Design, Synthesis And Screening Of Thiazolidinone Derivatives

Non-small-cell lung cancer (NSCLC) is one of the most deadly cancer and accounts for over 1 minion deaths every year. For inoperable patients, chemical therapy remains the last hope of life maintain. Currently, chemical therapy usually fails for two reasons. On one hand, few chemical therapy agents have good selectivity. They can kill the cancer cells as well as normal cells. Once patients are too weak to take next chemical therapy, their time comes soon. On the other hand, agents are only temporarily successful for most cancer patients and will be noneffective when multidrug resistance was acquired by tumor cells. To solve these problems, new agents with higher selectivity to cancer cells and lower toxicity to normal cells should be developed. Furthermore, the new agents should be able to kill multidrug resistant tumor cells if possible. The over-expression of MDR-1 gene encoded transmembrane, ATP-dependent, drug efflux transporter P-gp is reported to be an important mechanism of multidrug resistance. Since inhibition of P-gp may arise more by-effects, to overcome MDR, agents should not be the substrate of P-gp.Two thiazolidinone derivatives have been identified to inhibit the growth of paclitaxel-sensitive and -resistant NSCLC cell lines H460 and H460/TaxR. Both of them showed relatively low toxicity toward NHFB. To search more active compounds and reveal structure-activity relationship for cytoselective anticancer activity, a series of thiazolidinone derivatives were designed, synthesised and screened. Before this work, Hongyu Zhou had concentrated on this field. 185 2-arylimino-4-thiazolidinones and 17 2-arylimino-3-substituted-4-thiazolidinones were successfully prepared using solution phase parallel synthesis method and 45 2-aryl-4-thiazolidinones were synthesized using fluorous chemistry method. All compounds were tested against H460, H460/TaxR and NHFB. At last, 11 compounds were confirmed and selected for dose-response studies; the 50% inhibitory concentrations (IC50) of the 11 compounds for H460 and H460taxR cells were as low as 300 nM. For most of active compounds, NHFB did not reach 50% cell killing at the highest compound concentration used (100μM).SAR analysis showed that substitution groups were dominantly electron-donating groups at the 2-or 4-position for both rings. Substitution at phenylimino position allowed groups such as -Me, -Cl at both the 2- and 4-positions. However, substitution at benzylidene position was restricted to only the -NMe2 group at the 4-position. Anti-cancer molecule pharmacophore was generated with 11 most active compounds. The results indicated that two hydrogen bond acceptors and three hydrophobic regions were common features for all active compounds.Although former compounds gave encouraging bioactivity, there is still a long way to move on. We noticed that the diversity of the library was limited, better compound may be acquired using news amines and aldehydes. And more compounds will doubtlessly make our SAR conclusion further justified. What's more, the solubility of the compounds in water was too poor for in vivo experiments.Here we designed a library of 27 2-arylimino-4-thiazolidinones. We calculated the Mlogp, H-bond donor and receptor of all compounds with 'Accord for Excel' to make sure that the compounds conform to rule of 5. It is supposed that some active compounds could be found and more information about the structure-activity-relationship will help us to design new libraries.During the synthesis of the library, we found that the explored route did not fit our compounds. New literature review was done and several routes were tried. Finally we found a way to form our product at an acceptable yield. Further exploration was made to see if better reaction suitable for solution phase parallel synthesis but the result was disappointing. Thus, most of the reactions were done one by one instead of parallel.The library was purified by column chromatography. After analysis by LC/MS and NMR, the library was screened with H460, H460/TaxR and NHFB cell lines. Two compounds, A5 and Cl were found active to H460 and H460/TaxR at the concentration of 25μM. NHFB cells were seldom killed at the same time.It was proved that substitution groups were at the 2-or 4-position for both rings. But substitution at benzylidene position needn't be only the -NMe2 group at the 4-position. More compounds shall be synthesized and screen to prove if two hydrogen bond acceptors and three hydrophobic regions are inflexible standard of active compound. If the compound must be that hydrophobic to maintain its activity, maybe we should try nano-carrier instead of adding hydrophilic groups to the molecular.