基于结构多样性不对称全合成策略进行Lingzhilactone B、Ganoapplanin和Sinensilactam A的全合成、结构优化及生物活性评价

Diabetic nephropathy (DN), also known as diabetic kidney disease, is the chronic loss of kidney function occurring in those with diabetes mellitus. Incidence rate of DN in China is rising and DN has become the secondary cause of end-stage renal disease next to glomerulonephritis. Because of complex metabolic disorder, it is more difficult than other kidney disease to treat once DN develops to end-stage kidney disease. Therefore timely prevention and treatment is of great significance to DN. Oxidative stress is a major cause for diabetic nephropathy. Up-regulation of the key anti-oxidative transcription factor, nuclear factor-erythroid 2-related factor 2(Nrf2), was found to prevent the development of diabetic nephropathy. It’s extremely urgent to discover new Nrf2 activator for DN treatment. Lingzhilactone B、 Ganoapplanin and Sinensilactam A were meroterpenoids isolated from precious medicinal fungus lingzhi could promote Nrf2 activities and inhibit oxidative stress, fibrosis and show no toxicity in rodent experiments, they were potential anti-DN medications. Diversity-oriented asymmetric synthesis strategy will be carried out in this program to design and synthesis Lingzhilactone B、 Ganoapplanin 、Sinensilactam A and their derivatives. After biological evaluation of synthesized compounds, the influence of different substitutes and pharmacophores on the anti-DN activity will be elucidated. Our study will pave the way for the development of potent anti-DN drugs with identified target and good druggability.

糖尿病肾病(DN)是由糖尿病引发的慢性肾功能衰竭疾病，目前已成为导致终末期肾脏病仅次于各种肾小球肾炎的第二位原因。由于DN存在复杂的代谢紊乱现象，一旦发展到终末期肾脏病，往往比其他肾脏疾病的治疗更加棘手，因此及时防治对于延缓DN意义重大。氧化应激是导致DN的一个重要原因，而上调Nrf2可以延缓DN的病情发展，因此寻找新型的Nrf2激活剂用于防治DN迫在眉睫。从珍贵药材灵芝中分离提取的Lingzhilactone B、 Ganoapplanin、Sinensilactam A等化合物能够活化Nrf2 、抑制氧化应激和纤维化，且在小鼠体内无毒性，是潜在的DN防治药物。本项目拟采用结构多样性不对称合成策略，完成天然产物和衍生物的设计与合成。通过活性筛选，揭示化合物中不同取代基、药效团与Nrf2激动活性之间的规律，发现低毒高效的先导化合物。为今后开发作用靶点明确，成药性优良的抗DN药物奠定基础。

糖尿病肾病(DN)是由糖尿病引发的慢性肾功能衰竭疾病，目前已成为导致终末期肾脏病仅次于各种肾小球肾炎的第二位原因。由于DN存在复杂的代谢紊乱现象，一旦发展到终末期肾脏病，往往比其他肾脏疾病的治疗更加棘手，因此及时防治对于延缓DN意义重大。氧化应激是导致DN的一个重要原因，而上调Nrf2可以延缓DN的病情发展，因此寻找新型的Nrf2激活剂用于防治DN迫在眉睫。从珍贵药材灵芝中分离提取的Lingzhilactone B、 Ganoapplanin、Sinensilactam A等化合物能够活化Nrf2 、抑制氧化应激和纤维化，且在小鼠体内无毒性，是潜在的DN防治药物。本项目拟采用结构多样性不对称合成策略，完成天然产物和衍生物的设计与合成。通过活性筛选，揭示化合物中不同取代基、药效团与Nrf2激动活性之间的规律，发现低毒高效的先导化合物。为今后开发作用靶点明确，成药性优良的抗DN药物奠定基础。