Absolute Configuration Of Fusicomycins And Anti-Tumor Mechanism

Hepatocellular carcinoma is the most common type of cancer with high fatality.Malignant tumor local invasion and distant metastasis characteristics lead to a high mortality rate.Tissues related to tumor metastasis are becoming research focus,it's crucial to find effective anticancer drugs consequently.Our research group isolated a unique type of 5/8/5 tricyclic diterpenoids from Streptomyces violascens in the earlier work,which are named as fusicomycin A,fusicomycin B and isofusicomycin A.Preliminary experiments indicate that fusicomycins have broad antitumor activity,and show significant inhibiting effect to hepatocellular carcinoma SMMC-7721 cell lines.In order to elucidate the stereochemistry of the isolated fusicomycins,we carry out structure modification of the compounds by means of bringing heavy atom in the structure framework firstly,and then characterize absolute configuration of fusicomycins in the method of X-ray crystallographic analysis.The preliminary structure-activity relationship indicates that the polyketone side chain at C-19 made a great contribution to the cytotoxicity,while an hydroxyl at C-12 or C-14 significantly decreased the cytotoxic activity.Would healing assay and transwell invasion metastasis assays showed that the compounds have an effect on SMMC-7721's invasion and migration;Furthermore,we applied assays of western-blot and real-time PCR to explore the mechanism.The results suggest that the new diterpenoids inhibited the enzymatic activity of matrix metalloproteinase-2(MMP-2)and matrix metalloproteinase-9(MMP-9),and down-regulating the expressions of MMP-2 and MMP-9 at both the protein and mRNA levels to influence the migration and invasion of cancer cells.