Phenoxyaromatic Acid Analogues as Novel Radiotherapy Sensitizers: Design, Synthesis and Biological Evaluation

Radiotherapy is a vital approach for brain tumor treatment. The standard treatment for glioblastoma (GB) is maximal surgical resection combined with radiotherapy and chemotherapy. However, the non-sensitivity of tumor cells in the hypoxic area of solid tumors to radiotherapy may cause radioresistance. Therefore, radiotherapy sensitizers that increase the oxygen concentration within the tumor are promising for increasing the effectiveness of radiation. Inspired by hemoglobin allosteric oxygen release regulators, a series of novel phenoxyacetic acid analogues were designed and synthesized. A numerical method was applied to determine the activity and safety of newly synthesized compounds. In vitro studies on the evaluation of red blood cells revealed that compounds 19c ( increment P-50 = 45.50 mmHg) and 19t ( increment P-50 = 44.38 mmHg) improve the oxygen-releasing property effectively compared to positive control efaproxiral ( increment P-50 = 36.40 mmHg). Preliminary safety evaluation revealed that 19c exhibited no cytotoxicity towards HEK293 and U87MG cells, while 19t was cytotoxic toward both cells with no selectivity. An in vivo activity assay confirmed that 19c exhibited a radiosensitization effect on orthotopically transplanted GB in mouse brains. Moreover, a pharmacokinetic study in rats showed that 19c was orally available.

Automated summary

Radiotherapy is an essential treatment for brain tumors, but radioresistance caused by the non-sensitivity of tumor cells in hypoxic areas can reduce its effectiveness. This study designed and synthesized novel compounds that increase the oxygen concentration within tumors to enhance the sensitivity to radiation. In vitro experiments demonstrated that certain compounds effectively improved oxygen-releasing properties compared to the positive control, and safety evaluation indicated their low cytotoxicity. Furthermore, animal studies confirmed the radiosensitization effect of one compound on orthotopically transplanted glioblastoma.