类黄酮启发的分子的脚手架叠加层：发现2,3-二甲吡啶-4-氨基/胺作为双HTOPO-II和微管蛋白靶向抗癌药物
Scaffold overlay of flavonoid-inspired molecules: Discovery of 2,3-diaryl-pyridopyrimidin-4-imine/ones as dual hTopo-II and tubulin targeting anticancer agents
影响因子:4.70000
分区:医学2区 / 有机化学1区 生化与分子生物学2区
发表日期:2024 Nov
作者:
Meenu Saini, Subarno Paul, Ayan Acharya, Sushree Subhadra Acharya, Chanakya Nath Kundu, Sankar K Guchhait
摘要
已经发现，在美国食品和药物管理局批准的所有药物中，几乎一半是根据天然产品（NP）的灵感开发的。在这里，我们报告了一种新型的生物活性黄酮类似脚手架类似物的脚手架的策略，并安装了药物挑战的基序，这导致发现了超过原始NPS功能效率的抗癌药物。类似物，2,3-二亚吡啶吡啶-4- imine/imine/一个是通过硝化剂稳定的Quaternary immonium ylide有效合成的，因为掩盖的合成和PD催化激活的激活方法。与NP相比，这些NP-Analogs表现出分化的功能。双重抑制人拓扑异构酶II（HTOPO-II）酶和微管蛋白聚合，以及针对各种癌细胞系的明显抗增殖作用，包括许多耐药性癌细胞。最活跃的化合物5L表现出对癌细胞迁移能力的显着抑制，并阻止了细胞周期中的G1/S相变。化合物5L在各种钥匙细胞周期调节蛋白的表达模式中引起明显的影响。凋亡蛋白，Bax，caspase 3和p53的上调，以及抑制凋亡蛋白的下调，BCL-XL，Cyclin D1，Cyclin E1和NF-κB，这表明分子5L在凋亡轴信号轴线的效率上的高效率。化学信息学分析表明，2,3-二芳基-吡啶蛋白-4-氨基胺/含有独特的与药物相关的化学空间，很少以天然产物和良好的物理化学，ADMET，ADMET和药代动力学相关的特征来代表。与原始天然产物和两种抗癌药物，依托泊苷（HTOPO-II抑制剂）和5-氟尿劳（5-FU）相比，发现所研究类似物的抗癌潜力更为有效。
Abstract
Almost half of all medicines approved by the U.S. Food and Drug Administration have been found to be developed based on inspiration from natural products (NPs). Here, we report a novel strategy of scaffold overlaying of scaffold-hopped analogs of bioactive flavones and isoflavones and installation of drug-privileged motifs, which has led to discovery of anticancer agents that surpass the functional efficiency of the original NPs. The analogs, 2,3-diaryl-pyridopyrimidin-4-imine/ones were efficiently synthesized by an approach of a nitrile-stabilized quaternary ammonium ylide as masked synthon and Pd-catalyzed activation-arylation methods. Compared to the NPs, these NP-analogs exhibited differentiated functions; dual inhibition of human topoisomerase-II (hTopo-II) enzyme and tubulin polymerization, and pronounced antiproliferative effect against various cancer cell lines, including numerous drug-resistant cancer cells. The most active compound 5l displayed significant inhibition of migration ability of cancer cells and blocked G1/S phase transition in cell cycle. Compound 5l caused pronounced effect in expression patterns of various key cell cycle regulatory proteins; up-regulation of apoptotic proteins, Bax, Caspase 3 and p53, and down-regulation of apoptosis-inhibiting proteins, BcL-xL, Cyclin D1, Cyclin E1 and NF-κB, which indicates high efficiency of the molecule 5l in apoptosis-signal axis interfering potential. Cheminformatics analysis revealed that 2,3-diaryl-pyridopyrimidin-4-imine/ones occupy a distinctive drug-relevant chemical space that is seldom represented by natural products and good physicochemical, ADMET and pharmacokinetic-relevant profile. Together, the anticancer potential of the investigated analogs was found to be much more efficient compared to the original natural products and two anticancer drugs, Etoposide (hTopo-II inhibitor) and 5-Flurouracile (5-FU).