Chemical Biology Laboratory, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 607, India.
Bioorg Med Chem. 2010 Jan 15;18(2):526-42. doi: 10.1016/j.bmc.2009.12.015. Epub 2009 Dec 11.
A series of novel quinazolinone linked pyrrolobenzodiazepine (PBD) conjugates were synthesized. These compounds 4a-f and 5a-f were prepared in good yields by linking C-8 of DC-81 with quinazolinone moiety through different alkane spacers. These conjugates were tested for anticancer activity against 11 human cancer cell lines and found to be very potent anticancer agents with GI(50) values in the range of <0.1-26.2microM. Among all the PBD conjugates, one of the conjugate 5c was tested against a panel of 60 human cancer cells. This compound showed activity for individual cancer cell lines with GI(50) values of <0.1microM. The thermal denaturation studies exhibited effective DNA binding ability compared to DC-81 and these results are further supported by molecular modeling studies. The detailed biological aspects of these conjugates on A375 cell line were studied. It was observed that compounds 4b and 5c induced the release of cytochrome c, activation of caspase-3, cleavage of PARP and subsequent cell death. Further, these compounds when treated with A375 cells showed the characteristic features of apoptosis like enhancement in the levels of p53, p21 and p27 inhibition of cyclin dependent kinase-2 (CDK2) and suppression of NF-kappaB. Moreover, these two compounds 4b and 5c control the cell proliferation by regulating anti-apoptotic genes like (B-cell lymphoma 2) Bcl-2. Therefore, the data generated suggests that these PBD conjugates activate p53 and inhibit NF-kappaB and thereby these compounds could be promising anticancer agents with better therapeutic potential for the suppression of tumours.
合成了一系列新型喹唑啉酮连接的吡咯并苯二氮杂卓（PBD）缀合物。通过将 DC-81 的 C-8 与不同的烷烃间隔物连接的喹唑啉酮部分，以良好的收率制备了这些化合物 4a-f 和 5a-f。这些缀合物针对 11 个人类癌细胞系进行了抗癌活性测试，发现它们是非常有效的抗癌剂，GI（50）值在<0.1-26.2μM 的范围内。在所有的 PBD 缀合物中，对其中一个缀合物 5c 进行了针对 60 个人类癌细胞系的测试。该化合物对个别癌细胞系具有活性，GI（50）值<0.1μM。与 DC-81 相比，热变性研究显示出有效的 DNA 结合能力，这些结果进一步得到了分子建模研究的支持。对 A375 细胞系进行了这些缀合物的详细生物学研究。结果表明，化合物 4b 和 5c 诱导细胞色素 c 的释放，激活 caspase-3，PARP 的切割以及随后的细胞死亡。此外，当用 A375 细胞处理这些化合物时，显示出凋亡的特征，如 p53、p21 和 p27 的水平升高，细胞周期蛋白依赖性激酶-2（CDK2）的抑制和 NF-kappaB 的抑制。此外，这两种化合物 4b 和 5c 通过调节抗凋亡基因（如 B 细胞淋巴瘤 2）Bcl-2 来控制细胞增殖。因此，产生的数据表明，这些 PBD 缀合物激活 p53 并抑制 NF-kappaB，从而这些化合物可能是具有更好的治疗潜力的有前途的抗癌剂，可用于抑制肿瘤。
