Development Of Novel Approaches Toward The Synthesis Of Various Heterocycles And Drug Analogues For Drug Discovery

We aim to construct a high quality and unique small molecule library with scaffold diversity, which is comprised of nitrogen-containing heterocycles, oxygen-containing heterocycles and drug analogues. The library will be then screened in cell level for the discovery of new anti-cancer and anti-bacterial small molecules. In case of successful identification of anti-cancer and anti-bacterial small molecules, corresponding chemical probes will be synthesized for chemical-proteomic identification of cellular targets. The long-term goals of our research are the discovery of new anti-cancer and anti-bacterial targets and new inhibitors, which could be further used for drug discovery.The beginning of our research is development of new synthetic methods for small molecule library construction. In this dissertation, we devoted to developing new synthetic methods for nitrogen-containing heterocycles synthesis, oxygen-containing heterocycles synthesis and late-stage drug modification. The results were summarized as follows:3-Ethoxycyclobutanones were used as 1,3-dielectrophile and tricarbonsynthon for the synthesis of various nitrogen-containing heterocycles, such as pyrazoles and quinolines, for the first time. A novel convenient and efficient method for the preparation of pyrazoles through Lewis acid-catalyzed union of 3-ethoxycyclobutanones and monosubstitutedhydrazines was developed. The reaction demonstrated high yields and complete regioselectivity. Similarly, an efficient approach toward the synthesis of 2-alkylquinolines via Lewis acid mediated [3+3] annulation reaction between 3-ethoxycyclobutanones and aromatic amines was developed. The method was used for the synthesis of 8-aminoqunolines and 1,10-phenanthrolines. 3-Ethoxycyclobutanones could also be used for the synthesis ofβ-enamino ketones, which were the building blocks for various heterocycles, such as pyazoles, pyrimidines, oxazoles, pyridinones, indolones, indoles, pyrrolones and quinolones. Thus, starting from 3-ethoxycyclobutanones, we can get a small nitrogen-containing heterocycle library with scaffold diversity.2-Acyl phenols are the building blocks for various oxygen-containing heterocycles, such as chromanones, benzofuran-3(2H)-ones, benzoxazoles, xanthones and dibenzooxazepines. A novel Pd(II)-catalyzed ortho-selective C-H oxygenation reaction for phenols synthesis was discovered. Starting from aryl ketones, benzoates, benzamides, acetanilides, and sulfonamides, a series of multi-substituted phenols was obtained in highs yields. 2-Acyl phenols, produced from oxygenation of aryl ketones, were utilized for the synthesis of various above mentioned oxygen-containing heterocycles. The method was also used for late-stage modification of anti-inflammatory drug Ibuprofen ester. Similarly, an efficient and convenient approach towards 2-acyl phenols through Ru(II) and Rh(II)-catalyzed regio- and chemoselective C-H oxygenation was developed. A few different 2-acylphenols were prepared in gram-scale, which proved the practicality of this method. Its utility was exemplified in further applications in oxygen-containing heterocycle synthesis and late-stage modification of drug Fenofibrate. Thus, using transition-metal-catalyzed C-H activation reactions, we can get a variety of oxygen-containing heterocycles and drugs analogues.In summary, through development of new synthetic methods, we have constructed a small molecule library comprised of nitrogen-containing heterocycles, oxygen-containing heterocycles and drug analogues. Phenotype-based screening was ongoing for the discovery of new anti-cancer and anti-bacterial small molecules and targets.