Incorporation of amino moiety to alepterolic acid improve activity against cancer cell lines: Synthesis and biological evaluation.,Bioorganic Chemistry

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Incorporation of amino moiety to alepterolic acid improve activity against cancer cell lines: Synthesis and biological evaluation.
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2020-03-12 , DOI: 10.1016/j.bioorg.2020.103756
Sheng Zhang ₁ , Niping Feng ₁ , Jinwen Huang ₂ , Minglong Wang ₁ , Lei Zhang ₁ , Junjie Yu ₁ , Xiling Dai ₁ , Jianguo Cao ₁ , Guozheng Huang ₃

Affiliation

Aleuritopteris argentea (S. G. Gmél.) Fée is a medicinal fern consisting of an ent-labdane diterpene, i.e. alepterolic aicd, as the major metabolite. We recently isolated grams of alepterolic acid from A. argentea enabling subsequent structural modification. By incorporation of amino moiety to alepterolic acid, fifteen amide derivatives were synthesized, characterized, and further biological evaluated regarding their activity against four cancer cells and normal human liver cells. The potency of synthesized amides dramatically improved as compared to alepterolic aicd itself. The best hit (compound 11) inhibits HeLa cells with an IC50 of 7.39 ± 0.80 μM, and is nearly nontoxic to normal cells. Compound 11 exhibits an inhibitory effect on the colony forming ability of the four cancer cells, especially of HeLa cells. Moreover, it induces apoptosis of HeLa cells by decreasing mitochondrial membrane potential and altering expression of apoptosis-associated proteins. Release of cytochrome c, activation of caspases-3, caspases-9 and alteration of Bax/Bcl-2 balance was detected in the biological assays. These results imply that compound 11 can inhibit the proliferation of cervical cancer cell line HeLa and induce apoptosis through the mitochondrial pathway. These findings encourage further rational structural modification of 15- carboxyl group of alepterolic acid.

中文翻译：

将氨基部分掺入到链烷酸中可改善对癌细胞系的活性：合成和生物学评估。

Aleuritopteris argentea（SGGmél。）Fée是一种药用蕨类植物，它由对马丹烷二萜，即alepterolic aicd，作为主要代谢产物组成。我们最近从A. argentea分离了几克alepterolic acid，可以进行后续的结构修饰。通过将氨基部分掺入到链烷酸中，合成，表征了15种酰胺衍生物，并对它们对四种癌细胞和正常人肝细胞的活性进行了生物学评估。与alepterolic aicd本身相比，合成酰胺的效力大大提高。最佳命中化合物（化合物11）抑制HeLa细胞，IC50为7.39±0.80μM，对正常细胞几乎无毒。化合物11对四种癌细胞，特别是HeLa细胞的集落形成能力表现出抑制作用。此外，它通过降低线粒体膜电位并改变凋亡相关蛋白的表达来诱导HeLa细胞凋亡。在生物学测定中检测到细胞色素c的释放，caspases-3，caspases-9的活化以及Bax / Bcl-2平衡的改变。这些结果暗示化合物11可以抑制宫颈癌细胞系HeLa的增殖并通过线粒体途径诱导细胞凋亡。这些发现鼓励了对十八酸的15-羧基的进一步合理的结构修饰。这些结果暗示化合物11可以抑制宫颈癌细胞系HeLa的增殖并通过线粒体途径诱导细胞凋亡。这些发现鼓励了对十八酸的15-羧基的进一步合理的结构修饰。这些结果暗示化合物11可以抑制宫颈癌细胞系HeLa的增殖并通过线粒体途径诱导细胞凋亡。这些发现鼓励了对十八酸的15-羧基的进一步合理的结构修饰。

更新日期：2020-03-12

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