Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
Bioorg Med Chem. 2011 Mar 15;19(6):1987-98. doi: 10.1016/j.bmc.2011.01.055. Epub 2011 Feb 2.
A series of N-mustard-quinazoline conjugates was synthesized and subjected to antitumor studies. The N-mustard pharmacophore was attached at the C-6 of the 4-anilinoquinazolines via a urea linker. To study the structure-activity relationships of these conjugates, various substituents were introduced to the C-4 anilino moiety. The preliminary antitumor studies revealed that these agents exhibited significant antitumor activity in inhibiting various human tumor cell growths in vitro. Compounds 21b, 21g, and 21h were selected for further antitumor activity evaluation against human breast carcinoma MX-1 and prostate PC-3 xenograft in animal model. These agents showed 54-75% tumor suppression with low toxicity (5-7% body-weight changes). We also demonstrate that the newly synthesized compounds are able to induce DNA cross-linking through alkaline agarose gel shift assay and inhibited cell cycle arrest at G2/M phase.
合成了一系列 N-芥喹唑啉缀合物，并进行了抗肿瘤研究。N-芥类药通过脲键连接到 4-苯胺基喹唑啉的 C-6 上。为了研究这些缀合物的构效关系，在 C-4 苯胺部分引入了各种取代基。初步的抗肿瘤研究表明，这些化合物在体外抑制各种人肿瘤细胞生长方面表现出显著的抗肿瘤活性。选择化合物 21b、21g 和 21h 进一步评估其对动物模型中人乳腺癌 MX-1 和前列腺 PC-3 异种移植物的抗肿瘤活性。这些药物表现出 54-75%的肿瘤抑制作用，且毒性低（体重变化 5-7%）。我们还证明，新合成的化合物能够通过碱性琼脂糖凝胶电泳迁移率实验诱导 DNA 交联，并抑制细胞周期停滞在 G2/M 期。
