State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
J Med Chem. 2010 Mar 25;53(6):2589-600. doi: 10.1021/jm100025u.
Based on the advantages of multitarget drugs for cancer treatment, a new class of naphthalimides was designed, synthesized, and proved to inhibit topoisomerase II (topo II), induced lysosomal membrane permeabilization (LMP), and ultimately caused apoptosis and cell death. The majority of compounds 7a-d and 8a-d potently inhibited the growth of the five tested cancer cell lines with IC(50) values ranging from 2 to 10 microM and are more active than amonafide, a naphthalimide that was in phase III clinical trials. These compounds were tested for their interactions with DNA and their cell-free topo II inhibition activities, which demonstrated these compounds were weak DNA binders but modest topo II inhibitors. Furthermore, compounds 7b-d were found to notably induce LMP and exhibited better antiproliferative activity compared with their single-target analogues. All of the newly synthesized compounds were demonstrated to efficiently induce apoptosis via a mitochondrial pathway. Accordingly, a new paradigm was suggested for the design of novel multitarget anticancer drugs.
基于多靶标药物在癌症治疗方面的优势，设计、合成了一类新的萘酰亚胺类化合物，并证实其能够抑制拓扑异构酶 II（topo II），诱导溶酶体膜通透性（LMP），最终导致细胞凋亡和死亡。大多数化合物 7a-d 和 8a-d 能够强烈抑制五种测试的癌细胞系的生长，IC50 值范围为 2 到 10 μM，比正在进行 III 期临床试验的萘酰亚胺类药物氨萘非特（amonafide）更具活性。这些化合物还进行了与 DNA 的相互作用及其无细胞拓扑异构酶 II 抑制活性的测试，结果表明这些化合物是弱 DNA 结合物，但对拓扑异构酶 II 有一定的抑制作用。此外，还发现化合物 7b-d 能明显诱导 LMP，并表现出比其单靶标类似物更好的抗增殖活性。所有新合成的化合物都被证明能够通过线粒体途径有效地诱导细胞凋亡。因此，提出了一种设计新型多靶标抗癌药物的新范例。
