Cyclic Pifithrin-Alpha是一种非常有效的p53抑制剂,它在转录水平上抑制p53表达,EC50在30nM左右[1]。将Cyclic Pifithrin-Alpha与其它多种抑制微管药物结合使用能有效促进细胞有丝分裂期间的聚集,导致细胞凋亡加剧,无迹象表明进入G1期。这表明p53的转录活性在有丝分裂期间纺锤体的损伤形成有重要作用[2]。In vitro 以及 in vivo 实验均表明Cyclic Pifithrin-Alpha能极有效的抑制p53的活性导致凋亡并且不会对其它信号通路的凋亡前反应。Cyclic Pifithrin-Alpha有望成为一种新型药物前体,并在神经病理学和癌症治疗副作用方面得到广泛应用[3]。
[1] Pietrancosta N, et al. Novel cyclized Pifithrin-alpha p53 inactivators: synthesis and biological studies. Bioorg Med Chem Lett. 15(6):1561-4(2005).
[2] Zuco V, Zunino F. Cyclic pifithrin-alpha sensitizes wild type p53 tumor cells to antimicrotubule agent-induced apoptosis. Neoplasia. 10(6):587-96(2008).
[3] Pietrancosta N, et al. Imino-tetrahydro-benzothiazole derivatives as p53 inhibitors: discovery of a highly potent in vivo inhibitor and its action mechanism. J MedChem. 49(12):3645-52(2006).