Synthesis And Activity Study Of Olaparib And Its Derivatives

Although remarkable progress has been made in cancer diagnosis and treatment technologically in recent years,the survival percent of the cancer patients is still much low.Thus,researchers have attached much attention to the development of antitumor drugs,especially the development of new drugs which have a different treatment way from traditional drugs.With the gradual familiarity with the mechanism and function of PARP in DNA reparation,PARP inhibitors as antitumor drugs to treat cancer have pulled a new prologue.Olaparib(AZD2281,KU-0059436),a small molecule and PARP-1 inhibitor,is an oral drug developed by KuDOS Pharmaceuticals Ltd.,which is a wholly owned subsidiary of AstraZeneca.Olaparib kills tumor cells by inhibiting DNA damage repair process of tumor cells and synthetic lethality.As a new antitumor drug,Olaparib can be used alone or combined with alkylating agent and platinum drug to enhance the curative effect of chemotherapy.However,the synthesis of Olaparib at present still have the shortage of long experimental route,complex operation and low yield and so on.Based on this,we want to design a new synthetic route to improve Olaparib synthesis situation.At the same time,we also hope that we can give analogues derived from Olaparib which can provide more possibilities for clinical treatment.Based on literatures published,we finally chose 2-carboxybenzaldehyde and dimethyl phosphonate as reactants to get phosphorus Ylide reagent in this work,which reacted with 2-fluoro-5-formylbenzonitrile for Wittig-horner reaction.After hydrolysis,cyclization and acidification,an important intermediate,2-fluoro-5-((4-oxo-3H-phthalazin-1-yl)methyl)benzoic acid(compound 3),was obtained and then directly reacted with 1-(cyclopropanecarbonyl)piperazine for a condensation reaction to get the target Olaparib(compound 5)under the catalysis of O-(Benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium Hexafluorophosphate.This work had also made a series of optimization to the synthetic route of Olaparib,including reaction temperature,catalyst and the choice of the deacid reagent,to get a higher yield and an easier experimental operation.At the same time,we chose the important intermediates in the synthesis of Olaparib,2-fluoro-5-((4-oxo-3H-phthalazin-1-yl)methyl)benzoic acid(compound 3),to react with amino-compounds in the common drugs on the market for a condensation reaction to get Olaparib analogues: O-1,O-2,O-3 and O-4.We tested the antitumor activity of Olaparib and its analogues by measuring their halfmaximal inhibitory concentration(IC50)for human breast cancer cells HCC-1937 and MDA-MB-436 to assess inhibitory ability of the cell proliferation for the synthetic drugs.And the IC50 values were also used to evaluate antitumor activity of these five compounds.Compared with previous Olaparib synthetic route,this work has many advantages,such as cheaper reaction reactants,less reaction steps,easer reaction procedures and better post-treatment optimization.This designed reaction route has much more feasibility and can reach 31.65% for Olaparib total yield,which has great potential in pilot test.According to IC50 obtained from the antitumor activity experiment,we may safely draw the conclusion that the antitumor activity of the synthetic Olaparib analogues,O-1,O-2,O-3 and O-4,is higher than that of Olaparib.In conclusion,this work successfully optimized the synthesis route of Olaparib and derivatively obtained four Olaparib analogues.The antitumor activity of Olaparib analogues,O-1,O-2,O-3 and O-4,is higher than that of Olaparib,which provides more antitumor choices.