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Abstract <p><b>Objective:</b> To discover novel small-molecule anticancer agents, we designed and synthesized a series of structurally diverse 4<i>H</i>-pyran derivatives <b>2a–2g</b> and evaluated their antiproliferative activity against human gastric cancer cells. <b>Methods:</b> A one-pot multicomponent reaction strategy was systematically optimized by screening solvents, catalyst loadings, reaction times, and reactant molar ratios. The optimized protocol—utilizing 4-dimethylaminopyridine (DMAP) as an organocatalyst in ethanol—afforded the target heterocycles under mild conditions within 20 min in high yields (80–91%). Structure–activity relationship (SAR) analysis revealed that the electronic properties and regiochemistry of the phenyl ring substituents heavily dictated both synthetic efficiency and cytotoxicity. <b>Results and Discussion:</b> Notably, the <i>para</i>-fluoro <b>2a</b> and <i>para</i>-methyl <b>2d</b> derivatives exhibited the most potent antiproliferative effects against SGC-7901 cells, with half-maximal inhibitory concentrations (IC<sub>50</sub>) values of 10.81 ± 0.32 and 12.73 ± 0.24 μM, respectively, significantly outperforming the reference flavonoid apigenin (IC<sub>50</sub> = 29.47 ± 0.27 μM). These findings underscore the dual role of electronic effects in modulating chemical reactivity and biological efficacy. <b>Conclusions:</b> establishing a rapid, sustainable synthetic framework and identifying promising lead candidates for preclinical anticancer drug development.</p>

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Design and Synthesis of Structurally Tailored 4H-Pyran Derivatives as Potent Therapeutics for Precision Gastric Cancer Targeting

  • 期刊论文

  • 发表日期：

    2026年6月3日

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  • Shichao Yan,
  • Zuojun Qu,
  • Junpeng Chi,
  • Zhe Xu,
  • Aifeng Yang,
  • Zhen Lv,
  • Hong Li

摘要

Abstract

Objective: To discover novel small-molecule anticancer agents, we designed and synthesized a series of structurally diverse 4H-pyran derivatives 2a–2g and evaluated their antiproliferative activity against human gastric cancer cells. Methods: A one-pot multicomponent reaction strategy was systematically optimized by screening solvents, catalyst loadings, reaction times, and reactant molar ratios. The optimized protocol—utilizing 4-dimethylaminopyridine (DMAP) as an organocatalyst in ethanol—afforded the target heterocycles under mild conditions within 20 min in high yields (80–91%). Structure–activity relationship (SAR) analysis revealed that the electronic properties and regiochemistry of the phenyl ring substituents heavily dictated both synthetic efficiency and cytotoxicity. Results and Discussion: Notably, the para-fluoro 2a and para-methyl 2d derivatives exhibited the most potent antiproliferative effects against SGC-7901 cells, with half-maximal inhibitory concentrations (IC50) values of 10.81 ± 0.32 and 12.73 ± 0.24 μM, respectively, significantly outperforming the reference flavonoid apigenin (IC50 = 29.47 ± 0.27 μM). These findings underscore the dual role of electronic effects in modulating chemical reactivity and biological efficacy. Conclusions: establishing a rapid, sustainable synthetic framework and identifying promising lead candidates for preclinical anticancer drug development.