一种合成海洋生物碱Fascaplysin及其具有治疗潜力的衍生物的新型温和方法。
A New Mild Method for Synthesis of Marine Alkaloid Fascaplysin and Its Therapeutically Promising Derivatives.
发表日期:2023 Jul 25
作者:
Oleg A Tryapkin, Alexey V Kantemirov, Sergey A Dyshlovoy, Vladimir S Prassolov, Pavel V Spirin, Gunhild von Amsberg, Maria A Sidorova, Maxim E Zhidkov
来源:
Bone & Joint Journal
摘要:
罗红素是一种海洋生物碱,由于其丰富多样且强效的生物活性,被认为是一种领先的潜在药物候选者。作为一种抗癌剂,罗红素由于在癌细胞中对多个靶点的作用,包括抑制细胞周期蛋白依赖激酶4(CDK4)和诱导内在凋亡,具有巨大的潜力。同时,由于与DNA的交替堆积造成的剧烈毒性,限制了对其结构优化的研究。此外,对其衍生物合成方法的研究也十分有限。在本研究中,我们报道了一种基于低温紫外线季铵化的罗红素衍生物合成的新方法,用于合成热敏性9-苄氧罗红素和6-叔丁基罗红素。9-苄氧罗红素被用作起始化合物以获得9-羟基罗红素。然而,后者被发现在化学上非常不稳定。与罗红素相比,6-叔丁基罗红素在DNA交替堆积方面表现出明显的降低,而其细胞毒性仅略有降低。因此,对于罗红素及其衍生物的细胞毒性效应,需要对DNA交替堆积的影响提出质疑。
Fascaplysin is a marine alkaloid which is considered to be a lead drug candidate due to its diverse and potent biological activity. As an anticancer agent, fascaplysin holds a great potential due to the multiple targets affected by this alkaloid in cancer cells, including inhibition of cyclin-dependent kinase 4 (CDK4) and induction of intrinsic apoptosis. At the same time, the studies on structural optimization are hampered by its rather high toxicity, mainly caused by DNA intercalation. In addition, the number of methods for the syntheses of its derivatives is limited. In the current study, we report a new two-step method of synthesis of fascaplysin derivatives based on low temperature UV quaternization for the synthesis of thermolabile 9-benzyloxyfascaplysin and 6-tert-butylfascaplysin. 9-Benzyloxyfascaplysin was used as the starting compound to obtain 9-hydroxyfascaplysin. However, the latter was found to be chemically highly unstable. 6-tert-Butylfascaplysin revealed a significant decrease in DNA intercalation when compared to fascaplysin, while cytotoxicity was only slightly reduced. Therefore, the impact of DNA intercalation for the cytotoxic effects of fascaplysin and its derivatives needs to be questioned.