College of Pharmacy, Catholic University of Daegu, Gyeongsan, Gyeongbuk 712-702, Republic of Korea.
Bioorg Med Chem. 2010 Feb;18(3):1010-7. doi: 10.1016/j.bmc.2009.12.069. Epub 2010 Jan 4.
We synthesized 12 benzoxanthone derivatives classified as three different groups based on the tetracyclic ring shapes and evaluated their pharmacological activities to find potential anticancer agents. In the cytotoxicity test, most compounds showed effective cancer cell growth inhibition against the HT29 and DU145 cell lines. Among the compounds tested, compound 19 was the most effective in the cancer cell lines tested. Compound 9 showed dual inhibitory activities against DNA relaxation by topoisomerases I and II. The% inhibition of compound 9 on topoisomerase I was comparable to that of camptothecin. Compound 9 efficiently blocked topoisomerase II function by almost threefold than etoposide at 20 microM. Compound 19 had selective topoisomerase II inhibitory activity at 100 microM. The DNA cross-linking test revealed that only compounds 8 and 19, which possess epoxy groups, cross-linked DNA duplex, while 14 did not. From the combined pharmacological results, we proposed that the target through which compound 19 inhibits cancer cell growth may be the DNA duplex itself and/or DNA-topoisomerase II complex.
我们合成了 12 种苯并恶嗪酮衍生物，根据四环形状将其分为三组，并评估了它们的药理活性，以寻找潜在的抗癌药物。在细胞毒性试验中，大多数化合物对 HT29 和 DU145 细胞系表现出有效的癌细胞生长抑制作用。在所测试的化合物中，化合物 19 在测试的癌细胞系中最有效。化合物 9 对拓扑异构酶 I 和 II 的 DNA 松弛具有双重抑制活性。化合物 9 对拓扑异构酶 I 的抑制%与喜树碱相当。化合物 9 在 20 μM 时对拓扑异构酶 II 的抑制作用比依托泊苷强近三倍。化合物 19 在 100 μM 时具有选择性拓扑异构酶 II 抑制活性。DNA 交联试验表明，只有具有环氧基团的化合物 8 和 19 才能使 DNA 双链交联，而化合物 14 则不能。根据综合的药理结果，我们提出化合物 19 抑制癌细胞生长的靶标可能是 DNA 双链本身和/或 DNA-拓扑异构酶 II 复合物。
