Synthesis And Bioactivities Of Pyrazole Derivatives And Rhodamine B-based PH Fluorescent Probes

Part I:Pyrazole derivatives represent an important category of nitrogen-containing heterocycles. Compound with pyrazole framework displays diverse biological activities such as anti-cancer, anti-inflammatory, anti-microbial, anti-oxidant, anti-depressant, anti-angiogenesis and anti-influenza activities. Moreover, some of the derivatives have been applied in the field of medicine, such as Celecoxib, Sildenafil, Zaleplon and Riociguat.Metal-based complexes have been playing a prominent role in the medicinal chemistry area since the discovery of cisplatin. During the past years, numerous new promising organometallic complexes were reported to exhibit high anti-cancer activity, including Au complexes, Rh complexes, Ru complexes and ferrocene derivatives. Incorporation of the ferrocene fragment into an organic molecule often results in excellent biological activities due to its similarities in aromaticity and lipophilicity of morphology to the benzene ring, along with the particular redox property.In this part, we designed and synthesized several series of novel pyrazole derivatives. Their structures were characterized by means of IR,1H NMR, HRMS and X-ray diffraction. The biological activities and, optical properties of the compounds were also investigated.Chapter1, we reviewed the applications of pyrazole and ferrocene derivatives in the biological activity and the synthetic methods of pyrazole fused heterocyclic derivatives. We also summarized the influence of microwave irradiation on chemical reaction and the chirality on drugs.Chapter2, a series of novel ferrocenyl pyrazole-containing chiral aminoethanol derivatives were synthesized by microwave-assisted reaction. Structural features were confirmed by IR,1H NMR, X-ray diffraction and mass spectroscopy. Preliminary biological evaluation showed that all the compounds could suppress the growth of A549and H322lung cells.Chapter3, a series of novel chiral ferrocenylpyrazolo[1,5-a][1,4]diazepin-4-one derivatives were synthesized under the microwave-assisted condition. Their structures were determined by IR,1H NMR, HRMS and X-ray analysis. As was indicated in the preliminary biological evaluation, some compounds were able to suppress the growth of A549, H322and H1299lung cancer cells.Chapter4, a series of novel chiral3-ferrocenyl-l-(2-hydroxy-3-(arylamino) propyl)-1H-pyrazole-5-carbohydrazide derivatives were successfully synthesized and their structural features were confirmed by virtue of IR,1HNMR, HRMS. Preliminary biological evaluation showed that some compounds could suppress A549lung cancer cells growth.Chapter5, a series of novel1-arylmethyl-3-aryl-H’-((7-(diethylamino)-2-oxo-2H-chromen-3-yl)methylene)-1H-pyrazole-5-carbohydrazide derivatives were synthesized. Their structures were determined by IR,1H NMR, HRMS and X-ray diffraction analysis. The absorption and fluorescence characteristics were investigated in tetrahydrofuran, toluene and ethanol.Part II:Intracellular pH plays a pivotal role in many biological behaviors, such as cell growth, apoptosis, autophagy, ion transport, homeostasis and enzymatic activity. The intracellular microenvironment has various pH values, for instance, the cytosol has slightly basic pH values (pH～7.2), whereas the interior of lysosome and endosome is slightly acidic (pH4.0-6.0). Aberrations of the intracellular pH homeostasis in organelles can lead to cellular dysfunctions and affect human physiology, causing serious diseases such as Alzheimer’s disease, stroke and cancer. Therefore, monitoring pH changes inside living cells is of great importance for gaining insights into cellular metabolisms, physiological and pathological process.Fluorescent sensors have attracted much attention for assessing intact and subcellular pH due to their high sensitivity and selectivity, unrivaled spatiotemporal resolution, simple operation and nondestructive use in cells. Rhodamine dyes have been widely used for metal ion detection and intracellular imaging on account of their excellent biocompatibility and photophysical properties. In this part, we reported three rhodamine-based pH fluorescent probes RML, RC1and RC2.Chapter1, we reviewed the recognition mechanisms of fluorescent probes and the research on the application of pH fluorescent probes in recent years.Chapter2, we synthesized a rhodamine-based pH fluorescent sensor RML, in which a lysosome-targetable group,4-(2-aminoethyl)morpholine, is introduced. The probe has long absorption and emission wavelengths, high sensitivity and selectivity. It is also membrane permeable. The probe with pKa5.16is suitable for monitoring pH in acidic organelles. It has been successfully applied in monitoring pH changes inside living cells and can selectively stain lysosomes.Chapter3, novel ratiometric pH probes RC1and RC2were successfully designed and synthesized. These two ratiometric pH probes were constructed by integrating a coumarin fluorophore as an FRET donor into the rhodamine B fluorophore as an FRET acceptor. Probe RC1and RC2could be used for the ratiometric measurement of pH values in range2.20-4.20(RC1) and4.20-6.00(RC2) with high selectivity.