摘要： 磺酰胺类药物因其多样的生物活性（抗癌、抑菌、抗炎等）成为药物开发的热点。课题组前期发现胃泌素释放肽受体（gastrin-releasing peptide receptor， GRPR）抑制剂RH-1402通过抗炎机制减轻顺铂肾毒性。在此研究基础上，通过结构修饰构建5个含磺酰胺基团的新型衍生物（3a-3e），并系统评价其生物活性谱。结果显示，3a和3b对人慢性髓系白血病细胞K562表现出显著的抗增殖活性\[IC50分别为（10.5±1.1） μmol/L和（12.8±2.0） μmol/L\]。衍生物3d不仅对肠球菌表现出优异的抑制作用（MIC=62.5 μg/mL），还可显著缓解顺铂引发的肾损伤，在体外模型中使小鼠肾小管上皮细胞（mRTEC）存活率从基线的50%提升至68.1%±3.2%，并同步下调肾损伤标志物KIM-1及关键炎症因子（TNF-α、IL-6、MCP-1）的表达水平。研究表明，磺酰胺结构的引入成功拓展了RH-1402衍生物的生物活性谱，其中，多效化合物3d兼具抗肿瘤、抑菌及肾保护功能，具备作为多功能候选药物开发的潜力。

关键词： 磺酰胺衍生物,  胃泌素释放肽受体,  RH-1402,  构效关系,  抑菌活性 

Abstract: Sulfonamide drugs have emerged as a hotspot in drug development due to their diverse bioactivities （anticancer, bacteriostatic, anti-inflammatory, and others）. Our previous study identified the gastrin-releasing peptide receptor （GRPR） inhibitor RH-1402 as a renal protectant against cisplatin-induced nephrotoxicity through anti-inflammatory mechanisms. Based on these findings, five novel sulfonamide-containing derivatives （3a-3e） were designed and synthesized through structural modification, followed by a systematic evaluation of their biological profiles. The results revealed that compounds 3a and 3b displayed significant antiproliferative activity against human K562 chronic myeloid leukemia cells \[IC50=（10.5±1.1） μmol/L and （12.8±2.0） μmol/L, respectively\]. Notably, derivative 3d demonstrated remarkable dual functionality: it exhibited potent bacteriostatic activity againstEnterococcus（MIC=62.5 μg/mL） and significantly mitigated cisplatin-induced renal injury. In thein vitromodels, 3d improved the cell viability of murine renal tubular epithelial cells （mRTEC） from 50% to 68.1%±3.2%, while concurrently downregulating the expression of the renal injury marker KIM-1 and key inflammatory cytokines （TNF-α, IL-6, MCP-1）. This study demonstrated that the introduction of the sulfonamide structure successfully expanded the biological activity spectrum of RH-1402 derivatives. Among them, the multifunctional compound 3d exhibited anticancer, bacteriostatic, and nephroprotective properties, making it a promising candidate for further drug development.

Key words: sulfonamide derivatives,  gastrin-releasing peptide receptor,  RH-1402,  structure-activity relationship,  bacteriostatic activity 

收稿日期:

基金资助: 安徽省重点研究与开发计划项目（S202004a06020068）