Design,Synthesis And Biological Evaluation Of Oriented Compound Libraries Derived From Three Scaffolds

A small molecule library with high-quality is the foundation of high-throughput screening(HTS)and lead compound discovery.In this thesis,we used pharmacophore stitching and scaffold hopping strategies to design and synthesize a focused library with novel chemical structures and spatial diversity.Guided with biological activity,we obtained a series of small molecules with excellent anti-tumor activity through the structure and activity relationship(SAR)study,which provides important lead compounds for further anti-tumor drug development.The thesis includes the following parts:In the first chapter,we have constructed a heteroaryl amide library and evaluated antitumor activity.Based on a high-throughput cytotoxicity screening,we designed and synthesized 42 heteroaryl amide derivatives based on the 'hit' ?-1.Through systematic SAR study,we obtained the best compound ?-40(N-(2-(benzofuran-2-yl)benzyl)-4Hpyrrolo[2,3-d]thiazole-5-carboxamide).The results showed that ?-40 was effective in inhibiting a variety of human cancer cell lines with IC50s between 9 and 70 nM,and it's active against multidrug resistance(MDR)cell lines as well.Further study demonstrated that ?-40 binds to the colchicine pocket and depolymerizes microtubule with unique mechanism,resulting in mitotic cell cycle arrest.In vivo efficacy study revealed that ?-40 also substantially inhibited tumor growth in mouse xenograft of paclitaxel-resistant HeLa cells(HeLaR).Therefore,?-40 could serve as a lead for developing new drugs to overcome multidrug resistance.In the second chapter,we set up a 2,4-disubstituted quinazoline library and assessed its inhibitory activity against kinase STK19.Based on the hit ?-1,we have designed and synthesized a total of 43 2,4-disubstituted quinazoline derivatives,which were evaluated using STK19 biochemical assay.Among them,?-26 was identified as a potent and highly selective STK19 inhibitor with biochemical IC50s of 24.04 nM and 467.4 nM against STK19 and G9a,respectively.Having good pharmacokinetic properties,?-26 not only effectively blocked N-RAS-driven melanoma cell growth,but also inhibited tumor growth in mouse xenograft model of N-RAS driven melanoma cell lines.Together,our findings provide a new and viable therapeutic strategy for melanomas harboring N-RAS mutations.In the third chapter,we built a library of five-membered and six-membered fused aza-heterocyclic compounds and assessed its activity for promoting degradation of KRASG12V.Using a high-throughput screening that specifically monitors the degradation of K-RASG12V,the hit ?-1 was obtained.A focus compound library having the core structure of ?-1,five-membered and six-membered fused aza-heterocycle was designed and synthesized.Among them,?-19,?-22 and ?-43 promoted the degradation of K-RASG12V higher than 50%at 20 ?M,which were working through binding to NEDD4-1.?-60 exhibited anti-cancer activity both in cancer cell and mouse xenograft model of SW620 cells in vivo.Taken together,our results provide a new potential approach for targeting K-RAS driven cancer through RAS degradation.In summary,we have successfully identified a series compounds with potent anticancer activities,including new tubulin inhibitor ?-40,STK19 inhibitor ?-26 and KRASG12V degrader,which would laid the foundation for the development of new anticancer drugs.