3-苯基-1H-吡唑拼接吲哚衍生物的无催化剂合成及抗肺癌活性

Catalyst-free Synthesis and Anti-lung Cancer Activity of 3-Phenyl-1 H-pyrazole-indole Hybrid Derivatives

摘要

为寻找新型抗肺癌活性分子, 以5-苯基-2,4-二氢-3H-吡唑-3-酮、 苯甲醛和吲哚为原料, 通过一锅法反应合成了21个3-苯基-1H-吡唑拼接吲哚衍生物, 其结构通过核磁共振氢谱(¹H NMR)、 核磁共振碳谱(¹³C NMR)和高分辨率质谱(HRMS)表征. 通过体外抗肺癌活性筛选发现, 大多数目标化合物对肺癌A549细胞及A549/DDP细胞具有较好的抑制活性, 其中化合物4n 对耐药株A549/DDP 的半效抑制浓度[IC₅₀=(0.085±0.003) μmol/L]是阳性对照顺铂的29倍. 机制研究结果表明, 化合物4n能够阻滞A549/DDP细胞G₀/G₁期, 并诱导细胞发生凋亡; 分子对接结果表明, 其抗肿瘤活性可能与AKt1, Tubulin及P-gp等靶点有关. 化合物4n可作为后续优化与深入机制研究的抗肺癌候选化合物.

Abstract

In order to discover novel anti-lung cancer agents, a series of 21 novel 3-phenyl-1H-pyrazole-indole hybrid derivatives was designed and synthesized via a one-pot reaction employing 5-phenyl-2,4-dihydro-3H-pyrazol-3-one, benzaldehyde, and indole as starting materials. All synthesized compounds were characterized by means of ¹H NMR, ¹³C NMR and HRMS. In vitro anti-lung cancer activity screening revealed that most of the target compounds exhibited potent inhibitory effects against both the A549 cell line and the A549/DDP cell line. Notably, compound 4n demonstrated exceptional activity against the resistant A549/DDP cells, with an IC₅₀ value of (0.085±0.003) μmol/L, which was 29-fold than the positive control cisplatin. Mechanistic studies indicated that compound 4n significantly arrested the cell cycle of A549/DDP cells at the G₀/G₁ phase and induced apoptosis. Molecular docking results suggested that its antitumor activity may be associated with interactions involving multiple targets, including AKt1, tubulin, and P-gp. Compound 4n represents a promising anti-lung cancer lead candidate for subsequent structural optimization and comprehensive mechanistic investigation.

关键词

吲哚 / 吡唑 / 衍生物 / 抗肺癌活性

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基金资助

贵州省卫生健康委科学技术基金(gzwkj[2026]134)

遵义市科技合作计划([2025]238)

遵义市科技合作计划(CXZX[2025]6)

遵义市科技合作计划(KCTD[2025]90)

遵义医药高等专科学校科研团队建设项目([2026]02)

遵义医药高等专科学校科研团队建设项目([2026]03)