| Combinatorial chemistry is also called combinatorial science. It includes the chemical synthesis, computer aided, high-throughput screening, big data statistics, model establishment and application. Its parallel synthesis, analysis, purification and high-throughput screening technology have been widely used. Nano technology is a recent research focus. Nanomaterials’unique size effect brings greatly novel physical and chemical properties compared withthe conventional materials. The combination of nano materials and combinatorial chemistry can accelerate the research and development of new nano materials, shorten the optimization time of the nano catalysts, and quickly screen and optimize the functional nanomaterials. In the first part of this thesis, we established a nano-combinatorial gold nanoparticle library as a discovery platform to reveal major molecular components for PFOS sequestration. We first introduced a new F-F interaction and compared its effect on the PFOS removal process with the traditional electrostatic and hydrophobic interactions. The second part of this thesis reports our efforts to optimize both aqueous solubility and anti-cancer activity of leading thiazolidinone compounds using combinatorial lead optimization libraries. It showed the high efficiency and practicality of combinatorial chemistry and high throughput screening.Destruction and restoration of environment is an important factor to the sustainable development of society at present. Removal of the existing environmental pollutants is an important part of the environmental remediation process. On May 9, 2009, the United Nation Environment Programmer reviewed the list of the persistent organic pollutants and added the perfluorooctane acid and its salts (PFOS) and amine (PFOA) compounds. But before this, PFOS and its precursors have produced for as long as half a century. Lots of PFOS have enterred the environment and the human body. Because of its extremely good stability, the PFOS pollution is a persistent problems. The PFOS has been detected in a lot of open waters because of its stability and biological accumulation. PFOS has been found not only in the open water, but also in people’s food and drinks even the human body has found the existence of PFOS. PFOS accumulation in vivo can cause significant toxicity. For example, it can suppresses the immune system, affect the metabolism of mitochondria, cause liver cell damage, damage the reproductive cells, reduce the ability of reproduction and fertility, affect fetal development, change gene expression, interfere with the enzyme activity, destruction of cell membrane structure, change thyroid function and so on. Due to the extremely strong stability of PFOS, the methods of simple redox and microbial degradation, which are commonly used to deal with pollutants, are not effective in removing PFOS.The occurrence and treatment of disease is an important factor for the sustainable development of human beings. Lead compound optimization is the key step for the treatment of various diseases. A lead compound in drug discovery is a chemical compound that has pharmacological or biological activity likely to be therapeutically useful, but still has suboptimal structure that requires modification to fit better to the target. Its chemical structure was used as a starting point for chemical modifications in order to improve potency, selectivity, or pharmacokinetic parameters. Furthermore, newly invented pharmacologically active moieties may have poor druglikeness and require chemical modification to become drug-like enough to be tested biologically or clinically. Identification of the leading compounds is the first step in the development of new drugs. Once lead compounds have been identified, three things need to be done:improving the precursor to the target specificity with the application of medicinal chemistry; optimization compounds pharmacokinetics properties and biological availability and animals preclinical testing. Some defects existed in the lead compounds, such as lack of activity, high toxicity, poor selectivity, unreasonable pharmacokinetic properties and so on. Modification of lead compounds constructure and further optimization are the key elements to make it the ideal drug.Part 1:Molecular Determinants for Optimal PFOS SequestrationDue to its eco-environmental and biological impacts, the on-site detection and removal of trace amount of PFOS have become an imperative task. To achieve these missions, some fundamental understandings of the molecular interactions for PFOS sequestration are essential. In this work, we established nano-combinatorial gold nanoparticle library as a discovery platform to reveal major molecular components for PFOS sequestration. Our expectations are that these findings will help to design on-site analysis probes and nano matrices for removing PFOS at low concentrations. We revealed that the optimal molecular sequestration of PFOS by functionalized GNPs (f-GNPs) required simultaneous electrostatic and fluorine-fluorine (F-F) interactions. From the expriments, we found that F-F interaction is much stronger than the hydrophobic interaction. We designed a dual-ligand functionalized gold nanoparticle model. The amino group carries a positive charge in neutral and slightly acidic solutions. This may provide electrostatic