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 Dimerostemma aspilioides led to the isolation of the germacranolide tomenphantin A (1), along with three new analogues (2–4). 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 IC₅₀ values ranging from 0.40 to 7.7 μM. The structures and relative configurations of compounds 1–4 were elucidated by analysis of the spectroscopic data, in particular NMR spectroscopy. The most active among these was compound 1 (IC₅₀ = 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 G₂/M phase followed by apoptosis. The activity of compound 1 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 1, as leads for the development of drug candidates to fight sensitive and resistant leukemia cells.

中文翻译：

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来自 Dimerostemma asspilioides 的 Germacrane 型倍半萜内酯的细胞毒活性。

需要作为细胞毒性药物同时挑战癌症多药耐药性的有效候选药物，鼓励在阿根廷中部的植物中寻找这些药物。从所述细胞毒性提取物生物测定引导的分级分离Dimerostemma aspilioides导致germacranolide tomenphantin A（的分离1）中，用三种新类似物（沿2 - 4）。它们分别有效抑制白血病细胞系 K562 和 CCRF-CEM 及其抗性变体 Lucena 1 和 CEM/ADR5000 的增殖，IC ₅₀值范围为 0.40 至 7.7 μM。的结构和化合物的相对构型1 - 4通过分析光谱数据，特别是核磁共振光谱来阐明。其中最活跃的是化合物1 (IC ₅₀ = 0.40–5.1 μM)，因此，它被选为机制研究的模型，这表明其抗增殖作用是由细胞周期停滞在 G ₂ / M 期，然后是细胞凋亡。鉴于对外周血单核细胞没有细胞毒性，化合物1的活性是选择性的。结果显示了这些化合物，特别是化合物1的潜力，作为开发候选药物以对抗敏感和抗性白血病细胞的先导物。