Synthesis Of γ-hydroxy Acetylenic Esters Derivatives And Their Evalution As Anti-cancer And Anti-inflammatory Agents

Drugs from natural products have been chosen to treat diseases since antiquity.Polyacetylenic are a unique structure with biological functions as one of the wide variety drug candidates from natural products,widely existing in kinds of plants and marine organism.With the development of chemical technology and studies during last decades,thousands of active acetylenic metabolites have been isolated and identified from traditional medicine plants,which display abundant biological activities,such as anticancer,anti-inflammatory,antifungal,antimicrobial,antiviral.But the mechanism of these compounds is still not clear.In order to investigate the effort of acetylenic structure on the activity of drug,a series of compounds have been synthesized,based on the previous works for γ-hydroxyl acetylenic esters.These compounds,containing acetylenic ester groups into small medicine molecular,were detected kinds biological activity,contains antitumor and anti-inflammatory.The work mainly includes the following aspects.Design and synthesis of many kinds of compounds containing acetylenic ester.(1)Compounds obtained from isatin(1H-indole-2,3-dione),by replacement of substituent at the indole ring and addition of acetylenic ester in 3 keto.Synthesis methods have been optimized by attempt of kinds of catalyzer and experimental conditions.Not only introduction of the acetylenic ester at carbonyl group,the replacement in 1 keto also plays important aspect in biological activity.(2)On the basis of previous work on the γ-hydroxy acetylenic esters in benzaldehyde,γ-amidogen acetylenic esters compounds were synthesized.(3)Acetylenic ester were introducted into kinds of heterocyclic group.Detected the anticancer activity of compounds.(1)Hela and MDA cell lines were chosen for the screening of the antitumor ability among obtained compounds.The structure activity analysis was carried out by the IC50 from activity test,and designing new compounds by replacement groups.Anticancer ability of isatin derivatives can increased dramatically by introduction acetylenic ester in carbonyl of 3-keto.Replacement of groups in 1-keto of insatin also can significantly improve the activity of compounds.The compound L-37 was the most potent in screening.(2)Compound L-37 and some others were selected for studying the mechanims of the antitumor.We confirmed the Hela cells were inhibited by apoptosis in a time and dose-dependent.In the subsequent experiments,compounds show the ability of inducing apoptosis through caspase-3/9 pathway,which may activated through the PI3K/AKT pathway.(3)According to detection of Rhodamine 123 and ROS content,the compounds were promoted significantly increased ROS in tumor cells,showed that such compounds can induce mitochondrial membrane potential changes in tumor cells,which contributes to the cell apoptosis.Therefore,compounds involved in this study induced apoptosis of tumor cells through variety of ways,so as to effectively inhibit the proliferation of tumor cells.Detected the anti-inflammatory activity of compounds.As synthesised compounds have similar structure with indomethacin,the anti-inflammatory activity were detected based antitumor experiments.(1)L-37,L-39,L-18 and other compounds which showed good performance in antitumor exprements,were selected to detect NO release inhibition in RAW 264.7 cells.These compounds showed high anti-inflammatory ability as the anticancer activity,which can inhibite NO release in low level.Compound L-37 can inhibit NO release rate reached 50% in 1 μ M.(2)The enzyme experiment indicates that the compound has obvious inhibiting effect on PGE2,and found that the compounds showed same effect in COX-1,COX-2,5-LOX expression.(3)L-37 listed similar anti-inflammatory effect in mice as celecoxib in the further animal experiments.The results show that the compounds have potential application in anti-inflammatory activitySynthesised compounds showed pronounced double activity of anti-tumor and anti-inflammatory.Due to inflammation and cancer are closely related,as a dual inhibitor,the compounds have great potential for development.