石蒜碱是药用石蒜科植物的有效成分之一,是重要的异喹啉类生物碱.石蒜碱拥有刚性的环系骨架、连续的手性中心、三级胺等独特的化学结构特征.同时其药理活性丰富多样,近年来,针对其抗癌、抗病毒、抗炎、抗寄生虫、抑制乙酰胆碱酯酶活性的研究越来越多,尤其在抗癌、抗病毒方面石蒜碱表现出较大潜力,特别是新型冠状病毒SARS-CoV-2研究.石蒜碱各种药理活性的作用机制复杂且新颖,是当前的研究热点.为了更好地梳理有关石蒜碱的研究进展,为其机制探讨和结构修饰提供思路,本文着眼于石蒜碱的药理活性和构效关系进行了系统的总结.

含笑内酯是来自天然植物的愈创木烷型倍半萜内酯,具有多重药理作用.近年来,为了提高含笑内酯的生物活性和血药浓度,对其结构进行了大量修饰与改造,发现了一系列活性优于含笑内酯以及更具成药性研究的含笑内酯衍生物.本文总结了含笑内酯作用机制、结构修饰、生物活性及构效关系的相关研究进展.

Objective: Parthenolide (PTL) induces anti-tumor effects via the nuclear factor kappa B (NF-κB) signaling pathway. MCL3, a PTL derivative, is a sesquiterpene lactone synthesized by the rearrangement and subsequent oxidation of PTL. The aim of this study was to elucidate the antitumor activity and mechanism of action of MCL3 in glioblastoma (GBM). Materials and Methods: The effects of MCL3 on G422 cell proliferation, apoptosis, invasion, and angiogenesis in vitro were measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometry, the cell invasion, and tube formation assays. The subcutaneously transplanted G422 xenograft model was used to detect the effect of MCL3 on tumor growth in vivo. Pathological changes were analyzed by immunohistochemical staining. The effects of MCL3 on NF-κB and Stat3 transcriptional activities were examined using a dual-luciferase reporter assay. Protein levels related to the NF-κB/ interleukin (IL)-6/Stat3 signaling pathway were determined using western blot analysis. Results: MCL3 inhibited GBM cell proliferation, invasion, and angiogenesis in a concentration-dependent manner. Moreover, MCL3 decreased the transcriptional activities of NF-κB and Stat3. MCL3 suppressed tumor growth in the subcutaneously transplanted G422 xenograft model, while the inhibition rate was 79% in tumor weight at 40.0 mg/kg. MCL3 blocked the NF-κB/IL-6/Stat3 signaling pathway in G422 cells and tumor tissues, resulting in the downregulation of Stat3 target genes related to apoptosis, invasion, etc., Conclusion: The results show that MCL3 might inhibit G422 GBM growth partly due to the inhibition of the NF-κB/IL-6/Stat3 signaling pathway.

An efficient and mild method has been developed for the amination of β-methoxy amides (γ-lactones) including natural products michelolide, costunolide and parthenolide derivatives by using lithium chloride in good yields. This reaction is applicable to a wide range of substrates with good functional group tolerance. Mechanism studies show that the reactions undergo a LiCl promoted MeOH elimination from the substrates to form the corresponding α,β-unsaturated intermediates followed by the Michael addition of amines.

BACKGROUND:For decades, a great deal of research work has been done to synthesize ellipticine and its derivatives because of their potential antitumor properties and anti-HIV activities. However, the resonance structures in different media, a low level of solubility at physiological pH and systemic toxicity have prevented the use of ellipticine as a therapeutic agent. Besides, the low yield and complex steps of ellipticine synthesis limit its application. METHODS:A high-yield synthetic procedure of ellipticine has been optimized, and the total yield was up to 50% without silica gel column chromatography. Novel hexacyclic ellipticine derivatives were synthesized by coupling ellipticine with o-aminobenzoic acid. Their cytotoxicities against HCT116, MGC803, HT29 and MCF-7 tumor cells were evaluated. RESULTS:The synthesis process of ellipticine was optimized, and the total yield of the synthetic route was increased to 50% through several operation steps optimization. Fourteen ellipticine hexacyclic derivatives were synthesized. The synthetic compounds were screened for anti-tumor activity in vivo and in vitro, and some of the derivatives had good anti-tumor activity. CONCLUSION:Compared with ellipticine, the compound 1l showed higher antitumor activity and better tolerance to tumor models. The compound 1l treatment increased the percentage of late apoptotic cells from 3.1% (DMSO) to 21.6% (20.0 μM) in NCI-H460 cells. It also was observed the effect of 1l on G2 phase arrest was similar as that of ellipticine. The mechanism of action indicated compound 1l could be a topoisomerase IIα poison. These studies provided the basis for the pharmacodynamics and toxicology of ellipticine, and further clarifies the structureactivity relationship of antitumor activity of ellipticine.