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

Molecules

Bingting Li¹  Jiajia Chang²  Yangrong Xu²  Xinlin Yan²  Shi Hou²  Junhai Xiao²  Hongquan Zhang²  Jialin Guo²  Chunxi Wen²  Song Li² 

[1] Institute of Health Service and Transfusion Medicine, Beijing 100850, China;National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China;

关键词: phenoxyacetic acid;    hemoglobin;    tumor cell;    radiotherapy sensitizers;    molecular docking;   

DOI  :  10.3390/molecules27082428

来源: DOAJ

【 摘 要 】

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 (∆P₅₀ = 45.50 mmHg) and 19t (∆P₅₀ = 44.38 mmHg) improve the oxygen-releasing property effectively compared to positive control efaproxiral (∆P₅₀ = 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.

【 授权许可】

Unknown