PO.CH01.07 · 化学
新型磺酰胺-芳香胺杂合物：合成、细胞毒性筛选及抗癌活性的转录组学洞察
Novel sulfonamide-aromatic amine hybrids: Synthesis, cytotoxic screening, and transcriptomic insights into anticancer activity
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
癌症仍然是全球死亡原因之一和一项重大的全球健康挑战。这些挑战归因于药物耐药、肿瘤复杂性和异质性等因素。使用小分子的靶向治疗因其能够选择性抑制癌细胞生长同时最大限度减少脱靶效应而成为一种有前景的方法。在本研究中，我们评估了由3-甲酰基-4-羟基苯磺酰氯（FHS）合成的一系列衍生物对多种癌细胞的细胞毒性作用。目的是鉴定具有强效抗癌活性和良好选择性特征的化合物以供进一步开发。合成过程以FHS为起始原料，经过一系列化学反应生成标记为C3至C10的化合物库。这些化合物通过多种分析技术进行表征，包括熔点测定、氢核磁共振（1H NMR）、碳-13核磁共振（13C NMR）和红外（IR）光谱，以确认其结构完整性。使用磺酰罗丹明B（SRB）测定法评估细胞毒性，应用于一个广泛的癌细胞系panel，分类包括结直肠癌（HT-29、MC38、CT26和COLO 205）、肝癌（C3a和PLC/PRF）、胰腺癌（Suit-2、MiaPaca2、As-PC1、Panc 02.03、CI66）、乳腺癌（MDA-MB-468、MDA-MB-231、BT20、MCF7、4T1、4T1紫杉醇耐药株、JIMT-1、ZR-75-1、E0771、T47D和HCC1806）以及卵巢癌（OVCAR-5）细胞系。测试了正常乳腺上皮细胞系MCF10a以分析安全性。基于SRB测定，7种化合物在多种癌症模型中表现出程度不一但显著的细胞毒性。最有效的化合物C5被选中进行进一步分析，以通过转录组学分析确定其细胞毒性作用的机制。转录组学结果显示对照组与处理组之间有十个基因的log2倍数变化。这些基因与DNA损伤诱导转录本4、FXYD结构域离子转运调节因子4和CHAC1（谷胱甘肽特异性γ-谷氨酰环转移酶1）相关。进一步的体内实验和验证实验正在进行中，以确定对细胞毒性最重要的通路。
查看英文原文 English abstract
Cancer remains one of the causes of mortality worldwide and a major global health challenge. These challenges are attributed to factors such as medication resistance, tumor complexity, and heterogeneity. Targeted therapy with small molecules has emerged as a promising approach due to its ability to selectively inhibit cancer cell growth while minimizing off-target effects. In this study, a series of derivatives synthesized from 3-formyl-4-hydroxy benzene sulfonyl chloride (FHS) were evaluated for their cytotoxic effects on various cancer cells. The objective was to identify compounds with potent anticancer activity and favorable selectivity profiles for further development. The synthesis process began with FHS as the starting material, subjected to a series of chemical reactions to generate a library of compounds labeled C3 through C10. These compounds were characterized by using a combination of analytical techniques, including melting point determination, Proton Nuclear Magnetic Resonance ( 1 H NMR), Carbon-13 Nuclear Magnetic Resonance ( 13 C NMR), and Infrared (IR) spectroscopy to confirm their structural integrity. Cytotoxic effects were evaluated using Sulforhodamine B (SRB) assay for cytotoxicity was applied to an extensive panel of cancer cell lines, categorized into such as colorectal cancer (HT-29, MC38, CT26and COLO 205), hepatic (C3a and PLC/PRF), pancreatic (Suit-2, MiaPaca2, As-PC1 and Panc 02.03, CI66), breast (MDA-MB-468, MDA-MB-231, BT20, MCF7, 4T1, 4T1 paclitaxel resistant, JIMT-1, ZR-75-1, E0771, T47D, and HCC1806) and ovarian (OVCAR-5) cell lines. Normal breast epithelial cell line MCF10a was tested to analyze safety. Based on the SRB assay, 7 compounds exhibited variable but significant cytotoxicity in various cancer models. The most effective compound, C5, was chosen for further analysis to identify mechanism of its cytotoxic effect by transcriptomic analysis. The transcriptomic results showed ten genes with log2 fold change between control and treatment. These genes were related to DNA damage inducible transcript 4, FXYD domain containing ion transport regulator 4 and CHAC1 (glutathione-specific gamma-glutamylcyclotransferase 1). Further in vivo experiments and validation experiments are in progress to determine the most significant pathway for cytotoxicity.
利益披露 Disclosure
M. A. Eltokhy, None..
E. A. Fayed, None..
M. S. Abusaif, None..
A. Ragab, None..
Y. A. Ammar, None..
S. Radwan, None..
S. K. Srivastava, None.