yl]carbamates 1 and 2 were synthesized from a common precursor 3 or its 3′-stannylated derivative. The cytotoxicity of compound 1 was evaluated in several neuroblastoma and glioblastoma cell lines and in the NCI 60-cell assay. Biodistribution was conducted in mice after oral administration of compound 2 to determine tissue and brain uptake. Result: Lethal concentrations (LC₅₀s) of compound 1 in neuroblastoma and glioblastoma are >15 × lower compared with compound 3, a drug currently tested in clinical studies in pediatric and adult brain tumors. Growth inhibition concentrations (GI₅₀) are in the nanomolar range in 60 cancer cell lines. When compound 1 is combined with a 4-Gy dose of radiation, <0.5% of cells retain their reproductive integrity. Increased hydrophobicity of new agents greatly enhances their brain uptake after oral administration. Conclusions: Compound 1 is potently cytotoxic in a wide range of human cancer cell lines. Its structure allows incorporation of imaging and therapeutic radionuclides. It is therefore expected that compound 1 can be developed into a novel theranostic modality across a wide range of malignancies.