Rexahn Pharmaceuticals, Inc., Rockville, MD 20850, USA.
Bioorg Med Chem. 2012 Feb 1;20(3):1303-9. doi: 10.1016/j.bmc.2011.12.026. Epub 2011 Dec 27.
Based on the anticancer activity of novel quinoxalinyl-piperazine compounds, 1-[(5 or 6-substituted alkoxyquinoxalinyl)aminocarbonyl]-4-(hetero)arylpiperazine derivatives published in Bioorg. Med. Chem.2010, 18, 7966, we further explored the synthesis of 7 or 8-substituted quinoxalinyl piperazine derivatives. From in vitro studies of the newly synthesized compounds using human cancer cell lines, we identified some of the 8-substituted compounds, for example 6p, 6q and 6r, which inhibited the proliferation of various human cancer cells at nanomolar concentrations. Compound 6r, in particular, showed the lowest IC(50) values, ranging from 6.1 to 17nM, in inhibition of the growth of cancer cells, which is better than compound 6k (compound 25 in the reference cited above). In order to select and develop a leading compound among the quinoxaline compounds with substitutions on positions 5, 6, 7 or 8, the compounds comparable to compound 6k in in vitro cancer cell growth inhibition were chosen and their pharmacokinetic properties were evaluated in rats. In these studies, compound 6k showed the highest oral bioavailability of 83.4%, and compounds 6j and 6q followed, with 77.8% and 57.6%, respectively. From the results of in vitro growth inhibitory activities and the pharmacokinetic study, compound 6k is suggested for further development as an orally deliverable anticancer drug.
基于新型喹喔啉-哌嗪化合物的抗癌活性，我们进一步探索了 7 或 8 位取代喹喔啉哌嗪衍生物的合成。从使用人癌细胞系进行的新合成化合物的体外研究中，我们确定了一些 8 位取代的化合物，例如 6p、6q 和 6r，它们在纳摩尔浓度下抑制各种人类癌细胞的增殖。特别是化合物 6r，在抑制癌细胞生长方面显示出最低的 IC50 值，范围为 6.1 至 17nM，优于化合物 6k（上述参考文献中的化合物 25）。为了在具有 5、6、7 或 8 位取代的喹喔啉化合物中选择和开发先导化合物，选择了与化合物 6k 在体外癌细胞生长抑制中相当的化合物，并在大鼠中评估了它们的药代动力学特性。在这些研究中，化合物 6k 表现出最高的口服生物利用度 83.4%，化合物 6j 和 6q 紧随其后，分别为 77.8%和 57.6%。从体外生长抑制活性和药代动力学研究的结果来看，化合物 6k 被认为是进一步开发成可口服的抗癌药物。
