Fine Chemical and Natural Products Laboratory, Research Institute of Natural Resources and Sustainability José Sánchez Labrador S.J. (IRNASUS-CONICET), School of Chemistry, Catholic University of Córdoba, Córdoba X5016DHK, Argentina.
J Nat Prod. 2020 Jun 26;83(6):1909-1918. doi: 10.1021/acs.jnatprod.0c00115. Epub 2020 Jun 4.
The need for effective candidates as cytotoxic drugs that at the same time challenge cancer multidrug resistance encouraged a search for these in plants of central Argentina. Bioassay-guided fractionation of the cytotoxic extract from led to the isolation of the germacranolide tomenphantin A (), along with three new analogues (-). These efficiently inhibited the proliferation of the leukemia cell lines K562 and CCRF-CEM and their resistant variants, Lucena 1 and CEM/ADR5000, respectively, with IC values ranging from 0.40 to 7.7 μM. The structures and relative configurations of compounds - were elucidated by analysis of the spectroscopic data, in particular NMR spectroscopy. The most active among these was compound (IC = 0.40-5.1 μM), and, therefore, this was selected as a model for a mechanistic study, which revealed that its antiproliferative effect was mediated by cell cycle arrest in the G/M phase followed by apoptosis. The activity of compound was selective, given the absence of cytotoxicity toward peripheral blood mononuclear cells. The results show the potential of these compounds, and in particular of compound , as leads for the development of drug candidates to fight sensitive and resistant leukemia cells.
需要有效的候选药物作为细胞毒性药物，同时挑战癌症多药耐药性，这促使人们在阿根廷中部的植物中寻找这些药物。从具有细胞毒性的提取物中进行基于生物测定的分离，导致分离出倍半萜烯托马品 A（），以及三个新的类似物（-）。这些化合物有效地抑制了白血病细胞系 K562 和 CCRF-CEM 及其耐药变体 Lucena 1 和 CEM/ADR5000 的增殖，IC 值范围为 0.40 至 7.7 μM。通过分析光谱数据，特别是 NMR 光谱，阐明了化合物 - 的结构和相对构型。这些化合物中最活跃的是化合物 （IC = 0.40-5.1 μM），因此选择其作为机制研究的模型，该研究表明其抗增殖作用是通过细胞周期阻滞在 G/M 期后细胞凋亡介导的。鉴于化合物 对外周血单核细胞没有细胞毒性，因此其活性具有选择性。结果表明这些化合物，特别是化合物 ，具有作为开发候选药物的潜力，以对抗敏感和耐药白血病细胞。
