Design,Synthesis And Bioactivity Study Of Isoquinolones

Part 1:Design,synthesis and evaluation of isoquinolones as mPGES-1 inhibitor Microsomal prostaglandin E2 synthetase-1(mPGES-1)locates in the downstream of arachidonic acid pathway,which contains lots of enzymes relating with lipometabolism.Under physiological conditions,mPGES-1 catalyzes PGH2 into PGE2 directly together with cPGES and mPGES-2.When stimulated with IL-1β and TNFa,mPGES-1 expresses aboundantly and overproduces much excess PGE2 to mediate the process of inflammation.Nevertheless the expression of cPGES and mPGES-2 are maintained.Consequently,mPGES-1 can be considered as a promising target to develop a new generation of anti-inflammatory drugs.Despite all this,there is still no real selective inhibitor used in clinic.Based on mPGES-1 structure and binding model of inhibitor-protein reported previously,our group select PF-9184 for further investigate.Sufficiently combining CADD method,comformational restriction,bioisosterism and scaffold hopping,we design and synthesized three series of promising mPGES-1 inhibitors sharing the same isoquinolonic framework,most of which displayed nice bioactivities and docking scores to mPGES-1 protein or inflammatory cells.In synthetic work,experiments were started with parabromoaniline,substitutented aromatic boric acids,p-nitrophenyl acetate etc.as materials.After a series of complicated chemical reactions containing Suzuki-Miyaura cross-coupling reaction,Heck reaction,cyclization and so on.Eventually,29 compounds were synthesized and identified using 1H NMR、LC-MS.The newly synthesized derivatives were assessed for their anti-inflammatiory activities in vitro.The results indicated that derivatives K17 and L7 perfom 99.53%and 86.31%inhibition at 1μM respectively in transwell assay.Part 2:Total synthesis of 7-O-glucoside isoquinoloneTo solve the problem of sourcing sufficient quantities of 7-O-glucoside isoquinolone,a 12-step total synthesis route which contains redox reaction,hydrolysis of ester,glycosylation etc.is described using 3-hydroxybenzoic acid as material.The determination of synthesis route determines from the yields of glycosylation with different glycosyl donors.