School of Veterinary Medicine, Henan University of Animal Husbandry and Economy, Zhengzhou 450046, China.
High & New Technology Research Center, Henan Academy of Sciences, Zhengzhou 450002, China.
Eur J Pharm Sci. 2023 Aug 1;187:106466. doi: 10.1016/j.ejps.2023.106466. Epub 2023 May 16.
To overcome the metabolic instability of cordycepin (adenosine deaminase (ADA) metabolic deamination and plasma degradation) and obtain better bioactivity, three novel kinds of cordycepin derivatives 1a-1c containing unsaturated fatty acids including linoleic acid, arachidonic acid and α-linolenic acid, respectively, were designed and synthesized. In terms of antibacterial activity, the synthesized compounds 1a and 1c showed enhanced activity than cordycepin in the tested bacterial strains. 1a-1c also exhibited enhanced antitumor activity against four cancer cell lines (human cervical cancer cell line HeLa, human non-small cell lung cancer cell line A549, human breast cancer cell line MCF-7, and human hepatoma cell line SMMC-7721) compared with cordycepin. Notably, 1a and 1b showed better antitumor activity even compared with positive control 5-Fluorouracil (5-FU) in HeLa, MCF-7 and SMMC-7721. The cell cycle assay indicated that when compared with cordycepin, 1a and 1b could significantly inhibit the cell propagation trapped in S and G2/M phases and increase the percentage of cells trapped in G0/G1 in HeLa and A549, which might provide a synergistic antitumor mechanism evidence different from cordycepin. Last but not the least, 1a and 1b displayed improved stability both in ADA solution and mouse plasma compared with cordycepin and 1a owns a solubility of 130 μg/mL in PBS. These results offer a novel insight into the primary structure and activity relationship of how the unsaturated fatty acid chain could affect the bioactivity of cordycepin, which also represents a series of cordycepin analogs with obviously improved bioactivity and enhanced stability, therefore promoting its druggable enhancement.
为了克服虫草素（腺苷脱氨酶（ADA）代谢脱氨和血浆降解）的代谢不稳定性并获得更好的生物活性，设计并合成了三种新型的虫草素衍生物 1a-1c，它们分别含有亚油酸、花生四烯酸和α-亚麻酸等不饱和脂肪酸。在抗菌活性方面，合成的化合物 1a 和 1c 在测试的细菌菌株中表现出比虫草素更强的活性。与虫草素相比，1a-1c 对四种癌细胞系（人宫颈癌细胞系 HeLa、人非小细胞肺癌细胞系 A549、人乳腺癌细胞系 MCF-7 和人肝癌细胞系 SMMC-7721）也表现出增强的抗肿瘤活性。值得注意的是，1a 和 1b 甚至比阳性对照 5-氟尿嘧啶（5-FU）在 HeLa、MCF-7 和 SMMC-7721 中显示出更好的抗肿瘤活性。细胞周期检测表明，与虫草素相比，1a 和 1b 可以显著抑制 HeLa 和 A549 中细胞增殖被困在 S 和 G2/M 期，并增加细胞停留在 G0/G1 期的百分比，这可能提供了与虫草素不同的协同抗肿瘤机制证据。最后但并非最不重要的是，1a 和 1b 在 ADA 溶液和小鼠血浆中的稳定性均优于虫草素，并且 1a 在 PBS 中的溶解度为 130μg/mL。这些结果为不饱和脂肪酸链如何影响虫草素的生物活性提供了新的见解，也代表了一系列虫草素类似物，其生物活性和稳定性明显提高，从而促进了其可开发性的增强。
