1.Design,Synthesis And Biological Evaluation Of Novel PARP-1/2 Inhibitors 2.Methodology Study Of Cascade Synthesis Of Thieno [2,3-c]coumarins

Poly(ADP-ribose)polymerase-1,or PARP-1,is the most abundant and bestcharacterized member of the PARP family of nuclear enzymes.PARP-1 is involved in the signaling of DNA damage through its ability to recognize and rapidly bind DNA single-and double-strand breaks.Then PARP-1 can catalyze the transfer of ADP-ribose units to proteins using nicotinamide adenine dinucleotide(NAD+)as the substrate,resulting in the formation of long and branched poly(ADP)ribose(PAR)chains.PARP-1 has been the focus of over 20 medicinal chemistry programs in a wide range of therapeutic areas encompassing stroke,cardiac ischemia,diabetes and cancer,of which ischemia and cancer hold the most promise.The PARP-1 inhibitor has two potential applications in cancer therapy.The one application is as a chemopotentiator.PARP-1 inhibitors can be used in combination with DNA damaging chemotherapeutics or radiation to kill the cancer cells.The other application is as stand-alone therapy to kill the BRCA-1/2deficient tumor cells.At present,most PARP-1 inhibitors in clinic research or appear on the market are not selective on PARP subtype,at least not selective on PARP-1 and PARP-2.Although,the activity of PARP-2 was reported to be necessary for embryonic growth.The functions of PARP-2 are still not fully understood due to the lack of selective inhibitors.With the aim to discover high potent PARP-1/2 inhibitors with PARP-1/2 selectivity,two different series of PARP-1/2 inhibitors are designed.A nitrogen-sulfur nonbonding interaction in the design of new phthalazin-1(2H)-ones as PARP-1/2 inhibitors was utilized.Two series of compounds were designed and synthesized and the result could provide useful clues for future molecular design.There are many bioactive products bearing coumarin moiety,and these compounds are used for preliminary studies including anti-virus,anticancer,anti-inammatory,anticoagulant,etc.Thieno-coumarins,a class of thieno-fused coumarin derivatives,have attracted great interest from researchers due to their bioactivities,but works for systematic synthesis of thieno-coumarins are quite rare.A one-pot transition-metal-free,base-mediated synthesis of a novel series of functionalized thieno[2,3-c]coumarins via a cascade reaction from chromones has been developed.This cascade reaction involves a Michael addition–Knoevenagel condensation–intramolecular cyclization.These methodologies have significant advantages such as transition-metal-free,broad substrate tolerance,high yields,mild conditions,etc.Structure diversity could be easily achieved with these protocols.