Cascade-based Construction Of Privileged Substructure And Discovery Of Antitumor Lead Compounds

Privileged substructures play an important role in p DOS(privileged-substructure-based diversity oriented synthesis). In this thesis, a variety of facile cascade reaction were applied to construct privileged substructures and several antitumor lead compounds were found. The thesis is divided into three chapters as follows:(1) Organocatalytic asymmetric synthesis and structure-activity relationship of novel spiropyrazolone antitumor scaffold;(2) Enantioselective organocatalytic Michael addition of isorhodanines to α, β-unsaturated aldehydes;(3) Facile construction of pyrrolo[1,2-b]isoquinolin-10(5H)-ones via a redox-amination-aromatization-Friedel-Crafts acylation cascade reaction and discovery of novel Topoisomerase inhibitors. 1. Organocatalytic asymmetric synthesis of novel spiropyrazolone scaffold with potent antitumor activity1.1. Organocatalytic asymmetric synthesis of novel spiropyrazolone antitumor scaffold with potent activity: design, synthesis and structure-activity relationshipPhenotypic screening of high quality compound library is an effective strategy to discover novel bioactive molecules. Previously, we developed the divergent organocatalytic cascade approach to efficiently construct a focused library with scaffold diversity and successfully identified a novel spiropyrazolone antitumor scaffold. Herein, a series of spiropyrazolone derivatives were designed, synthesized and assayed. Most of them showed good in vitro antitumor activity with a broad spectrum. Preliminary structure-activity relationship for the substitutions and the stereo configuration were obtained. Compound 5k showed good antitumor activity and could effectively induce cancer cell apoptosis, which represents a good starting point for the development of novel antitumor agents.1.2. Organocatalytic asymmetric synthesis of novel pyrazolonespirocyclohexadienone scaffold with potent antitumor activity Novel pyrazolonespirocyclohexadienone scaffold was constructed through organocatalytic asymmetric synthesis. Several compounds with the novel scaffold showed in vitro antitumor activity and compound 5k showed the best antitumor activity, which represents a good starting point for the development of novel antitumor agents. 2. Enantioselective organocatalytic Michael addition of isorhodanines to α, β-unsaturated aldehydesMichael reaction of substituted isorhodanines with α, β-unsaturated aldehydes in the presence of catalytic amount of a chiral secondary amine is presented. This transformation proceeds in good to high yields furnishing the corresponding 4,5-disubstituted isorhodanine adducts in good to excellent enantioselectivities. The synthetic application of the resulting 4,5-disubstituted isorhodanines as versatile building blocks for the rapid synthesis of chiral isorhodanines. Moreover, due to diverse bioactivity of isorhodanines, the new derivatives reported herein will inspire medicinal chemists to investigate their pharmacological activity and discover drug leads. 3. Facile construction of pyrrolo[1,2-b]isoquinolin-10(5H)-ones via a redox-amination-aromatization-Friedel-Crafts acylation cascade reaction and discovery of novel Topoisomerase inhibitorsAn efficient redox-amination-aromatization-Friedel-Crafts acylation cascade process from trans-4-hydroxyproline and 2-formylbenzolic acids has been developed for the synthesis of pyrrolo[1,2-b]isoquinolin-10(5H)-ones. The process displays a relatively broad substrate scope. Their preliminary biological activity as Top inhibitors was explored for the first time. Compound 3h was a potent dual inhibitor of Top1 and Top2 with good antitumor activity, which represents a promising lead compound as anticancer agent for drug discovery.4. ConclusionIn summary, a variety of facile cascade reaction were applied to construct privileged substructures and several antitumor lead compounds were identified. A total of 160 new derivatives were designed and synthesized, 3 new antitumor lead compounds were discovered by biological evaluation. This thesis provided several good examples of combining organic synthesis methodology with medicinal chemistry to discover small-molecule antitumor agents and also provided the basis for the development of novel antitumor agents.