Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, PR China; Department of Allergy, The Third Affiliated Hospital of Shenzhen University, Shenzhen 518020, PR China.
Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, PR China.
Eur J Med Chem. 2018 May 10;151:158-172. doi: 10.1016/j.ejmech.2018.03.072. Epub 2018 Mar 27.
Fifty 1,3-dioxyxanthone nitrates (4a ∼ i-n, n = 1-6) were designed and synthesized based on molecular similarity strategy. Incorporation of nitrate into 1,3-dioxyxanthones with electron-donating groups at 6-8 position brought about synergistic anticancer effect. Among them, compound 4g-4 was confirmed the most active agent against HepG-2 cells growth with an IC of 0.33 ± 0.06 μM. It dose-dependently increased intramolecular NO levels. This activity was attenuated by either NO scavenger PTIO or mitochondrial aldehyde dehydrogenase (mtADH) inhibitor PCDA. Apoptosis analysis indicated different contributions of early/late apoptosis and necrosis to cell death for different dose of 4g-4. 4g-4 arrested more cells on S phase. Results from Western Blot implied that 4g-4 regulated p53/MDM2 to promote cancer cell apoptosis. All the evidences support that 4g-4 is a promising anti-cancer agent.
基于分子相似性策略，设计并合成了 50 种 1,3-二氧杂蒽酮硝酸盐（4a-i-n，n=1-6）。在 6-8 位带有供电子基团的 1,3-二氧杂蒽酮中引入硝酸盐，带来了协同的抗癌作用。其中，化合物 4g-4 被证实对 HepG-2 细胞生长的抑制活性最强，IC 为 0.33±0.06 μM。它剂量依赖性地增加了内源性 NO 水平。该活性可被 NO 清除剂 PTIO 或线粒体乙醛脱氢酶（mtADH）抑制剂 PCDA 减弱。凋亡分析表明，不同剂量的 4g-4 对细胞死亡的早/晚期凋亡和坏死有不同的贡献。4g-4 将更多的细胞阻滞在 S 期。Western Blot 结果表明，4g-4 通过调节 p53/MDM2 促进癌细胞凋亡。所有证据都表明，4g-4 是一种很有前途的抗癌药物。
