Solid-phase Synthesis And Biological Evaluation Of Quinazoline Libraries And The Application Of Samarium Reagents In Organic Synthesis

Quinazoline derivatives are recognized as a class of important heterocycles for their pharmacological properties, such as anticonvulsant, sedative, antihypertensive, vasodilator, antiinflammatory, antibiosis, phosphodiesterase inhibitors and fibrinogen receptor antagonists.Combinatorial chemistry has been well accepted as a new synthetic concept which originated in the 1980's. Due to it's efficiency in synthesis of large numbers of individual compounds as well as mixture-based combinatorial libraries in a short time frame and facility in high-throughput screening, combinatorial chemistry has become a powerful methodology in the research of medicinal chemistry. The progress of lead compound discovery has been great propelled after the emergence of the combinatorial chemistry.In this dissertation, 75 individual new quinazoline derivatives were synthesized from the resin-bound 4-chloro-7-fluoro-6-nitroquinazoline using parallel synthetic strategy for the biological evaluation of selected tumor cell lines. A mixture-based combinatorial library contains 1080 quinazoline derivatives and 10 individual 6,7-methoxyl-4-arylaminequinazolines were also synthesized for the biological evaluation of EGFR tyrosine kinase inhibitors. From the biological evaluation results, a series of quinazoline derivatives were found to have cytotoxicity against A549 cell line and nine of these compounds were found to have the potent effect. Three of these compounds were found to be biological active against six selected tumor cell lines. One compound has the potent cytotoxicity against most of the tumor cell lines compared with IRESSA and has been selected for the further investigation.Since Kagan first introduced the SmI₂ in the organic synthesis in the 1980's, samarium diiodide has been widely used in organic chemistry. Compared with samarium diiodide, metallic samarium is relative cheaper, more available and disposable. What's more, many organic reactions could be accompliched through the mediation of the metallic samarium. In this dissertation, metallic samarium catalyzed aroyl substitution reaction ofβ-keto esters and one-pot reductive conversion of nitroarenes to N-arylacetamides mediated by metallic samarium were reported which braoden the application of the metallic samarium in organic synthetic chemistry.