Computer Aided Regioselective Construction And Anti-toumor Activities Of1,3-Diazaheterocycle Fused[1,2-α][1,8]Naphthyridine Derivatives

In recent years, it has been demonstrated that the1,8-naphthyridine nucleus was possesses a broad range of pharmacological activities, including inhibition of enzymes, antagonism or agonism of receptors, as well as anticancer, antibacterial, anti-inflammatory, and antioxidant activities. Although many different synthetic approaches for1,8-naphthyridine building blocks have been introduced, few strategies have been successfully developed for concise and efficient access to highly functionalized final products. Therefore, it is necessary to overcome these limitations and continue our previous endeavors in paralleled build up libraries of target compounds.In this thesis, we reported a one-step and regioselective synthesis of a series of novel and highly functionalized1,3-diazaheterocycle fused [1,2-a][1,8]naphthyridine derivatives (3) in57-95%yields from starting materials, i.e.,2-Chloroquinoline-3-carbaldehydes (ClQuAlds)(1) and Heterocyclic Ketene Aminals (HKAs)(2), which employed1,4-dioxane as the solvent, piperidine as the catalyst and under a temperature of75℃for20hours by aza-ene addition and cascade-cyclization reaction. This synthetic route is a concise, wild, transition-metal-free, and environmental benign protocol with cheap and facile starting materials. At the same time, it also validated the rationality, effectivity, and practicability of the proposed theoretical predictions which performed by computational chemistry.In order to evaluate the biological activities of the compounds3, our further investigations into the in vitro anti-tumor experiments toke place which based on the screening of five tumor cell strains, viz., HCT116, NCI-H460, Skov-3, HT29, and A549. It was observed that compounds3w,3a,31,3u, and3v presented excellent and specific inhibition to different tumor cell strains which were more potent than commercial drug-DDP.In conclusion, we have developed a computer aided, synthesis centered, and drug screening targeted interdisciplinary method which based on the application of synthetic chemistry, computational chemistry, and chemical biology. It avoided meaningless waste of time and resources in screening of synthons in real synthesis. Some novel naphthyridine derivatives with potential biological activities also achieved. This method not only continued our previous endeavors in HKAs relied fabrication of heterocyclic compound libraries but also supplied a gap, in part, of biological activities of naphthyridine derivatives. We therefore anticipate that this approach will extend to various heterocycles, and thereby may be of value for others investigate the natural product-liked heterocycles for developing novel synthetic methodologies.