Design and synthesis of biologically active triazines and triphenylethylenes as potential antibiotics and anticancer agents

Selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) are commonly prescribed for the treatment of breast cancer. However, the use of SERMs and AIs is compromised by congenital and acquired drug resistance and severe side effects. Compounds with dual AI and estrogen SERM activities are supposed to be beneficial and have special advantages for the treatment of breast cancer, including delayed drug resistance and fewer side effects. This dissertation aims to develop a series of agents with dual AI and SERM activity based on norendoxifen, a known metabolite of the widely used SERMs tamoxifen. A short and efficient synthetic route was established to prepare norendoxifen and its E and Z isomers. The testing results confirmed the potent AI and SERM activity of norendoxifen, rendering it the first substance with dual AI and SERM activity. Subsequently, a series of norendoxifen analogues were designed based on a structure-based optimization approach and prepared via multi-step organic synthesis. This led to the discovery of a series of analogues with dual AI and SERM activity. The most potent compound, 4'-hydroxynorendoxifen, displayed improved potency and superior cytochrome P450 selectivity compared with norendoxifen. A series of norendoxfien analogues without the aminoethoxy side chain were also synthesized. These compounds also displayed comparable AI and ER binding affinity with norendoxifen, and they represent a new series of dual AI/SERM agents for further evaluation. Another project described in this dissertation is the development of 1,2,4-triazine analogues as novel antibiotics that target inorganic pyrophosphatase (PPase). Based on a lead identified from high-throughput screening (HTS), a series of structurally related 1,2,4-triazine analogues were prepared via an efficient synthetic pathway to improve the PPase inhibitory and antibiotic activities. Several prepared triazine analogues displayed improved antibiotic activities over the HTS lead. The best compound, 140h, showed promising antibiotic activities against a wide variety of drug-resistant Staphylococcus aureus strains, as well as activity versus Mycobacterium tuberculosis and Bacillus anthracis. Although there is a lack of correlation between the PPase inhibitory activity and antibiotic activity, the current series of 1,2,4-triazine analogues still presents a new antimicrobial scaffold for further development.