Synthesis And Antitumer Activities Of Curcumin Analogues

Cancer is a malignant disease threating human health seriously. It is the common aspiration of mankind to conquer cancer. Anticancer drugs are appearing an increasingly important position for the treatment of cancer. Development of efficient and low toxicity anticancer drugs is an indispensable work for conquering cancer.Curcumin is the main active ingredient of extract from roots and stem of turmeric plant. It has wide range of pharmacological activity. It has been demonstrated that the curcumin has a clear anti-tumor activity by many in vitro and animal experiments. Curcumin can inhibit cell growth of many kinds tumor. It has a broad spectrum of anti-cancer activities, it has low toxic and side effects, it can be used as anti-mutagens and anti-tumor promotion agents. It has a significant inhibitory effect to multi-stage of tumor growth, such as occurrence and development stage of tumor. And it can play a variety of performance to one kind of tumor. Curcumin has been considered as a third-generation cancer chemopreventive drug by American National Cancer Institute.However, curcumin itself is insoluble in water, its aqueous solution is instable at neutral to alkaline conditions. Its anti-tumor activity is low in vivo. Little absorb, rapid metabolism and low bioavailability have limited it’s application. It is necessary to make the appropriate structural modification of curcumin and synthetic compounds similar to the structural characteristics of curcumin to improve the stability and targeting of drugs, to enhance its anti-tumor activity, to reduce normal tissue toxicity, to screen low toxicity and efficient anticancer drug.With curcumin as the lead compound, research work in this thesis synthesized three series total 61 compounds of curcumin analogues. Many curcumin analogues with strong anti-tumor activity were found. The structure-activity relationship was studied.Total three series, sixty-one curcumin analogues were obtained by the reaction of aromatic formaldehyde or replace aromatic formaldehyde with six ketones (cyclohexanone, cyclopentanone,acetone, piperidone,tetrahydro-4H-pyran-4-one, tetrahydrothiopyran-4-one). 11 compounds were synthesized firstly:E11, F4, F9, F10, F11, EN1, EN3, FN1, FN3, ES, FS. The molecular structure of 61 curcumin analogues were characterized and confirmed by elementary analysis. FT-IR, 13C NMR and 1H NMR, and the compound obtained was the objective products.The antitumor activities in vitro were evaluated in Pc-3, Panc-1 and HT-29 cancer cells by MTT assay. The 50%inhibitory concentration (IC50) indicated that most of the curcumin analogues inhibited growth of human cancer cells such as Pc-3, Panc-1 and HT-29.35 curcumin analogues antitumor activity are several times stronger than curcumin,53 curcumin analogues had stronger antitumor activity than curcumin. The curcumin analogues E9、F9、E10、F10、E11、F11、EN1、FN1、EN2、FN2、FN3 had better antitumour activity, maybe some compounds will be new anticancer drugs. Especially the inhibitory activity of compounds E10 or F10 are 73 times stronger than curcumin to cancer cells PC-3. The advance research is being done in Susan Lehman Cullman Laboratory for Cancer Research of Rutgers University.Analysis for the structure-activity relationship showed that the curcumin analogues of benzene series(A-F), pyridine series(N), thiophene series(S) had stronger anticancer efficacy than curcumin, especially the pyridine series. The order of anti-tumor activity is:Series N> series A-F> series S.Single carbonyl bridge among structure can enhance curcumin analogue anti-tumor activity. In this paper, the intermediate of connecting bridge of all curcumin analogues are single carbonyl structure,90%compounds have stronger antitumor activity than curcumin, which indicate that intermediate connecting bridge is not necessary for antitumor activity.Single carbonyl structure influencing antitumor activity of curcumin analogues. The single carbonyl structure is tetrahydro-4H-pyran-4-one in every compound of group E (group EN, ES), the single carbonyl structure is tetrahydrothiopyran-4-one in every compound of group F (group FN, FS), the single carbonyl structure is piperidone in every compound of group D, the single carbonyl structure is acetone in every compound of group C, the single carbonyl structure is cyclohexanone in every compound of group A, the single carbonyl structure is cyclopentanone in every compound of group B. The order of antitumor activity is: Series A-F:E>F>D>C>A>BThe situation is different for series N and series S, probably because there is one nitrogen or one sulfur atom in the heterocyclic structure. The order of antitumor activity is:Series N:FN> EN> AN> BNSeries S:FS> ES> AS> BSIn addition, for series A-F, the group of-OH,-OCH3 or-OCH3,-OCH3 at 3,4 position of benzene ring can significantly improve the antitumor activity of curcumin analogues. More-OCH3 at position3 and 4 of benzene ring, stronger antitumor activity.