Synthesis and in vitro evaluation of radioiodine labeled hypoxia-targeted drugs containing 2-nitroimidazole and benzenesulfonamide groups

Designing new radiolabeled hypoxia-targeted drugs is of great help in the diagnosis of tumors. Hypoxia-targeted drugs with dual bioactive groups can enhance hypoxia selectivity, strengthen the binding of drugs to targets, and improve diagnostic accuracy compared with traditional hypoxia-targeted drugs containing only one nitroimidazole group. In this study, a series of novel radioiodine labeled tyrosine derivatives containing 2-nitroimidazole and benzenesulfonamide groups were synthesized and in vitro evaluated. In the uptake experiments of S180 cells that didn't express carbonic anhydrase IX (CAIX), the compound [¹³¹I]-3-(3-iodo-4-(2-(2-methoxyethoxy)ethoxy)phenyl)-2-(2-(2-nitro-1H-imidazole-1-yl)acetamido)-N-(2-(2-nitro-1H-imidazole-1-yl)ethyl)propenamide (¹³¹I-Tyr-05) containing two 2-nitroimidazole groups was modified from phenolic hydroxyl to methoxy to 2-(2-methoxyethoxy)ethoxy, gradually achieving improved membrane permeability and enhanced hydrophilicity. Compared with other compounds with similar structures but containing only one 2-nitroimidazole, it had higher hypoxic selectivity. In the uptake experiment of HeLa cells that expressed CAIX, [¹³¹I]-N-(3-(3-iodo-4-(2-(2-methoxyethoxy)ethoxy)phenyl)-1-((2-(2-nitro-1H-imidazole-1-yl)ethyl)amino)-1-oxopropan-2-yl)-4-sulfamoylbenzamide (¹³¹I-Tyr-06), which contained both 2-nitroimidazole and benzenesulfonamide group, achieved enhanced hypoxic uptake and selectivity through the combination of two targeting groups. The S180 cell blocking experiments of ¹³¹I-Tyr-05 and ¹³¹I-Tyr-06 showed that the benzenesulfonamide group of the compounds didn't inhibit cellular uptake, and inhibition of cytochrome P450 (CYP450) enzyme had no effect on cellular uptake. In silico ADMET evaluation showed that I-Tyr-05 and I-Tyr-06 possessed acceptable physicochemical and ADMET properties. In conclusion, this work demonstrated the advantages of hypoxia-targeted drugs containing dual bioactive groups compared to a single group, and also found it was a feasible approach to design new dual-targeted drugs by combining 2-nitroimidazole and benzenesulfonamide groups.