二萜生物碱为乌头属和翠雀属植物特征化学成分，具有显著抗肿瘤活性，但细胞毒性大限制了其开发利用。本申请前期自新疆特有5种乌头属、翠雀属植物中分离鉴定了99个二萜生物碱，筛选发现Deltaline具有抑制乳腺癌细胞增殖效果，但同时对正常细胞杀伤作用明显。利用计算机辅助药物设计，结合多样性修饰策略，通过多轮筛选，发现高效、低毒的新骨架二萜生物碱FY-311，能诱导乳腺癌细胞发生自噬和凋亡，靶向SIRT3调控自噬相关通路可能是该化合物发挥药效的作用机制，也是其毒性降低的原因。由此，本申请拟将FY-311进行合理药物设计和化学修饰，提高其靶向性和有效性，探究其靶向SIRT3在体内外发挥药效的机制。为发现新的靶标明确、机制清晰的天然抗乳腺癌候选药物奠定基础。

Diterpenoid alkaloids are characteristic chemical constituents of Aconitum and Delphinium plants, which have significant antitumor activity. But their development and utilization are limited by the cytotoxicity. In our previous research, ninety-nine diterpenoid alkaloids were isolated from five plants of Aconitum and Delphinium distributed in Xinjiang, China. The screening results showed that Deltaline could inhibit the proliferation of breast cancer cells, but at the same time, it had obvious killing effect on normal cells. Based on this, after structural modifications and several rounds of screening, we discovered a lead compound FY-311, with high efficiency and low toxicity. Targeting SIRT3 to regulate autophagy-related pathways may be the mechanism for the antitumor effect of this compound. Later, we proposed to carry out rational drug design and chemical modification based upon FY-311 to improve its targeting and effectiveness, and explore the mechanism of targeting SIRT3 in vivo and in vitro. In depth studies on the determination of target and mechanism of the most active compound will be conducted, would ground the further development of novel anti-breast cancer drug candidates with clear mechanism and unambiguous target.