Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China.
Bioorg Med Chem Lett. 2011 Sep 15;21(18):5251-4. doi: 10.1016/j.bmcl.2011.07.038. Epub 2011 Jul 19.
Sophoridine (1), a natural anticancer drug, has been used in China for decades. A series of novel N-substituted sophoridinic acid derivatives were synthesized and evaluated for their cytotoxicity with 1 as the lead. The structure-activity relationship indicated that introduction of an aliphatic acyl on the nitrogen atom might significantly enhance the anticancer activity. Among the compounds, 6b bearing bromoacetyl side-chain afforded a potential effect against four human tumor cell lines (liver, colon, breast, and lung). The mechanism of action of 6b is to inhibit the activity of DNA topoisomerase I, followed by the S-phase arrest and then cause apoptotic cell death, similar to that of its parent 1. We consider 6b promising for further anticancer investigation.
槐定碱（1）是一种天然抗癌药物，在中国已使用了几十年。我们以 1 为先导化合物，合成了一系列新型的 N-取代槐定堿酸衍生物，并对其细胞毒性进行了评价。构效关系表明，在氮原子上引入脂肪酰基可能会显著增强抗癌活性。在所合成的化合物中，带有溴乙酰侧链的 6b 对四种人肿瘤细胞系（肝、结肠、乳腺和肺）具有潜在的作用。6b 的作用机制是抑制 DNA 拓扑异构酶 I 的活性，随后 S 期停滞，然后导致细胞凋亡死亡，与母核 1 相似。我们认为 6b 具有进一步抗癌研究的潜力。
