SIRT2选择性激活剂的设计合成及活性评价

Sirtuin family is a group of NAD dependent histone deacetylases, and the functions of Sirtuins are implicated to cell metabolism, longevity and aging. As an important member of this family, SIRT2 deacetylates a series of protein substrates, such as α-tubulin, p53 and FOXO, and subsequently regulates related cellular activities, such as, mitosis, apoptosis and autophagy. Recently, SIRT2 attracted a lot of attention as it is reported to function of maintaining genome integrity, and SIRT2 knock-out mice are proved to have a much higher chance to develop various kinds of tumors compared to wild type mice. Therefore, the development of SIRT2 activator will be a very interesting strategy to prevent cancer..In the development of SIRT2 activator, we decided to screen a library of natural products against SIRT1/2/3. The fundamental aim of our screening is to lead several compounds that are able to activate SIRT2. The screening showed a series of isoflavones, such as, daidzein, as SIRT2 activators. Thus, daidzein was used as the core scaffold to discover the basic SAR for selective SIRT2 activation. Meanwhile, a known SIRT1 activator SRT1720 was reported with a moderate SIRT2 activation activity. SRT1720 was split to two heterocyclic rings being as the model to develop a library of fragments. The SAR information derived from the natural products and SRT1720 based fragments will be combined together to design novel SIRT2 selective activators. The active SIRT2 activators will be applied to a mice DMBA/TPA-induced skin tumorigenesis assay to evaluate the activity to prevent cancer.

SIRT2参与调控细胞有丝分裂、凋亡与自噬。最新研究证实：SIRT2能够维持生物体的基因组稳定，SIRT2基因敲除小鼠的肿瘤发生率远高于野生型小鼠。因此，激活SIRT2在延缓和抑制肿瘤发生方面具有重要功能。目前SIRT2选择性激活剂的设计与合成尚无报道，制备SIRT2选择性激活剂将为SIRT2的功能研究提供工具分子，为癌症化学预防的新药研究提供先导化合物。.本研究通过从(1)天然产物库中筛选SIRT2激活剂并探讨其核心结构与SIRT2选择性激活的构效关系，(2)探讨已知的SIRT1激活剂SRT1720(具有中等的SIRT2激活活性)的不同环系激活SIRT2的SAR，之后整合来源于上述不同先导物结构的SAR信息，设计优化合成新型小分子SIRT2选择性激活剂，并评价SIRT2激活剂对易致癌模型小鼠的保护作用。

SIRT2参与调控细胞有丝分裂、凋亡与自噬。SIRT2能够维持生物体的基因组稳定，SIRT2基因敲除小鼠的肿瘤发生率远高于野生型小鼠。因此，激活SIRT2在延缓和抑制肿瘤发生方面具有重要功能。SIRT2激活剂可以为癌症化学预防类新药研究提供候选药物。本研究完成以下工作 (1) 收集25个色原酮类天然产物，合成了62个色原酮类化合物； (2) 以Sirtris Pharmaceuticals公司的SIRT1激活剂-STR1720为参考化合物，设计、合成约90个小分子杂环化合物； (3) 筛选评价这150个化合物激活SIRT2活性的构效关系； (4) 根据活性筛选结果，选取1个SIRT2激活剂作为候选化合物，进行小鼠体内癌症预防模型的评价研究。.候选化合物小鼠口服给药实验的结果表明，候选化合物对易致癌小鼠模型具有良好的保护作用，经过6个月的连续DMBA/TPA小鼠皮肤涂抹致瘤实验后，不给药的对照组小鼠平均皮肤瘤为8.6个/只，阳性药物赛来昔布组（250mg/kg）小鼠平均皮肤瘤为13.3个/只。令人惊喜的是，候选化合物给药组（100mg/kg）小鼠平均皮肤瘤为5.1个/只，具明显的统计学差异（P<0.001）。候选化合物表现出非常明显的小鼠皮肤易致癌模型的保护活性。.本研究课题完成了既定的考核指标，获取的候选化合物具有明显的小鼠皮肤易致癌模型的保护活性，将进一步开发其作为具有临床价值的肿瘤预防药物。