美国食品和药物管理局批准的所有药物中几乎有一半是根据天然产物 (NP) 的灵感开发的。在这里，我们报告了一种新的策略，即生物活性黄酮和异黄酮的支架跳跃类似物的支架覆盖以及药物特权基序的安装，这导致了超越原始纳米颗粒功能效率的抗癌药物的发现。通过腈稳定的季铵叶立德作为掩蔽合成子和 Pd 催化的活化芳基化方法，有效合成了类似物 2,3-二芳基-吡啶并嘧啶-4-亚胺/酮。与 NP 相比，这些 NP 类似物表现出不同的功能；双重抑制人类拓扑异构酶-II (hTopo-II) 酶和微管蛋白聚合，并对多种癌细胞系（包括多种耐药癌细胞）具有显着的抗增殖作用。最活跃的化合物5l对癌细胞的迁移能力表现出显着的抑制作用，并阻断细胞周期中的G1/S期转变。化合物5l对多种关键细胞周期调节蛋白的表达模式产生显着影响；凋亡蛋白 Bax、Caspase 3 和 p53 上调，凋亡抑制蛋白 BcL-xL、Cyclin D1、Cyclin E1 和 NF-κB 下调，这表明分子 5l 在凋亡信号中具有高效率轴干扰潜力。化学信息学分析表明，2,3-二芳基-吡啶并嘧啶-4-亚胺占据了一个独特的药物相关化学空间，该空间很少由天然产物代表，并且具有良好的理化、ADMET 和药代动力学相关特征。总之，我们发现所研究的类似物的抗癌潜力比原始天然产物和两种抗癌药物依托泊苷（hTopo-II 抑制剂）和 5-Flurouracile (5-FU) 更有效。版权所有 © 2024 Elsevier Inc.版权所有。

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).Copyright © 2024 Elsevier Inc. All rights reserved.