N-(3-甲基苯基)-4-(4-吡啶)-2-噻唑胺

简介

N-(3-甲基苯基)-4-(4-吡啶)-2-噻唑胺属于4-吡啶基-2-苯胺基噻唑（PAT）类化合物，对肾细胞癌（RCC）细胞具有细胞毒作用。晚期肾癌预后较差，肾细胞癌（RCC）往往对标准治疗无效。因此，晚期RCC的治疗具有尚未满足的临床需求。

生物活性

STF-62247对缺乏VHL的肾细胞具有选择毒性和抑制细胞生长作用作用于VHL缺陷的细胞比作用于野生型(VHL+)选择性高25倍。

体外研究

In vitro, STF-62247 shows cytotoxicity and tumor growth inhibitory activity against wild-type VHL and VHL-deficient renal cell carcinoma (RCC) in a HIF-independent manner with IC50 of 16 μM and 0.625 μM, respectively. Moreover, STF-62247 also leads to cell death by increasing acidification and inducing autophagy in VHL-deficient cells. STF-62247 specifically induces macroautophagy and enhances the fusion of autophagosome and lysosomes to form autolysosomes by interfering with Golgi-endoplasmic reticulum transport in cells that have lost VHL . A recent study shows that induction of autophagy by STF-62247 increases sensitivity of RCC under hypoxic conditions to radiation in a VHL-dependent manner.

体内研究

In vivo mouse model, STF-62247 at a dose of 8 mg/kg byby intraperitoneal injection significantly reduces tumor growth of VHL-deficient SN12C tumor cells.

制备方法

在回流温度下，将溴酮氢溴酸盐（1.13 g，4.03 mmol）和3-甲基苯基硫脲（0.67 g，4.03 mmol）在EtOH（20 mL）中的混合物搅拌3 h。将混合物冷却至20℃，用水（50mL）稀释，将pH调节至约3。将其与NH3水溶液在8℃下混合，并将混合物在20℃下搅拌2h。过滤沉淀物，用水（5mL）洗涤并干燥。粗固体通过柱色谱法纯化，用EtOAc / pet的梯度（50-100％）洗脱得到N-(3-甲基苯基)-4-(4-吡啶)-2-噻唑胺（0.94 g，87％），为乳白色粉末。