渥曼诺龙衍生物对MDA-MB-231乳腺癌细胞的差异效应
Differential Effect of Wortmannolone Derivatives on MDA-MB-231 Breast Cancer Cells.
作者信息
Acuña Ulyana Munoz, Curley Robert W, Fatima Nighat, Ahmed Safia, Chang Leng Chee, DE Blanco Esperanza J Carcache
机构信息
Division of Pharmacy Practice and Science, College of Pharmacy, The Ohio State University, Columbus, OH, U.S.A.
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, U.S.A.
出版信息
Anticancer Res. 2017 Apr;37(4):1617-1623. doi: 10.21873/anticanres.11492.
BACKGROUND/AIM: The survival rate of women diagnosed with triple-negative breast-cancer (TNBC) remains low. Hence, this study aimed at the chemical and biological optimization of furanosteroid derivatives for the treatment of this type of malignancy using TNBC cells.
MATERIALS AND METHODS
Semi-synthetic analogs of wortmannolone () that negatively affected the aberrant pathways in tumor cells were evaluated in hormone-independent breast cancer cells using western blot and cell-cycle analysis.
RESULTS
Wortmannolone derivatization generated NF-ĸB inhibitors as new lead structures for further development. Compound () was found to be the most significantly active lead.
CONCLUSION
Structure-activity analysis in the present study showed that acetylation of the hydroxyl groups and substitution on C3 and C17 of wortmannolone enhanced biological activity. Alpha-substitution of the acetyl group in C3 on ring A (compound ) resulted in ROS inducing effect; however, presence of an acetyl group in β-position of C3 displayed the highest NF-ĸB p65 inhibitory activity (0.60 μM).
背景/目的：被诊断为三阴性乳腺癌（TNBC）的女性患者生存率仍然很低。因此，本研究旨在对呋喃甾类衍生物进行化学和生物学优化，以便使用TNBC细胞来治疗这类恶性肿瘤。
材料与方法
使用蛋白质印迹法和细胞周期分析法，在激素非依赖性乳腺癌细胞中评估了对肿瘤细胞异常途径有负面影响的渥曼青霉素（）的半合成类似物。
结果
渥曼青霉素衍生化产生了NF-κB抑制剂，作为进一步开发的新先导结构。发现化合物（）是活性最显著的先导物。
结论
本研究中的构效分析表明，渥曼青霉素羟基的乙酰化以及C3和C17上的取代增强了生物活性。A环上C3处乙酰基的α取代（化合物）产生了ROS诱导效应；然而，C3的β位存在乙酰基时表现出最高的NF-κB p65抑制活性（0.60 μM）。
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