Design,Synthesis And Antitumor Activity Of Novel Potent Inhibitors Of Poly(ADP-ribose) Polymerase

Poly(ADP-ribose)polymerase-1(PARP-1)plays a significant role in the DNA repair process of the base excision repair(BER)pathway which can repair the single strand breaks of DNA by catalyzing the transfer of ADP-ribose from NAD+ to its receptors.To some tumor cells,who highly dependent on the DNA repair process of the base excision repair pathway to repair their DNA damages,inhibition of PARP-1’s activity has become an important way to treat cancer.The followings are our main work:1.Synthesis,anti-tumor activity and structure-activity relationships of 2-thioxo-2,3-dihydroquinazolin-4(1H)-one derivativesThe synthesis of 2-thioxo-2,3-dihydroquinazolin-4(1H)-one derivatives can divided into three steps.Firstly,anilines are reacted to benzaldehydes in an acid con-dition to form imide compounds and then a reduction reaction is carried out to afford secondary amines;secondly,acid chloride is prepared and reaction with ammonium thiocyanate to obtain 2-thio-xo-2,3-dihydroquinazolin-4(1H)-one derivatives’ nucleus;finally,a condensation reaction is implemented to afford target compounds.We apply the Alarm blue method and AZD2281 as positive control compound which is currently the only FDA approved the listing of PARP 1/2 inhibitor to test the anti-tumor activity in vitro of 2-thioxo-2,3-dihydro-quinazolin-4(1H)-one derivatives we had synthesized.we find that the activity of the whole series of compounds are very good.The compound 2-14,2-15,2-21 and 2-22(IC50 value respectively are 3.9nM,5.3nM,6.2nM and 8.3nM)show strong anti-tumor activity.Preliminary structure-activity relationship can be summarized:(1).Some fluorine atoms introduced into the appropriate positions of 2-thioxo-2,3-dihydroquinazol-in-4-(1H)-ones can improve the activity and introduced more,the activity increased more;(2).The volume of space in the end of the compounds can affect the activity and the activity is best when the structure in the end is 2-pyrimidinyl,cyclopentyl-formyl,cyclohexylformyl and cyclobutylformyl group;(3).a piperazine ring in structure is more beneficial than the homopiperazine ring.2.A new method prepared 1,3,5-substituted pyrazole derivativesCascade reaction,including nucleophilic substitution and addition cyclization,catalyzed by Cu+ salt between substituted aryl hydrazonoyl halides and terminal alkynes could produce 1,3,5-trisubstituted pyrazoles.The method employed easily available aryl hydrazonoyl halide and terminal alkynes as starting materials,under 45℃ in green acetonitrile/water solvent,regioselectively generating 1,3,5-trisubstituted pyrazoles in high yield.Above all,functional groups containing active hydrogen would not disturb this reaction,example for carboxyl and hydroxyl.In this article,fifteen pyrazole derivatives with different substituent group were achieved by this method.So it could be a general method to synthesize 1,3,5-trisubstituted pyrazoles.