Maeruines A-E，从Maerua siamensis茎中提取的难以捉摸的吲哚生物碱及其对环氧合酶和HT-29结直肠癌细胞增殖的抑制作用

Maeruines A-E, elusive indole alkaloids from stems of Maerua siamensis and their inhibitory effects on cyclooxygenases and HT-29 colorectal cancer cell proliferation

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PHYTOCHEMISTRY

影响因子:3.4

分区:生物学2区 / 生化与分子生物学2区植物科学2区

发表日期:2025 Jan

作者: Sasiwimon Nukulkit, Nonthaneth Nalinratana, Thammarat Aree, Utid Suriya, Rutt Suttisri, Nitra Nuengchamnong, Hsun-Shuo Chang, Chaisak Chansriniyom

DOI: 10.1016/j.phytochem.2024.114291

keywords: Capparaceae; Cyclooxygenases; HT-29 cell proliferation; Indole alkaloids; Maerua siamensis

摘要

从Maerua siamensis的茎中分离出五种之前未描述的吲哚生物碱，命名为Maeruines A-E（1-5），它们具有Imine-2H-thieno[2,3-b]indol-3(8H)-one骨架。通过光谱技术[NMR、MS、IR和UV]以及单晶X射线衍射解析其化学结构。Maeruine D（4）在体外显示出选择性环氧合酶-2（COX-2）抑制活性，IC50为29.72±6.36 μM。分子动力学模拟显示，Maeruine D能与人类COX-2形成稳定复合物，主要由疏水相互作用驱动。此外，研究还发现包括Val349、Leu352、Leu384、Val523和Ala527在内的五个氨基酸残基为热点位点，可能导致其高结合亲和力和选择性。它还对HT-29结直肠癌细胞表现出细胞毒性，IC50为29.32±4.76 μM，在0.1-10 μM浓度范围内，显著抑制细胞增殖，且由促炎细胞因子白细胞介素-1β（IL-1β）诱导，具有剂量依赖性。

Abstract

Five previously undescribed indole alkaloids, maeruines A-E (1-5), bearing imino-2H-thieno[2,3-b]indol-3(8H)-one skeleton, were obtained from the stems of Maerua siamensis. Their chemical structures were elucidated using spectroscopic techniques [NMR, MS, IR, and UV], and single-crystal X-ray diffraction. Maeruine D (4) displayed selective cyclooxygenase-2 (COX-2) inhibitory activity in vitro with an IC50 of 29.72 ± 6.36 μM. Molecular dynamics simulations revealed that maeruine D could form a stable complex with human COX-2, predominantly driven by hydrophobic interactions. In addition, five amino-acid residues including Val349, Leu352, Leu384, Val523, and Ala527 were identified as hot-spot ones, which may lead to high binding affinity and selectivity. Furthermore, it exhibited cytotoxicity against HT-29 colorectal cancer cells with an IC50 of 29.32 ± 4.76 μM, and, at 0.1-10 μM, significantly inhibited their proliferation, induced by the proinflammatory cytokine interleukin-1β (IL-1β), in a dose-dependent manner.