Design,synthesis And Biological Activity Evaluation Of [1,2,4] Triazolo [1,5-a] Pyrimidine Derivatives

Despite its simple structure,[1,2,4]triazolo[1,5-a]pyrimidine heterocycle has a wide range of biological activities,including antibacterial,antiviral,and anticancer activities,which makes it a privileged skeleton for the development of new drug.Since the structure of[1,2,4]triazolo[1,5-a]pyrimidine ring is similar to purine,which is often used to substitute purine ring.Constructing novel and diverse[1,2,4]triazolo[1,5-a]pyrimidine compounds and studying their biological activities have become a current hot spot.By adoptingc extensive drug design strategies to introduce different substituents into the[1,2,4]triazolo[1,5-a]pyrimidine scaffold to enrich its novelty and diversity results in compounds with novel or better biological activities,which lays the foundation for the further development of[1,2,4]triazolo[1,5-a]pyrimidine drugs.The work described herein includes the following 4 parts:1.Design,synthesis and biological activity evaluation of[1,2,4]triazolo[1,5-a]pyrimidine inhibitors targeting DCN1-UBC12 protein-protein interactionBy screening our in-house compound library,we discovered the hit compound El(also known as WS-291),which moderately inhibited DCN1(IC50=5.82 μM).Based on the crystal structure of DCN1-UBC12,we docked WS-291 with DCN1 and then designed and synthesized a series of[1,2,4]triazolo[1,5-a]pyrimidine DCN1 inhibitors E1-E44.Among these compounds,compound E31(also called WS-383)could effectively block the interaction between DCN1 and UBC12(IC50=11 nM),selectively inhibit the Neddylation of cullin3/1,and induce p21,p27 and NRF2 accumulation.2.Design,synthesis and biological activity evaluation of novel dithiocarbamate[1,2,4]triazolo[1,5-a]pyrimidine inhibitors targeting DCN1-UBC12 protein-protein interactionBased on the discovered hit compound F1(also known as WS-493,IC50=12.23μM),we designed and synthesized a series of novel dithiocarbamate[1,2,4]triazolo[1,5-a]pyrimidine DCN1-UBC12 inhibitors F1-F55 by performing extensive drug design strategies.Among these compounds,compound F53(also known as WS-827)irreversibly blocked the DCN1-UBC12 interaction(IC50=61 nM).Further underlying mechanism indicated that WS-827 could effectively and selectively inhibit the Neddylation of cullin 3 and increase the level of NRF2 protein,while it has little effect on the expression of p21,p27 and CTD1 in both MGC-803 and KYSE70 cells.3.Design,synthesis and anti-cancer evaluation of[1,2,4]Triazolo[1,5-a]pyrimidine ABCB1 InhibitorsBy screening our in-house compound library,we found the hit compound WS-36,which was cellularly engaged to ABCB1 protein and enhanced the sensitivity of ABCB1-overexpressed SW620/Ad300 cells to paclitaxel(PTX).PTX,combined with WS-36 at a non-toxic concentration of 20 μM,inhibited cell survival of SW620/Ad300 cells(IC50=2.34 μM),better than single treatment of PTX(IC50=4.23 μM).Based on the binding mode of compound WS-36 and ABCB1,we designed and synthesized a series of[1,2,4]triazolo[1,5-a]pyrimidine ABCB1 inhibitors G1-G50.Among these compounds,compound G22(also known as WS-691)could significantly decrease the amount of PTX at a non-toxic concentration(IC50=22 nM,RF=192.25),and almost completely reverse the resistance of SW620/Ad300 cells to PTX.4.Design,synthesis and anti-cancer evaluation of[1,2,4]triazolo[1,5-a]pyrimidin chalcone ABCB1 inhibitorsIt has been reported that some of the reported ABCB1 inhibitors featuring similar structural characteristics-chalcone,such as flavonoids and chalcone,exhibited potent reversal activity by inhibiting ABCB1.To identify more safe and effective ABCB1 inhibitors,we tried to introduce various chalcone analogs into WS-691,and designed and synthesized a series of[1,2,4]triazolo[1,5-a]pyrimidin chalcone ABCB1 inhibitors H1-H48.Among these compounds,compound H22(also known as WS-898)could effectively and completely reverse the resistance of SW620/Ad300 cells to PTX(IC50=5 nM,RF=846)at a non-toxic concentration.In conclusion,we have designed and synthesized four series of 197 novel structure[1,2,4]triazolo[1,5-a]pyrimidine derivatives.Among these compounds,some compounds in series Ⅰ and series Ⅱ showed strong inhibitory activity against DCN1-UBC12,which enriched the structural types of DCN1-UBC12 inhibitors and provided novel ideas for the further design of DCN1-UBC12 inhibitors.Some compounds in series Ⅲ and series Ⅳ could effectively reverse the sensitivity of ABCB1-overexpressing SW620/Ad300 resistant cells to paclitaxel,which also enriched the structural types of ABCB1 inhibitors,providing a new direction for the design of ABCB 1 inhibitors in the future.