类黄酮启发分子骨架覆盖：发现2,3-二芳基吡哌啶-4-亚胺/酮作为双重hTopo-II和微管靶向抗癌药物

Scaffold overlay of flavonoid-inspired molecules: Discovery of 2,3-diaryl-pyridopyrimidin-4-imine/ones as dual hTopo-II and tubulin targeting anticancer agents

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BIOORGANIC CHEMISTRY

影响因子:4.7

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

DOI: 10.1016/j.bioorg.2024.107738

摘要

几乎一半获得的美国食品药品监督管理局（FDA）批准的药物是基于天然产物（NPs）启发而开发的。在此，我们报道了一种新颖的骨架覆盖策略，通过骨架跳跃模拟类似生物活性类黄酮和异黄酮的模拟物，并引入药物特权基序，成功发现了优于原始NPs的抗癌剂。该类模拟物——2,3-二芳基吡哌啶-4-亚胺/酮，通过硝腈稳定的季铵基烯丙基作为掩模合成前体，并采用钯催化的活化-芳基化方法高效合成。与天然产物相比，这些模拟物表现出差异化的功能，包括双重抑制人类拓扑异构酶II（hTopo-II）和微管聚合，及对多种癌细胞系（包括多药耐药细胞）的明显抗增殖作用。最活跃的化合物5l显著抑制癌细胞迁移能力，并阻断细胞周期中的G1/S转换。化合物5l影响多种关键细胞周期调控蛋白的表达；上调凋亡相关蛋白Bax、Caspase 3和p53，下调抑制凋亡的蛋白Bcl-xL、Cyclin D1、Cyclin E1和NF-κB，表明其在凋亡信号通路干扰中具有高效潜力。化学信息学分析显示，2,3-二芳基吡哌啶-4-亚胺/酮占据独特的药物相关化学空间，少见天然产物的代表，具有良好的理化性质、ADMET（吸收、分布、代谢、排泄、毒性）及药代动力学特性。综上，所研究的抗癌模拟物在抗癌效果上优于原始天然产物及两个抗癌药物——依托托品（hTopo-II抑制剂）和5-氟尿嘧啶（5-FU）。

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).