Study On The Pregnane Alkaloid Derivatives Synthesis And Their Structure-activity Relationship Of Anti-metastatic Effect

Metastasis is the fiducial markers of cancer,over 90%of the cancer patients will eventually lead to death by tumor metastasis.Chemotaxis,represents the capacity to detect an extracellular gradient of chemoattractants and directionally move to the higher concentration site.Recent studies reveal a key role of chemotaxis in cancer cell metastasis.It has been reported that epidermal growth factor eceptors(EGFR),as an important receptor tyrosine kinase on cell surface,have potent chemotactic effects on human breast cancer cells.In recent years,a large number of steroidal alkaloids have been isolated from Pachysandra axillaris distributed in southwestern mainland China and Japan,which has been used extensively in Hubei Province,People's Republic of China,as a Tujia traditional medicine against pain and stomach problems.The compounds have good anti-tumor metastatic effect.We use these compounds as lead compounds,through QSAR analysis,design serious pregnane-type steroidal alkaloids.Ring A link a N atom,Ring D C-16 position link hydroxyl,carbonyl and ester group.C-17 position link allyl group.Based on the retrosynthesis analysis,we choose epiandrosterone as the start reagent.Allyl group at C-17 compound through Wittig reaction,and the ketone at C-3 position through Jones reaction.Pregnane-type steroidal alkaloids at C-3 position through reactive amide.A tertiary amine compound synthesis at the C-3 position through the secondary amine compound alkylation and acylation of the N atom.C-16 through Riley reaction allylic methylene oxidized into a hydroxyl group and oxidation obtain a carbonyl group.In the after-treatment process has used recrystallization,column chromatography,high plate preparation separation technique.31 target compounds,all target structures were confirmed by 1H-NMR,13C-NMR spectrum identification,the identification of the part of the compound structure was confirmed by X-ray single crystal diffraction.MTT was used to determine the synthesis compounds.Then trans well chemotaxis was used to evaluating the role of inhibition of tumor cell migration.Through QSAR analysis the relationship between the pharmacophore and the result,wherein the structure in the C-3 position to the amide bond,improve anti-tumor cell migration stronger,the presence of hydroxyl,ketone group in the C-16 position make the effect better.Compound S 9-1 showed significant anti-metastasis effect.The metastatic inhibition ratio of value IC50 was 0.50 ?M on MDA-MB-231 cell line.