Zhang Xian, Cui Keni, Wang Xiaolu, Tong Yuanyuan, Liu Chihong, Zhu Yuechao, You Qidong, Jiang Zhengyu, Guo Xiaoke
State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Antioxidants (Basel). 2023 May 8;12(5):1062. doi: 10.3390/antiox12051062.
Ulcerative colitis (UC) is an idiopathic inflammatory disease of unknown etiology possibly associated with intestinal inflammation and oxidative stress. Molecular hybridization by combining two drug fragments to achieve a common pharmacological goal represents a novel strategy. The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway provides an effective defense mechanism for UC therapy, and hydrogen sulfide (HS) shows similar and relevant biological functions as well. In this work, a series of hybrid derivatives were synthesized by connecting an inhibitor of Keap1-Nrf2 protein-protein interaction with two well-established HS-donor moieties, respectively, via an ester linker, to find a drug candidate more effective for the UC treatment. Subsequently, the cytoprotective effects of hybrids derivatives were investigated, and DDO-1901 was identified as a candidate showing the best efficacy and used for further investigation on therapeutic effect on dextran sulfate sodium (DSS)-induced colitis in vitro and in vivo. Experimental results indicated that DDO-1901 could effectively alleviate DSS-induced colitis by improving the defense against oxidative stress and reducing inflammation, more potent than parent drugs. Compared with either drug alone, such molecular hybridization may offer an attractive strategy for the treatment of multifactorial inflammatory disease.
溃疡性结肠炎（UC）是一种病因不明的特发性炎症性疾病，可能与肠道炎症和氧化应激有关。通过结合两个药物片段以实现共同药理学目标的分子杂交代表了一种新策略。 Kelch样ECH相关蛋白1（Keap1）-核因子红细胞2相关因子2（Nrf2）途径为UC治疗提供了一种有效的防御机制，硫化氢（HS）也具有类似的相关生物学功能。在这项工作中，通过酯连接子分别将Keap1-Nrf2蛋白-蛋白相互作用的抑制剂与两个成熟的HS供体部分连接，合成了一系列杂合衍生物，以寻找对UC治疗更有效的候选药物。随后，研究了杂合衍生物的细胞保护作用，并确定DDO-1901为疗效最佳的候选药物，用于进一步研究其对葡聚糖硫酸钠（DSS）诱导的结肠炎的体内外治疗效果。实验结果表明，DDO-1901可以通过增强抗氧化应激防御能力和减轻炎症来有效缓解DSS诱导的结肠炎，比母体药物更有效。与单独使用任何一种药物相比，这种分子杂交可能为治疗多因素炎症性疾病提供一种有吸引力的策略。
