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<p>A novel series of benzyloxymethyl-substituted imidazo[1,2-a]pyridine derivatives (<b>IPO1-IPO14</b>) was designed, synthesized, and evaluated as potential anticancer agents. The compounds were synthesized via an efficient multistep strategy with satisfactory yields and structurally characterized by comprehensive <sup>1</sup>H, <sup>13</sup>C NMR, and LC-TOF analyses. Antiproliferative activities were evaluated against a panel of human cancer cell lines, including HepG2, A549, PC-3, MDA-MB-231, and MCF-7 cells; A549 non-small cell lung cancer and MDA-MB-231 triple-negative breast cancer cells showed the highest sensitivity. Among the tested compounds, <b>IPO8</b>, <b>IPO9</b>, <b>IPO10</b>, <b>IPO11</b>, and <b>IPO13</b> demonstrated the strongest antiproliferative activity. <b>IPO9</b> emerged as the most potent derivative, displaying significant cytotoxicity against A549 (IC<sub>50</sub> = 3.84&#xa0;µM) and MDA-MB-231 cells (IC<sub>50</sub> = 9.69&#xa0;µM), together with favorable selectivity profiles (SI = 23.02 and 15.31, respectively). Structure–activity relationship analysis revealed that para-alkoxy substitution enhanced antiproliferative potency and selectivity, whereas bulky aromatic or strongly electron-withdrawing substituents reduced biological activity. Mechanistic investigations suggested that the lead derivatives induced mitochondria-mediated intrinsic apoptosis through suppression of BCL-2, induction of Bax expression, elevation of the Bax/BCL-2 ratio, disruption of mitochondrial membrane potential, and activation of caspase-3. Among the tested compounds, <b>IPO9</b> consistently produced the strongest pro-apoptotic effects and, in MDA-MB-231 cells, exhibited more pronounced modulation of several apoptosis-related markers than the positive control doxorubicin. Further molecular docking studies revealed favorable binding interactions of <b>IPO9</b> within the BCL-2 binding pocket, providing computational support for the <i>in vitro</i> findings.</p> Graphical abstract <p></p>

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Synthesis and biological evaluation of benzyloxymethyl-substituted imidazo[1,2-a]pyridines as apoptosis-inducing anticancer agents through modulation of BCL-2/Bax signaling and caspase-3 activation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月26日

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  • Ege Arzuk,
  • İbrahim Pinar,
  • Burak Kuzu

摘要

A novel series of benzyloxymethyl-substituted imidazo[1,2-a]pyridine derivatives (IPO1-IPO14) was designed, synthesized, and evaluated as potential anticancer agents. The compounds were synthesized via an efficient multistep strategy with satisfactory yields and structurally characterized by comprehensive 1H, 13C NMR, and LC-TOF analyses. Antiproliferative activities were evaluated against a panel of human cancer cell lines, including HepG2, A549, PC-3, MDA-MB-231, and MCF-7 cells; A549 non-small cell lung cancer and MDA-MB-231 triple-negative breast cancer cells showed the highest sensitivity. Among the tested compounds, IPO8, IPO9, IPO10, IPO11, and IPO13 demonstrated the strongest antiproliferative activity. IPO9 emerged as the most potent derivative, displaying significant cytotoxicity against A549 (IC50 = 3.84 µM) and MDA-MB-231 cells (IC50 = 9.69 µM), together with favorable selectivity profiles (SI = 23.02 and 15.31, respectively). Structure–activity relationship analysis revealed that para-alkoxy substitution enhanced antiproliferative potency and selectivity, whereas bulky aromatic or strongly electron-withdrawing substituents reduced biological activity. Mechanistic investigations suggested that the lead derivatives induced mitochondria-mediated intrinsic apoptosis through suppression of BCL-2, induction of Bax expression, elevation of the Bax/BCL-2 ratio, disruption of mitochondrial membrane potential, and activation of caspase-3. Among the tested compounds, IPO9 consistently produced the strongest pro-apoptotic effects and, in MDA-MB-231 cells, exhibited more pronounced modulation of several apoptosis-related markers than the positive control doxorubicin. Further molecular docking studies revealed favorable binding interactions of IPO9 within the BCL-2 binding pocket, providing computational support for the in vitro findings.

Graphical abstract