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Study on the Structure-Activity Relationships and Synergism of Diverse Thiazolidinedione Molecular Probes in Compound Mixtures

Author: ZhangYing
Tutor: ZuoBing
School: Shandong University
Course: Medicinal Chemistry
Keywords: Small molecule probes Compound libraries Mixture In vitro screening P-glycoprotein
CLC: R96
Type: Master's thesis
Year: 2008
Downloads: 122
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Abstract

Lung cancer is one of the most common malignant tumor, the mortality rate ranks first in the malignancy worldwide. Although the anticancer efficacy of anti-cancer drugs has been a lot of progress, but patients with lung cancer five-year survival rate of only 15%, living in the bottom of which more than 85% of lung cancer from non-small cell lung cancer. Targeted therapy has become a hot spot of the current study of lung cancer, tumorigenesis, development is a complex problem, however, a single molecular targeted therapy appear gradually its drawbacks, multi-level, multi-target treatment systems biology more and more people concern. The rise of combinatorial chemistry and high-throughput screening method to accelerate the synthesis and screening of anticancer drugs speed is an important innovation in the field of drug development. Thiazolidinone class compounds are an important class of heterocyclic compounds, can not only selectively inhibiting the growth of tumor cells, but also effectively suppress the resistance of tumor cells is a promising anticancer drugs. This laboratory using combinatorial chemistry methods to design and synthesize a 170 compounds thiazolidinone class of small molecule compound library to be screened by a conventional biological activity screening methods, i.e. one by one on a single small molecule probes to determine the 10 kinds The active compounds of non-small cell lung cancer cell lines. View of the conventional drug screening methods can not make full use of the special structure of the compounds in the combinatorial chemistry information This paper presents a novel screening method for the composition of chemical compound libraries, the law compound is mixed after screening, is determined by analysis screening results reactive groups, and eventually found to have the activity of small molecule compounds. This screening method can more fully utilize the unique combination of chemical compounds structural information to analyze the structure - activity relationship of compounds. Study: 1 mixture, by the study Thiazolidone compounds on the inhibition of non-small cell lung cancer cell lines, analysis of the use of this method to the feasibility of screening anticancer drugs; 2, analysis of the interaction between a mixture of small and medium-sized molecular probe and affect the anticancer activity of the mixture; 3, the in vitro screening the thiazolidinone compound libraries compound mixture and found that a mixture of strong anticancer activity, for use with multi-target of the research and development of drugs; 4, through the thiazolidinone class of small molecule compounds inhibit P-glycoprotein role of this class of compounds drug targets for initial exploration. Methods: According to the theory of combinatorial chemistry and the compound obtained in the filter data, the compound has been synthesized the compound library selection, grouping selected 98 kinds of compounds, the volume of the four compounds, etc. are mixed in accordance with the relationship between structure and activity, constitutes 100 kind of mixture, and the mixture in accordance with the number of active compounds were divided into five groups, the following study: 1 mixture of role in paclitaxel-sensitive lung cancer cells H460 and paclitaxel-resistant lung cancer cells H460/taxR24 hours Morphological changes were observed situation initially identified a mixture of cell proliferation. 2, using the SRB method to detect the two non-small cell lung cancer cells were treated with a mixture of 72 hours after treatment, the survival analysis to identify possible drug activity groups. 3, select a mixture of a strong inhibition of lung cancer cells by using the SRB detection methods of human normal fibroblasts NHFB screening. 4, select a mixture of strong inhibition of lung cancer cells in a concentration-dependent experiments, the calculated GI ₅₀ value and the composition of the mixture of individual compounds GI ₅₀ value comparison. 5, according to the results of the pharmacophore model, selected from the compound library in line with the P-glycoprotein inhibitor, but does not meet the P-glycoprotein substrate conditions small molecular probes to study the inhibition of P-glycoprotein . Results: 1 mixture of two non-small cell lung cancer cell lines H460 cells, and H460/taxR cell treatment effect was observed under the microscope, we found that each group a mixture of cell proliferation inhibition varied, compared with control group , proliferation of cells treated with a mixture consisting of active compound after 4 minimal proliferation of cells treated with a mixture consisting of a non-active compound after four maximum. 2, through the SRB detection obtained a mixture of 100 kinds were acting on the cell proliferation rate H460 cells and H460/taxR cells after 72h. H460 cells as a screening model results show that the treatment of a mixture consisting of active compound after four average cell proliferation rate was 19%; average cell proliferation rate of the processing of the mixture after four non-active compound consisting of 65%; respectively by 1 42% of the average proliferation rate of the cells treated with a mixture consisting of the active compound with the other three non-active compound; H460/taxR cells as a result of the screening model display, the four active compound into a mixture of treated cells average proliferation rate of 5%, the processing of a mixture consisting of a non-active compound after four average cell proliferation rate was 72%, and the average proliferation rate of the treated cells consists of an active compound with the other three non-active compound, a mixture consisting of 35% . 3, select the stronger of the two on the inhibition of tumor cell mixture m56 and m91 and the corresponding individual compound half inhibition rate a GI ₅₀ value of the measured and compared, found the m56 the GI of ₅₀ value with the most active compounds the 284 GI ₅₀ value closest to; m91's GI ₅₀ value of the weakest four combinations of active compounds compounds 264 closest to. Wherein M56 m91 38,45,264 and 274 Compound No. equal volume mixture 187,284,264 and Compound No. 344 of equal volume mixture. 4, compound library 25 and 27 and No. 48, compound with taxol after mixing, and no change in paclitaxel alone, when the inhibitory effect on the drug-sensitive lung cancer cell lines H460, but the lung cancer cell lines that over-expression of P-glycoprotein of H460 / taxR inhibition significantly enhanced, the H460/taxR cell proliferation rate was reduced about 20%. Conclusion: 1, by analyzing the experimental results, the cell proliferation rate in accordance with small to large sort, select the strong inhibition of cell, i.e. cell proliferation rate smaller 50 mixture was analyzed, and statistics of the compound of the main group appears the frequency, according to the magnitude of frequency analysis of the possible reactive groups, by the analysis of the reactive groups speculated that a compound with anticancer activity. The results obtained by the mixture method of analysis of the active compound and has been reported in a single compound screening comparison, the conclusion is basically the same, thus proving vitro screening mixture method determines a compound having anticancer activity, the method is feasible. 2, the comparison of two lung cancer cell with the mixtures of each group after 72h, the average rate of cell proliferation, the proliferation rate of the size of each group the number of active compound mixture, containing more of the active compound treatment groups less cell proliferation, while the containing the active compound-treated cells proliferation stronger. Therefore, the interaction between the mixed compounds may affect some mixture of screening results, but the general point of view, the active compounds in the mixture still play a good anti-cancer, tumor suppressor role. Therefore, the idea is feasible to obtain the active compound from the mixture was filtered data analysis. 3, most of the compounds are mixed after the drug-resistant lung cancer cell lines H460/taxR cell inhibition than the sensitivity of lung cancer cell line H460 cells inhibition of a single compound screening results show on the H460 cells H460/taxR of cells inhibition substantially the same. Therefore, the mixed compound is expected as the reverse cell resistance multitargeted drug research and development. 4, mixed compound inhibitory effect does not only depend on cancer cells wherein the strongest cytostatic single compound, and may also depend on the binding ability of each compound and its target of action. 5, selected in this experiment Compound No. 25, 27 and 48 can suppress the function of the P-glycoprotein.

Study on the Structure-Activity Relationships and Synergism of Diverse Thiazolidinedione Molecular Probes in Compound Mixtures

Abstract

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