隐鱼茎细胞毒性强心苷(−)-隐苷A及其分子靶点,Journal of Natural Products

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隐鱼茎细胞毒性强心苷(−)-隐苷A及其分子靶点
Journal of Natural Products ( IF 3.3 ) Pub Date : 2023-05-22 , DOI: 10.1021/acs.jnatprod.3c00094
Yulin Ren ₁ , Elizabeth N Kaweesa ₂ , Lei Tian ₃ , Sijin Wu ₄ , Kongmany Sydara ₅ , Mouachanh Xayvue ₅ , Curtis E Moore ₆ , Djaja D Soejarto _{2,

7} , Xiaolin Cheng ₁ , Jianhua Yu ₃ , Joanna E Burdette ₂ , A Douglas Kinghorn ₁

Affiliation

一种强心苷环氧化物，(−)-cryptanoside A ( 1 )，是从老挝采集的Cryptolepis dubia的茎中分离出来的，通过分析其光谱和单晶 X 射线衍射数据，使用铜在低温下的辐射。这种强心苷环氧化物对多种测试的人类癌细胞系表现出有效的细胞毒性，包括 HT-29 结肠癌、MDA-MB-231 乳腺癌、OVCAR3 和 OVCAR5 卵巢癌以及 MDA-MB-435 黑色素瘤细胞，IC 50_值发现范围为 0.1–0.5 μM，与地高辛观察到的结果相当。然而，它表现出较低的活性（IC ₅₀与地高辛 (IC 50 0.16 μM)相比，针对 FT194 良性/非恶性人输卵管分泌上皮细胞 (IC _{50 0.16 μM) 的结果表明，与良性/非恶性细胞相比，其对人类癌症更具选择性活性。}(−)-Cryptanoside A ( 1 ) 还抑制 Na ⁺ /K ⁺ -ATP 酶活性并增加 Akt 和 NF-κB 的 p65 亚基的表达，但对 PI3K 的表达没有显示出任何影响。分子对接分析显示(−)-cryptanoside A ( 1 ) 与Na ⁺ /K ⁺ -ATPase结合，因此1可能直接靶向Na ⁺ /K ⁺ -ATPase 介导其癌细胞细胞毒性。

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The Cytotoxic Cardiac Glycoside (−)-Cryptanoside A from the Stems of Cryptolepis dubia and Its Molecular Targets

A cardiac glycoside epoxide, (−)-cryptanoside A (1), was isolated from the stems of Cryptolepis dubia collected in Laos, for which the complete structure was confirmed by analysis of its spectroscopic and single-crystal X-ray diffraction data, using copper radiation at a low temperature. This cardiac glycoside epoxide exhibited potent cytotoxicity against several human cancer cell lines tested, including HT-29 colon, MDA-MB-231 breast, OVCAR3 and OVCAR5 ovarian cancer, and MDA-MB-435 melanoma cells, with the IC₅₀ values found to be in the range 0.1–0.5 μM, which is comparable with that observed for digoxin. However, it exhibited less potent activity (IC₅₀ 1.1 μM) against FT194 benign/nonmalignant human fallopian tube secretory epithelial cells when compared with digoxin (IC₅₀ 0.16 μM), indicating its more selective activity toward human cancer versus benign/nonmalignant cells. (−)-Cryptanoside A (1) also inhibited Na⁺/K⁺-ATPase activity and increased the expression of Akt and the p65 subunit of NF-κB but did not show any effects on the expression of PI3K. A molecular docking profile showed that (−)-cryptanoside A (1) binds to Na⁺/K⁺-ATPase, and thus 1 may directly target Na⁺/K⁺-ATPase to mediate its cancer cell cytotoxicity.

更新日期：2023-05-22

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