State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Department of Organic Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
Eur J Med Chem. 2015 Jun 5;97:235-44. doi: 10.1016/j.ejmech.2015.04.057. Epub 2015 Apr 29.
Pyrazine-fused 23-hydroxybetulinic acid was synthesized by introducing a pyrazine ring between C-2 and C-3 position and further modifications were carried out by substitution of C-28 carboxyl group by ester and amide linkage to enhance the antitumor activity. The biological screening results showed that all of the derivatives exhibited more significant antiproliferative activity than the parent compound. In particular compound 12a exhibited the most potent activity with IC50 values of 3.53 μM, 4.42 μM and 5.13 μM against cell lines SF-763, B16 and Hela, respectively. In the preliminary mechanism study, 12a caused cell arrest in G1 phase and significantly induced apoptosis of B16 cells in a dose-dependent manner. Furthermore, the in vivo antitumor activity of 12a was validated (tumor inhibitory ratio of 55.6% and 62.7%, respectively) in mice with H22 liver cancer and B16 melanoma.
吡嗪并 23-羟基白桦酸通过在 C-2 和 C-3 位之间引入吡嗪环进行合成，并通过取代 C-28 羧基为酯和酰胺键进一步进行修饰，以增强抗肿瘤活性。生物筛选结果表明，所有衍生物均表现出比母体化合物更强的增殖抑制活性。特别是化合物 12a 对 SF-763、B16 和 Hela 细胞系的 IC50 值分别为 3.53 μM、4.42 μM 和 5.13 μM，表现出最强的活性。在初步的机制研究中，12a 导致细胞在 G1 期停滞，并以剂量依赖的方式显著诱导 B16 细胞凋亡。此外，在 H22 肝癌和 B16 黑色素瘤小鼠中验证了 12a 的体内抗肿瘤活性（肿瘤抑制率分别为 55.6%和 62.7%）。
