Abstract：
We have conducted an experimental and computational evaluation of new doxorubicin (4a-c) and β-lapachone (5a-c) analogs. These novel anticancer analogs were previously synthesized, but had not been tested or characterized until now. We have evaluated their antiproliferative and DNA cleavage inhibition properties using breast (MCF-7 and MDA-MB-231) and prostate (PC3) cancer cell lines. Additionally, cell cycle analysis was performed using flow cytometry. Computational studies, including molecular docking, pharmacokinetic properties, and an analysis of DFT and QTAIM chemical descriptors, were performed to gain insights into the electronic structure and elucidate the molecular binding of the new β-lapachone and doxorubicin analogs with a DNA sequence and Topoisomerase II (Topo II)α. Our results show that 4a analog displays the highest antiproliferative activity in cancer cell lines by inducing cell death. We observed that stacking interactions and hydrogen bonding are essential to stabilize the molecule-DNA-Topo IIα complex. Moreover, 4a and 5a analogs inhibited Topo\'s DNA cleavage activity. Pharmacodynamic results indicated that studied molecules have favorable adsorption and permeability properties. The calculated chemical descriptors indicate that electron accumulation in quinone rings is relevant to the reactivity and biological activity. Based on our results, 4a is a strong candidate for becoming an anticancer drug.
摘要：
我们已经对新的阿霉素（4a-c）和β-拉帕酮（5a-c）类似物进行了实验和计算评估。这些新的抗癌类似物是以前合成的，但直到现在还没有经过测试或鉴定。我们已经使用乳腺癌（MCF-7和MDA-MB-231）和前列腺癌（PC3）细胞系评估了它们的抗增殖和DNA切割抑制特性。此外,使用流式细胞术进行细胞周期分析。计算研究,包括分子对接，药代动力学特性，以及DFT和QTAIM化学描述符的分析，进行了深入了解电子结构并阐明了新的β-拉帕康和多柔比星类似物与DNA序列和拓扑异构酶II（TopoII）α的分子结合。我们的结果表明，4a类似物通过诱导细胞死亡在癌细胞系中表现出最高的抗增殖活性。我们观察到堆叠相互作用和氢键对于稳定分子-DNA-TopoIIα复合物至关重要。此外，4a和5a类似物抑制Topo的DNA切割活性。药效学结果表明，所研究的分子具有良好的吸附和渗透性能。计算的化学描述符表明，醌环中的电子积累与反应性和生物活性有关。根据我们的结果,4a是成为抗癌药物的有力候选者。
