PO.CH01.07 · 化学
功能化内酰胺的立体控制合成及其作为潜在抗三阴性乳腺癌药物的评价
Stereocontrolled synthesis and evaluation of functionalized lactams as potential anti-triple-negative breast cancer agents
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摘要 Abstract
中文摘要
三阴性乳腺癌（TNBC）是一种侵袭性亚型，约占病例的10-15%，其特征为ER、PR和HER2缺失，导致治疗手段有限。化疗耐药和肿瘤异质性凸显了对新型小分子药物的需求。药物化学家指出，立体中心可增强药物潜力；因此，如内酰胺这类手性含氮环状化合物备受重视。在此，我们报道了带有四个连续立体中心的功能化内酰胺的合成及其针对TNBC模型的抗癌评价。采用多样性导向的合成策略生成了40种结构各异的内酰胺。使用MTT法筛选这些化合物对三种TNBC细胞系（MDA-MB-231、BT-549和4T1）及一种正常乳腺上皮细胞系（MCF10A）的细胞毒性。通过克隆形成、划痕愈合、ROS和Boyden小室实验评估细胞生长和迁移。对癌细胞具有强细胞毒性而对MCF10A毒性低的化合物被选作进一步分析。通过免疫印迹和免疫荧光检测凋亡标志物以获得机制数据。使用SwissADME进行药代动力学和类药性预测。多种内酰胺表现出强效的抗增殖活性，IC₅₀值达亚微摩尔水平，鉴定出W11、W12和W23活性最强，其IC₅₀值在4T1中分别为（28.8、40.8和28.4）μM；在MDA-MB-231中分别为（40.7、38.7和21.6）μM；在BT-549中分别为（22.2、28.7和28.6）μM。以顺铂为对照，先导化合物W11、W12和W23显著且呈剂量依赖性地降低了ROS、克隆形成能力和迁移，提示其具有抗转移潜力。W11的EC₅₀最低（约23μM），而W12、W23和顺铂的EC₅₀值约为30-34μM。这些结果表明先导化合物可降低细胞活力并损害TNBC细胞的运动能力。机制研究揭示了凋亡通路的强烈激活。SwissADME预测其具有高胃肠道吸收、最佳的亲脂性（LogP<5）、符合Lipinski规则以及良好的生物可降解性。本研究鉴定出内酰胺W011、W012和W023作为TNBC有前景的小分子候选药物。它们对凋亡及其他通路（如ROS诱导）的调控，加上良好的预测药代动力学特征，支持进一步的临床前优化及向靶向TNBC治疗的开发。
查看英文原文 English abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype compromising ~ 10-15% of cases and defined by loss of ER, PR, and HER2, leading to limited therapies. Chemoresistance and tumor heterogeneity underscore the need for new small-molecule agents. Medicinal chemists note that stereocenters enhance drug potential; thus, chiral N-based cyclic compounds like lactams are valued. Here, we report the synthesis and anticancer evaluation of functionalized lactams bearing four contiguous stereocenters against TNBC models.A diversity-oriented synthesis strategy generated 40 structurally varied lactams. Compounds were screened for cytotoxicity against three TNBC (MDA-MB-231, BT-549, and 4T1) and one normal breast epithelial (MCF10A) cell lines using MTT assay. Clonogenic, wound-closure, ROS and Boyden chamber assays assessed growth and migration. Compounds with strong cancer-cell cytotoxicity and low MCF10A toxicity were selected for further analysis. Mechanistic data were obtained via immunoblotting and immunofluorescence for apoptosis markers. SwissADME was used for pharmacokinetic and drug-like predictions.Multiple lactams showed potent antiproliferative activity with sub-micromolar IC₅₀ values, identifying W11, W12, and W23 as the most active, with IC₅₀ values of (28.8, 40.8, and 28.4) μM in 4T1; (40.7, 38.7, and 21.6) μM in MDA-MB-231; and (22.2, 28.7, and 28.6) μM in BT-549. Lead compounds W11, W12, and W23 with cisplatin as control, significantly and dose-dependently reduced ROS, clonogenicity and migration, indicating anti-metastatic potential. W11 had the lowest EC₅₀ (~23 µM), while W12, W23, and cisplatin showed EC₅₀ values around 30-34 µM. These results indicate that the lead compounds reduce viability and impair TNBC cell motility. Mechanistic studies revealed robust activation of apoptosis pathways. SwissADME predicted high GI absorption, optimal lipophilicity (LogP<5), Lipinski compliance, and favorable biodegradability.This study identifies lactams W011, W012, and W023 as promising small-molecule candidates for TNBC. Their modulation of apoptotic and other pathways such as ROS-induction, along with favorable predicted pharmacokinetics, supports further preclinical optimization and development toward targeted TNBC therapy.
利益披露 Disclosure
L. Rahimian, None..
T. Omolekan, None..
O. Dutta, None..
K. Kousoulas, None..
T. Beng, None..
J. Chamcheu, None.