Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sitapur Road, Jankipuram Extension, Lucknow, 226031, UP, India.
Division of Cancer Biology, CSIR-Central Drug Research Institute, Sitapur Road, Jankipuram Extension, Lucknow, 226031, UP, India.
Eur J Med Chem. 2020 Feb 15;188:112011. doi: 10.1016/j.ejmech.2019.112011. Epub 2020 Jan 2.
Therapy resistance by evasion of apoptosis is one of the hallmarks of human cancer. Therefore, restoration of cell death by non-apoptotic mechanisms is critical to successfully overcome therapy resistance in cancer. By rational drug design approach, here we try to provide evidence that subtle changes in the chemical structure of spisulosine completely switched its cytotoxic function from apoptosis to autophagy. Our most potent molecule (26b) in a series of 16 synthesized derivatives showed robust autophagic cell death in diverse cancer cells sparing normal counterpart. Compound 26b mediated lethal autophagy induction was confirmed by formation of characteristic autophagic vacuoles, LC3 puncta formation, upregulation of signature autophagy markers like Beclin and Atg family proteins. Altogether, we have detected novel autophagy inducer small molecule which can be tested further for drug discovery research.
逃避细胞凋亡是人类癌症的特征之一。因此，通过非凋亡机制恢复细胞死亡对于成功克服癌症的治疗抵抗至关重要。通过合理的药物设计方法，我们试图提供证据表明，spisulosine 的化学结构的细微变化完全将其细胞毒性功能从细胞凋亡转变为自噬。我们在一系列合成的 16 种衍生物中最有效的分子（26b）在多种癌细胞中显示出强大的自噬细胞死亡，而对正常细胞没有影响。化合物 26b 通过形成特征性的自噬空泡、LC3 斑点形成、上调标志性的自噬标记物，如 Beclin 和 Atg 家族蛋白，证实了致命的自噬诱导作用。总之，我们已经检测到了一种新型的自噬诱导小分子，可以进一步进行药物发现研究。
