DataSheet1_Design, Synthesis, and Antileukemic Evaluation of a Novel Mikanolide Derivative Through the Ras/Raf/MEK/ERK Pathway.DOCX

Chronic myeloid leukemia (CML) accounts for a major cause of death in adult leukemia patients due to mutations or other reasons for dysfunction in the ABL proto-oncogene. The ubiquitous BCR–ABL expression stimulates CML by activating CDK1 and cyclin B1, promoting pro-apoptotic, and inhibiting antiapoptotic marker expression along with regulations in RAS pathway activation. Thus, inhibitors of cyclins and the RAS pathway by ERK are of great interest in antileukemic treatments. Mikanolide is a sesquiterpene dilactone isolated from several Asteraceae family Mikania sp. plants. Sesquiterpene dilactone is a traditional medicine for treating ailments, such as flu, cardiovascular diseases, bacterial infections, and other blood disorders. It is used as a cytotoxic agent as well. The need of the hour is potent chemotherapeutic agents with cytotoxic effects inhibition of proliferation and activation of apoptotic machinery. Recently, ERK inhibitors are used in clinics as anticancer agents. Thus, in this study, we synthesized 22-mikanolide derivatives that elucidated to be potent antileukemic agents in vitro. However, a bioactive mikanolide derivative, 3g, was found with potent antileukemic activity, through the Ras/Raf/MEK/ERK pathway. It can arrest the cell cycle by inhibiting phosphorylation of CDC25C, triggering apoptosis, and promoting DNA and mitochondrial damage, thus suggesting it as a potential chemotherapeutic agent for leukemia patients.

慢性髓系白血病（CML）是成人白血病患者死亡的主要诱因之一，其致病多与ABL原癌基因突变或其他功能异常相关。普遍存在的BCR-ABL融合基因表达可通过激活CDK1与细胞周期蛋白B1（cyclin B1）、上调促凋亡标志物表达并下调抗凋亡标志物表达，同时调控RAS通路激活，从而促进慢性髓系白血病的发生发展。因此，以细胞周期蛋白及ERK调控的RAS通路为靶点的抑制剂，在抗白血病治疗领域受到广泛关注。斑鸠菊内酯（mikanolide）是一类从菊科（Asteraceae）泽兰属（Mikania sp.）多种植物中分离得到的倍半萜双内酯（sesquiterpene dilactone）。倍半萜双内酯类化合物作为传统药物，可用于治疗流感、心血管疾病、细菌感染及其他血液系统病症，同时也可作为细胞毒素制剂使用。当前亟需兼具细胞毒性、可抑制肿瘤细胞增殖并激活凋亡通路的强效化疗药物。近年来，ERK抑制剂已作为抗癌药物应用于临床治疗。基于此，本研究合成了22-斑鸠菊内酯衍生物，经体外实验证实其具备强效抗白血病活性。其中活性优异的斑鸠菊内酯衍生物3g，可通过Ras/Raf/MEK/ERK通路发挥强效抗白血病作用：该衍生物可通过抑制CDC25C磷酸化阻断细胞周期，诱导细胞凋亡，并促进DNA与线粒体损伤，因此有望成为治疗白血病患者的潜在化疗药物。