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Diversity Modification and Structure-Activity Relationships of Two Natural Products 1β-hydroxy Alantolactone and Ivangustin as Potent Cytotoxic Agents

机译:两种天然产物1β-羟基丙内酯和伊万古斯丁作为有效的细胞毒剂的多样性修饰和结构-活性关系

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摘要

Sesquiterpene lactones (STLs) are a class of plant secondary metabolites widely found in nature with potent antitumor activities. In this work, two isolated STLs 1β-hydroxy alantolactone (>1) and ivangustin (>2) were derivatized through diversity-oriented strategy, and in vitro cytotoxic activity assessments were conducted against six cell lines including HeLa, PC-3, HEp-2, HepG2, CHO and HUVEC. The cytotoxic structure-activity relationship showed that the double bond between C5 and C6 was beneficial to improve activity; C1-OH oxidized derivatives showed a slight stronger activity, comparable to the positive drug etoposide (VP-16). Yet, C1-OH esterified derivatives decreased the potency which were different from those of 1-O-acetylbritannilactone (ABL) reported previously by us, and C13-methylene reductive and spiro derivatives resulted in almost complete ablation of cytotoxic activity. Mechanistic basis of cytotoxicity of the representative compound >1i was assayed to relate with apoptosis and cell cycle arrest. Furthermore, >1i inhibited TNF-α-induced canonical NF-κB signaling in PC-3 cells. Molecular modeling studies exhibited additional hydrogen bond interaction between >1i and the residue Lys37 of p65, indicating that >1i could form covalent protein adducts with Cys38 on p65.
机译:倍半萜内酯(STL)是一类植物次生代谢产物,在自然界广泛发现,具有强大的抗肿瘤活性。在这项工作中,两个分离的STLs1β-羟基丙内酯(> 1 )和伊万古斯丁(> 2 )通过以多样性为导向的策略衍生化,并针对其进行了体外细胞毒活性评估六种细胞系,包括HeLa,PC-3,HEp-2,HepG2,CHO和HUVEC。细胞毒性构效关系表明,C5和C6之间的双键有利于提高活性。与阳性药物依托泊苷(VP-16)相比,C1-OH氧化的衍生物显示出稍强的活性。然而,C1-OH酯化的衍生物降低了效能,这与我们先前报道的1-O-乙酰基溴化内酯(ABL)有所不同,C13-亚甲基还原和螺环衍生物几乎完全消除了细胞毒性。测定了代表性化合物> 1i 的细胞毒性机理,与细胞凋亡和细胞周期阻滞有关。此外,> 1i 抑制了PC-3细胞中TNF-α诱导的经典NF-κB信号传导。分子模型研究显示> 1i 与p65残基Lys37之间存在额外的氢键相互作用,表明> 1i 可以与p65上的Cys38形成共价蛋白加合物。

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