Lee Hyun-Jung, Kim Jin Sung, Park Se-Young, Suh Myung-Eun, Kim Hwa Jung, Seo Eun-Kyung, Lee Chong-Ock
Division of Medicinal Chemistry, College of Pharmacy, Ewha Woman's University, Seoul 120-750, South Korea.
Bioorg Med Chem. 2004 Apr 1;12(7):1623-8. doi: 10.1016/j.bmc.2004.01.029.
The 6,11-dihydro-pyridazo[2,3-b]phenazine-6,11-dione and 6,11-dihydro-pyrido[2,3-b]phenazine-6,11-dione derivatives were synthesized from 6,7-dichloro-5,8-phthalazinedione and 6,7-dichloro-5,8-quinolinedione, respectively, producing a series of new anticancer drugs. The cytotoxic activities of the prepared compounds were evaluated by a SRB (Sulforhodamine B) assay against the following tumor cell lines: A459 (human lung), SK-OV-3 (human ovarian), SK-MEL-2 (human melanoma), XF498 (human CNS), and HCT 15 (human colon). Almost all the derivatives of the 6,11-dihydro-pyridazo[2[,3-b]phenazine-6,11-dione and 6,11-dihydro-pyrido[2,3-b]phenazine-6,11-dione, tetracyclic heteroquinone analogues with four or three nitrogen atoms, exhibited excellent cytotoxicity on almost all the human tumor cell lines tested. Specifically, 6,11-dihydro-pyridazo[2,3-b]phenazine-6,11-dione (4a) exhibited potent activity against all the tumor cell lines, and in particular, its cytotoxic effect against HCT 15 (ED(50)=0.004 microg/mL) was 25 times greater than that of doxorubicin (ED(50)=0.093 microg/mL).
6,11 - 二氢 - 哒嗪并[2,3 - b]菲嗪 - 6,11 - 二酮和6,11 - 二氢 - 吡啶并[2,3 - b]菲嗪 - 6,11 - 二酮衍生物分别由6,7 - 二氯 - 5,8 - 酞嗪二酮和6,7 - 二氯 - 5,8 - 喹啉二酮合成，从而制备出一系列新型抗癌药物。通过SRB（磺酰罗丹明B）法对所制备化合物针对以下肿瘤细胞系进行细胞毒性活性评估：A459（人肺癌）、SK - OV - 3（人卵巢癌）、SK - MEL - 2（人黑色素瘤）、XF498（人中枢神经系统肿瘤）和HCT 15（人结肠癌）。几乎所有的6,11 - 二氢 - 哒嗪并[2,3 - b]菲嗪 - 6,11 - 二酮和6,11 - 二氢 - 吡啶并[2,3 - b]菲嗪 - 6,11 - 二酮衍生物，即含有四个或三个氮原子的四环杂喹啉类似物，对几乎所有测试的人类肿瘤细胞系均表现出优异的细胞毒性。具体而言，6,11 - 二氢 - 哒嗪并[2,3 - b]菲嗪 - 6,11 - 二酮（4a）对所有肿瘤细胞系均表现出强效活性，尤其是其对HCT 15的细胞毒性作用（ED(50)=0.004μg/mL）比阿霉素（ED(50)=0.093μg/mL）高25倍。
