Design And Synthesis Of Curcumin Analogues As Multidrug Resistance Reversal Agents

Cancer as one of the most serious diseases threating human health, its incidenceis growing every year. More and more researchers are engaged in the cancer treatmentstudies all around the world. Chemotherapy plays an important role in the treatment ofcancer. But, the occurrence of MDR in cancer cells has made the chemotherapygreatly ineffective. Studies showed that the chemotherapy failure of90%cancerpatients is caused by the emergency of MDR in cancer cells. So, the study anddevelopment of the MDR reversal agents has become the primary task in theanticancer studies.Curcumin as one of the anticancer active constituent in the traditional ChineseMedicine Curcuma Longa is of wide range of anticancer properties. Studies showedthat curcumin is effective in the inhibiting of lots of cancers, including Lung Cancer,Breast Cancer, Gastric Carcinoma, Colonic Cancer, Leukemia, Melanoma，andProstate Cancer and so on. It is reported that curcumin has low toxicity, definitelycurative effect, and multiple target therapy characteristic, which make it to be a hottopic in Medicinal Chemistry and Pharmacology. In addition, it is also reported thatcurcumin has the ability to increase the sensitivity of MDR cancer cells to thechemotherapy drugs, which approved the curcumin has the MDR reversal ability andproposed a new idea for the development of curcumin analogues using in theanticancer studies.The MDR generating has many mechanisms, while the most well-knownmechanism is the over-expression of drug efflux pump on cancer cell surfaces whichcould extrude chemotherapy drugs out of the cells and thus, reduced the accumulationof the chemotherapy drugs. P-glycoprotein (P-gp), Multidrug resistance-associatedprotein (MRP), and breast cancer resistance protein (BCRP) are members of asuperfamily of ATP-binding transporters that function as drug efflux pumps. P-gp is best studied in the three proteins. There are three generations of drugs forP-glycoprotein mediated multi-drug resistance. First generation P-gp modulators areeliminated because of their serious cytotoxicity and side effects. Second generationmodulators are eliminated because they could disturb the drug metabolism thoughthey have displayed lower cytotoxicity than the first generation. Third-generationmodulators were developed with the help of computer-aided drug design to improvethe properties of the compounds, including high effective, low toxic, high selectiveand so on. These words are still in process. So, searching for new P-glycoproteinmediated MDR reversal agents has become a hotspot.In this paper, we employed the curcumin as the leading compound, P-gp as thetarget, followed the known structure-active relationship summarized by formerresearches, and synthesized a novel series curcumin analogues in order to find somepotent MDR reversal agents with low cytotoxicity.In this paper, three different types of curcumin analogues with pyridine replacedthe β-diketone and different substituents on the phenyl group were synthesized.63target compounds were synthesized and58of them were new compounds withoutreported before. All the new compounds were characterized by NMR (1H NMR,13CNMR) and HRMS. The results demonstrate that it is easy to synthesize thesecompounds in good yields. Type A compounds could be get via4steps in the yields ofabout15%, type B compounds can be synthesized in3steps in the yields of about25%and type C compounds could be get in the yields of40%via3steps.36compounds of the synthetic curcumin analogues were selected to test thereversal activity for P-gp, BCRP and MRP1mediated MDR cancer cells as well as thecytotoxicity to different cell lines. For the P-gp modulating activity,15compoundsdisplayed better P-gp modulating activity than verapamil (Reversal Fold RF=5.4).Compound HA-5showed extremely strong P-gp modulating activity with the RFvalue86.0. Compounds HA-3, AJ-3also displayed potent P-gp modulating ability.Their RF achieved to be40.2and50.2. In addition, the synthetic compoundsdemonstrated strong reversal activity to the BCRP mediated MDR cell lines. Theresults showed that almost all the curcumin analogues have better BCRP modulating ability than curcumin I. The RF of HA-2~HA-6, HA-10, HA-11ranged from10to17.Compound HA-3, HA-5and HA-6with each RF is16.4,16.2and15.7indicates theyhave very strong BCRP modulating activity. Unfortunately, all the36compoundsdidn’t show any reversal ability to the MRP1mediated MDR cell lines. This maybecaused by the wide differences in substrate of MRP1from P-gp and BCRP.In addition,5kinds of different cell lines were employed for the compoundscytotoxicity testing. The results showed that some analogues including curcumin V,curcumin VI, HA-0, AJ-0, HE-0, LE-0displayed relative high cytotoxicity to somecell lines while the other compounds did not show high cytotoxicity. This indicatesthat the designed and synthesized curcumin analogue is a kind of effective and safeMDR reversal agents.In this paper, it is the first time to study the curcumin pyrimidine analogues as theMDR reversal agents. A novel series of curcumin pyrimidine analogues weresynthesized for improving their MDR reversal activity after studying the mechanismof MDR generation and the characteristic of the popular MDR reversal agents. Afterthe modification of the leading compound curcumin, we synthesized a series ofcompounds with high P-gp modulating activity and promising BCRP modulatingability. By analyzing the results, we further clarified the structure-relationshipbetween the compounds and the P-gp modulating, and we also got some preliminarystructure-relationship between the compounds and the BCRP modulating activity.This is of great significance for finding and developing novel series of effective andsafe MDR reversal agents.