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 (∆P = 45.50 mmHg) and (∆P = 44.38 mmHg) improve the oxygen-releasing property effectively compared to positive control efaproxiral (∆P = 36.40 mmHg). Preliminary safety evaluation revealed that exhibited no cytotoxicity towards HEK293 and U87MG cells, while was cytotoxic toward both cells with no selectivity. An in vivo activity assay confirmed that exhibited a radiosensitization effect on orthotopically transplanted GB in mouse brains. Moreover, a pharmacokinetic study in rats showed that was orally available.
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