Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, SAS Nagar, Mohali, Punjab 160062, India.
School of Biotechnology, KIIT deemed to be University, Campus-11, Patia, Bhubaneswar, Orissa 751024, India.
Bioorg Chem. 2024 Nov;152:107738. doi: 10.1016/j.bioorg.2024.107738. Epub 2024 Aug 22.
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).
近一半的美国食品和药物管理局批准的药物被发现是基于天然产物（NPs）的灵感开发的。在这里，我们报告了一种新的策略，即支架重叠支架跳跃生物活性黄酮和异黄酮的类似物，并安装药物特权基序，这导致发现了超越原始 NPs 功能效率的抗癌剂。这些类似物，2,3-二芳基-吡啶并嘧啶-4-亚胺/酮，通过腈稳定的季铵𬭩叶立德作为掩蔽合成子和 Pd 催化的活化-芳基化方法有效地合成。与 NPs 相比，这些 NP 类似物表现出不同的功能；对人拓扑异构酶-II（hTopo-II）酶和微管蛋白聚合的双重抑制作用，以及对各种癌细胞系的明显抗增殖作用，包括许多耐药癌细胞。最活跃的化合物 5l 显示出对癌细胞迁移能力的显著抑制作用，并阻断细胞周期中的 G1/S 期转变。化合物 5l 导致各种关键细胞周期调节蛋白的表达模式发生明显变化；上调凋亡蛋白 Bax、Caspase 3 和 p53，下调凋亡抑制蛋白 BcL-xL、Cyclin D1、Cyclin E1 和 NF-κB，表明分子 5l 在凋亡信号轴干扰潜力方面具有高效率。化学信息学分析表明，2,3-二芳基-吡啶并嘧啶-4-亚胺/酮占据了独特的药物相关化学空间，这在天然产物中很少见，具有良好的理化、ADMET 和药代动力学相关特征。总的来说，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-氟尿嘧啶（5-FU）相比，所研究的类似物的抗癌潜力要高效得多。
