Synthesis And Biological Evaluation Of Thiophene And Indole Carboxylic Acyl Shikonin Derivatives

Zicao (Lithospermum erythrorhizon) is a traditional Chinese medicine, and its main active components are Naphthoquinone compounds, which have many biological activities, such as antibacterium, anti-inflammatory, antitumor, antiviral, hepatoprotective and immunomodulatory. In recent years, as a nature extract antitumor compound, shikonin has been favored by many scholars. Therefore, the synthesis of a series of shikonin derivatives with high antitumor activity, good solubility and low cytotoxicity and research on the activities, has become the new research directions.Thiophene and indole heterocyclic compounds generally exist in clinical drug (such as:Duloxetine, Ceftofur, Bucindolol, Zolmitripan and so on). we hope that the heterocyclic carboxylic acid (including thiophene carboxylic acid and indole carboxylic acid) could be introduced into the molecular structure of shikonin, obtaining a series of shikonin derivatives and verify the activity of these compounds. Subsequent experiments showed that S3 (shikonin indole -3- propionate) and S8 (shikonin thiophene -3- acetate) showed few cell toxicity on human normal cells HFF (human foreskin fibroblast). The series of compounds had significant inhibitory activity on A875 (human melanoma cells), HeLa (human cervical carcinoma cell line) and HepG2 (human hepatoma cells). Among them, S3 and S8 have stronger inhibitory activity against A875 and HeLa cells. The tubulin depolymerization experiments showed that the series of compounds had good inhibitory activity on tubulin. Docking simulation showed that S3 could combine the active site of tubulin by cation-Ï€ bonds while S8 combined by multiple hydrogen bonds, and the interaction of S8 is higher than that of S3 obviously, which was in accordance with the antitumor activity results, proving that the series of shikonin derivatives could inhibit tubulin polymerization and ultimately inhibit the proliferation of tumor cells. In addition, cell apoptosis and cell cycle experiments also verified that S3 could effectively promote the apoptosis of human cervical carcinoma HeLa cells, and showed a concentration dependent.Therefore, in this study, we obtained some shikonin heterocyclic carboxylic acid derivatives which were a class of the toxicity with high efficiency and low toxicity. S3 and S8 showed significant inhibitory activity on tubulin, with in-depth research significance.