Design And Synthesis Of Anti-rental Failure Drug Total Synthesis Of Pyrroloiminoquinone Alkaloids

Chronic renal failure (CRF) is one of the most common refractory disease in our country. At present, kidney dialysis is an effective method of treating kidney failure, but its application is limited because of the cardiovascular complications and heavy economic burden. As a result, it is particularly important to find new drugs. XLF-343was first studied as a new drug for renal failure by us. But its poor solubility spured us to designe and synthesize28new compounds based on the lead compound XLF-343. All of the compounds have been determined by1H-NMR and LC-MS. In addition, the derivatives were tested for anti-renal activity and some compounds demonstrated inhibitory activity to renal failure. All of these researches have great value for summarizing the structure-activity relationship in order to find new drug of good activity and high bioavailability in treating chronic renal failure. Marine natural products Ammosamide B, Plakinidine D and Lymphostin are structurally unique pyrrolo[4,3,2-de]quinoline akaloids which exhibit excellent antitumor activities. Wherein the myosin targeted Ammosamide B exhibited significant in vitro cytotoxicity against human colon adenocarcinoma HCT-116cells; Plakinidine D was reported to have potent in vitro cytotoxicity against the human colon tumor cell line HCT-116, and recently Lymphostin was found to exhibite potent mTOR inhibitory activity. Nevertheless, the synthesis of the three compounds remained synthetically challenging as all of them share the same complicating structure skeleton and densely pack arrays of chemically sensitive functional groups. In this thesis, based on retrosynthetic analysis of the core structure of the natural products, we have studied a novel and efficient synthesis method in construction of pyrrolo[4,3,2-de]quinoline framework through the intramolecular electrophilic cyclization from commercially available1,5-difluoro-2,4-dinitrobenzene.This dissertation finished the following work:1) We have successfully accomplished the total synthesis of Ammosamide B in only5steps albeit in moderate overall yield (9.7%). The key step of the route involves the condensation of1,3-diamine-4,6-dinitrobenzene derivative with dimethyl2-ketoglutaconate, which effectively constructs the pyrrolidinone ring and the quinoline ring in a single step. This study proved novel method for rapidly and efficient synthesis of pyrroloquinoline alkaloids and their analogues.2) Based on the similar consideration, we have studied the total synthesis of Plakinidine D, and constructed the core of this natural product via intramolecular electrophilic cyclization reaction by using1,5-difluoro-2,4-dinitrobenzene and isatin as the starting material, and successfully synthesized the analogue of Plakinidine D in seven steps.3) Besides we have tried the total synthesis of Lymphostin which laid foundation for further study.4) The primary cytotoxicity of the compounds have been tested.This essay would allow access to the preparation of a variety of structural analogues for investigation of pharmacological structure-activity relationships.