Next-Generation Hypoxic Cell Radiosensitizers: Nitroimidazole Alkylsulfonamides,Journal of Medicinal Chemistry

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Next-Generation Hypoxic Cell Radiosensitizers: Nitroimidazole Alkylsulfonamides
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-01-11 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01678
Muriel Bonnet ₁ , Cho Rong Hong ₁ , Way Wua Wong ₁ , Lydia P. Liew _{1,

2} , Avik Shome ₁ , Jingli Wang ₁ , Yongchuan Gu _{1,

2} , Ralph J. Stevenson ₁ , Wen Qi ₃ , Robert F. Anderson _{1,

2,

3} , Frederik B. Pruijn _{1,

2} , William R. Wilson _{1,

2} , Stephen M. F. Jamieson _{1,

2,

4} , Kevin O. Hicks _{1,

2} , Michael P. Hay _{1,

2}

Affiliation

Innovations in the field of radiotherapy such as stereotactic body radiotherapy, along with the advent of radio-immuno-oncology, herald new opportunities for classical oxygen-mimetic radiosensitizers. The role of hypoxic tumor cells in resistance to radiotherapy and in suppression of immune response continues to endorse tumor hypoxia as a bona fide, yet largely untapped, drug target. Only nimorazole is used clinically as a radiosensitizer, and there is a dearth of new radiosensitizers in development. Here we present a survey of novel nitroimidazole alkylsulfonamides and document their cytotoxicity and ability to radiosensitize anoxic tumor cells in vitro. We use a phosphate prodrug approach to increase aqueous solubility and to improve tumor drug delivery. A 2-nitroimidazole and a 5-nitroimidazole analogue demonstrated marked tumor radiosensitization in either ex vivo assays of surviving clonogens or tumor regrowth delay.

中文翻译：

下一代缺氧细胞放射增敏剂：硝基咪唑烷基磺酰胺

立体定向身体放疗等放疗领域的创新，以及放射免疫肿瘤学的出现，为经典的模拟氧放射增敏剂带来了新的机遇。缺氧肿瘤细胞在放射疗法抗性和免疫应答抑制中的作用继续证明肿瘤缺氧是一种真正的但尚未开发的药物靶标。临床上仅将尼莫拉唑用作放射增敏剂，并且尚无开发中的新的放射增敏剂。在这里，我们目前对新型硝基咪唑烷基磺酰胺类药物进行调查，并记录它们的细胞毒性和在体外对缺氧肿瘤细胞放射增敏的能力。我们使用磷酸盐前药方法来增加水溶性并改善肿瘤药物的递送。

更新日期：2018-01-11

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