DataSheet5_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（Chronic myeloid leukemia, CML）因ABL原癌基因（ABL proto-oncogene）突变或其他功能异常，成为成人白血病患者的主要致死病因之一。普遍表达的BCR-ABL融合基因（BCR–ABL）通过激活细胞周期蛋白依赖性激酶1（CDK1）与细胞周期蛋白B1（cyclin B1），促进促凋亡标志物表达并抑制抗凋亡标志物表达，同时调控RAS通路（RAS pathway）的激活，进而驱动慢性髓系白血病的发生发展。因此，靶向细胞周期蛋白及细胞外调节蛋白激酶（extracellular signal-regulated kinase, ERK）调控的RAS通路的抑制剂，在抗白血病治疗领域备受关注。米卡诺内酯（mikanolide）是一类倍半萜双内酯（sesquiterpene dilactone），可从菊科（Asteraceae）泽兰属（Mikania sp.）的多种植物中分离得到。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疾病，同时也可用作细胞毒制剂（cytotoxic agent）。当前亟需兼具细胞毒活性、增殖抑制作用并可激活凋亡机制的强效化疗药物（chemotherapeutic agents）。近年来，细胞外调节蛋白激酶（extracellular signal-regulated kinase, ERK）抑制剂已作为抗癌药物应用于临床。因此，本研究合成了22-米卡诺内酯衍生物，经实验证实其在体外具有强效的抗白血病活性。其中，活性米卡诺内酯衍生物3g可通过Ras/Raf/MEK/ERK通路（Ras/Raf/MEK/ERK pathway）发挥强效抗白血病作用：该衍生物可通过抑制细胞分裂周期蛋白25C（CDC25C）的磷酸化阻滞细胞周期，诱导细胞凋亡，并促进DNA与线粒体损伤，提示其有望成为治疗白血病患者的潜在化疗药物。