溃疡性结肠炎(uc)是一种肠道慢性非特异性重大难治免疫性疾病，其致结肠癌恶变率高达40%。研究表明TNF-α是抗UC药物研发的重要关键靶点，目前虽已上市靶向TNF-a抗体抑制剂，但临床瓶颈是靶向TNF-α的小分子抗UC抑制剂在国内外基本是空白。申请者前期预研发现，金雀根药用天然植物优势骨架茚酮手性小分子(R)-TML-K-95-10，在除去羰基邻位苯环后显示了针对TNF-α靶点较好的结合作用，但由于在大鼠急性UC模型上仅以75 mg/kg为有效。为增强体内药效和生物利用度，本项目以其作为先导物，鉴于TNF-α的v型结构域的特点，拟运用生物电子等排/骨架跃迁等原理，以增强小分子与TNF-α结合作用为目的，设计合成茚酮单体/二聚体2个系列靶向TNF-α、高效、低毒抗UC口服新型小分子抑制剂；揭示作用模式、机制及对巨噬细胞表型分化和功能影响。一旦实施成功，将推动靶向抗UC天然小分子抑制剂的发现。

Ulcerative colitis (UC) is a kind of chronic nonspecific intestinal major refractory autoimmune disease, colon cancer progression rate is as high as 40%. Research suggests that TNF alpha is a new and hot UC target for drug development, however, small molecules targeting TNF alpha to cure UC is blank. In recent research, applicants found natural indanone chiral molecule (R) - TML - K - 95-10 separated from Caragana sinica Rehd removing the carbonyl adjacent benzene ring shows good effect on TNF alpha. But as a result of the active domain "V" type structure of hydrophobic pocket underused, acute treatment on the UC model in rats and the effect is only 75 mg/kg. Therefore, 2 series (indene monomer and dimer) of (R) - TML - K - 95-10 analogues were synthesized using the principle of bioisosteric replacement/scaffold hoping, from the target design enhance the combination of small molecules and winding glycine etc, targeting TNF alpha to gain high efficiency, low toxicity and effective to UC new small molecule inhibitors; and to reveal their role models, mechanism and its effect on the phenotypic differentiation and function of macrophages. If successful, it would promote the TNF alpha small molecule inhibitors to cure UC with great significance.