类风湿性关节炎是一种以关节和关节周围组织的非感染性炎症为主的全身性自身免疫性疾病，其致残 率高且治疗棘手，已成为世界公认的难治性疾病。我们在前期的研究中，从中药大红袍中分离 得到50余个新化合物，生物试验中显示出良好的免疫抑制活性和低细胞毒性，其中最新发现的 “Hirtellanine N” 活性优而毒性低。其B细胞抑制活性与环孢菌素相近，而T细胞抑制活性是Hirtellanine A 的五倍，其毒性是环孢菌素的三分之一，因此可作为候选药物进行进一步研究。但前期研究中也发现该化合物具有水溶性低, 稳定性差等缺点, 本课题拟通过对其化学结构的修饰，确定药效基团，建立其构效关系，提高其对T-淋巴细胞的抑制活性、改善水溶性及稳定性；并在动物模型上对其药效学进行验证，为研发拥有自主知识产权的治疗类风湿性关节炎的创新药物提供重要的依据和基础。

Hirtellanine N is an novel isoflavanol isolated from TCM herb Campylotropis hirtellae.The bioassay indicated that Hirteallanine N possess very potent immune suppressive activities. The IC50 of Hirtellanine N for T-cell inhibition is 0.13 µM while the IC50 for B-cell inhibition is 0.26 µM, Compared with cyclosporine, Hirtellanine N had similar activity in B-cell inhibition although it is less active to inhibit the T-cell. However, Hiratellanine N is much less toxic than Cyclosproine, hence, it could be an ideal lead for stracture- activity relation study. This project aim to have an in depth understanding about the SAR of Hirtellanine N. We plan to modify the substitutes on the A ring and B ring of the isoflavane backbone. To examine how the substitutions affect the biological activities. The modification on 3-OH group of Hirtellanine N will be one of the focus of the project, since the 3-OH group is the major cause of the instability of the compound. The T-cell inhibition model will be used as the primary indicator of the activities while the toxicity examined with MTT method will be used as the secondary indicator during the structure modification. The first milestone of the project is to identify the bioactive core of the compound. The further STR studies will be carried out to improve the activity of T-cell inhibition, improve stability and the solubility. After the best compound selected, the early safety assessment and the validation of the effectiveness on animal model will be carried out to identify the probability as the drug candidate for the treatment of Rheumatoid Arthritis.