Wan Qi, Deng Yan, Huang Yaoqing, Yu Zhihui, Wang Chunli, Wang Ke, Dong Jibin, Chen Ying
Department of Medicinal Chemistry School of Pharmacy Fudan University 826, Zhangheng Road Shanghai China.
Department of Pharmacology and Biochemistry School of Pharmacy Fudan University 826, Zhangheng Road Shanghai China.
ChemistryOpen. 2019 Dec 11;9(2):176-182. doi: 10.1002/open.201900228. eCollection 2020 Feb.
Fifteen novel furoxan-based nitric oxide (NO) releasing hybrids of estradiol derivatives were synthesized and evaluated in vitro anti-proliferative activity in MDA-MB-231, A2780, Hela and HUVEC cell lines. Most of them displayed potent anti-proliferative effects. Among the compounds, 4-bromo-3-((phenylsulfonyl)-1,2,5-oxadiazole 2-oxide)-oxy-propoxy-estradiol () exhibited the best activity with IC values of 3.58-0.0008 μM. Preliminary pharmacological studies showed that induced apoptosis and hardly affected the cell cycle of MDA-MB-231 cell line. NO-releasing capacity and inhibition of ERK/MAPK pathway signaling might explain the potent antineoplastic activity of these compounds. The preliminary structure-activity relationship (SAR) showed that steroidal scaffolds with a linker in 3-position were favorable moieties to evidently increase the bioactivities of these hybrids. Overall, these results implied that merited to be further investigated as a promising anti-cancer candidate.
合成了15种基于呋咱并释放一氧化氮（NO）的新型雌二醇衍生物杂化物，并在MDA-MB-231、A2780、Hela和HUVEC细胞系中评估了其体外抗增殖活性。其中大多数表现出强效的抗增殖作用。在这些化合物中，4-溴-3-((苯基磺酰基)-1,2,5-恶二唑2-氧化物)-氧基-丙氧基-雌二醇（）表现出最佳活性，IC值为3.58 - 0.0008 μM。初步药理学研究表明，可诱导MDA-MB-231细胞系凋亡，且几乎不影响其细胞周期。释放NO的能力以及对ERK/MAPK通路信号的抑制可能解释了这些化合物的强效抗肿瘤活性。初步的构效关系（SAR）表明，在3位带有连接基的甾体骨架是明显提高这些杂化物生物活性的有利基团。总体而言，这些结果表明，作为一种有前景的抗癌候选物，值得进一步研究。