interactions with the negative charged sulfonic acid group at this pH. The perfluoroalkyl chain provides fluorine-fluorine interactions with the whole body of PFOS. To better understand and optimize binding of PFOS, we further designed a combinatorial f-GNP library by diversity the length of perfluoroalkyl chain (SF01-SF03) and the pKa of amino group (SN01-SN03) to differentiate designed similar ligand with H replacing F atoms (SH01-SH03).Through the combinatorial chemistry synthesis method,18 kinds of functionalized gold nanoparticles have been produced. They were characterized by TEM, DLS, zeta potential and surface ligand uploading quantity to ensure the function of gold nanoparticles. Based on the adsorption of screening experiments with different pH, the percentages of electrostatic vs hydrophobic or F-F interactions were calculated. The dissection data showed that the ratio of electrostatic interaction over hydrophobic/F-F interactions between the f-GNPs and PFOS was only a slightly higher when the later was relatively weak (such as HI-3 or Fl-3). When the hydrocarbon or fluoroalkyl chain became longer (such as in H7-9 or F7-9), the hydrophobic or F-F interactions overpowered the electrostatic interactions. In the case of F7-9, the F-F interactions were about four times stronger than the electrostatic interaction.Two functional gold nanoparticles have been selected for the thermodynamic and kinetic absorption experiments. The adsorption of PFOS on gold nanoparticles was more fittable for the Freundlich monolayer model, the correlation coefficient was greater than 0.95. The kinetic model experiment shows that the rate of these three interaction is kelcctro>kf-f>khydro. The rate of the electrostatic adsorption is much higher than that of F-F, and the rate constant of F-F is 3 times of the hydrophobic interaction.This study first introduced the F-F interaction in the PFOS sequestration and compared it with the electrastic interaction and the hydrophobic interaction. It concluded that the F-F interaction as a noncovalent interactions in PFOS sequestration is more effective. It can help the design of the on-situ analysis probes and nano matrices for removing PFOS at low concentrations.Part 2:Improving both aqueous solubility and anti-cancer activity by assessing progressive lead optimization librariesBecause of its persistent low survival rate, lung cancer remains a top global threat. Therapeutic agents for lung cancer, especially for drug-resistant non-small cell lung cancer (NSCLC) are urgently needed. We previously reported a series of thiazolidinone compounds that targeted tubulin and heat shock proteins. These compounds can inhibited growth of NSCLC cells and the drug-resistant NSCLC cells with EC50 values around 1.0 μM while exhibiting a low toxicity to normal human fibroblasts (>100 μM). However, these compounds generally have a low aqueous solubility. Solubility is crucial in the success of a drug candidate. Compounds with low solubility not only cause problem for in vitro and in vivo assays, but also add significant burdens to drug development. In order to optimize lead compounds, exploring rapid and effective approaches for optimization of multi-parameters in a compound is necessary. This article reports our efforts to optimize both aqueous solubility and anti-cancer activity of leading thiazolidinone compounds using combinatorial lead optimization libraries.In order to improve aqueous solubility of thiazolidinone compounds, we first incorporated more polar R2 groups and diverse Ri groups in a combinatorial lead-optimization librar (Library 1,25 members). Compounds in Library 1 were screened for their aqueous solubility using a high throughput solubility assay and their cytoselective toxicity in NSCLC cell line H460, drug-resistant NSCLC cell line H460iaxR, and normal human fibroblasts (NHFB) using SRB assay. Only 3 compounds have enhanced the aqueous solubility. Due to the changes in its activity groups, the anti-cancer activity were decreased. Another 7 compounds have enhanced the anti-cancer activity, but the aqueous solubility didn’t get the promotion. We made another compounds library (Library 2,10 members) to further explore the effects of the new variable modification sites R3. The aqueous solubility results showed that R3 have played a more important role in determining compound solubility, When R3c= CH3, the aqueous solubility of compounds exhibited improvements. At the same time 3 anti-cancer activity compounds have been found. We conducted a computational study generating a pharmacophore using 10 active compounds. The pharmacophore showed a requirement for two hydrogen bond acceptor regions and three hydrophobic regions. These pharmacophore features match well with what we previously reported on anti-cancer thiazolidinone compounds. To further evaluate effect of R3 substitutions on compound’s anti-cancer efficacy, we determined EC50 values of compounds in Library 2. In summary, using progressive optimization library approach, we improved both aqueous solubility and cytoselective anti-cancer activity of lead compound 1.A new lead compound 31, with a 5-fold enhanced solubility and 10-fold improved anti-cancer activity has been found as a promising compound for further investigations. |
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