Design,Syntheses And Evaluation Of Bioactivities Of Oligocarbazoles

DNA is one of the classical targets for anticancer drugs.At present,the clinically used DNA alkylating agents(cisplatin)and DNA intercalators(doxorubicin)were DNA-targeting drugs.They produce great toxic side effects for the sake of their non-specific binding to DNA.So scientists recently focus on those non-B DNA specific binding drugs.DNA-specific recognition includes both the sequence-selective and the structure-selective recognition,the latter one mainly refers to the specific recognition of non-B DNA.In human genome,the proportion of repetitive sequences is as high as 50%,and simple repetitive sequences accounts for 3%of the total.Under the induction of factors,these simple repeats could form the secondary structure of non-B DNA.During DNA replication and transcription,the non B-DNA such as A-Tracts and G-quadruplex may involve important biological functions.Compared with classic B DNA,A-Tracts DNA have been studied much less.A-Tracts DNA consist of more than four consecutive An-Tn sequence,whose major groove larger than that of B-DNA.G-quadruplex DNA is another popular anti-tumor drugs targeting in recent years.It is formed by hydrogen bonding from the d[G3(T2AG3)3]sequence,inducted by K+or Na+.A-tract DNA and G-quadruplex DNA are located in different locations in the nucleus and are subject to different degrees of interference from the outside world.Therefore,the ligands may exhibit different antitumor activities.Chemists and pharmacist have synthesized the selective DNA ligands and probe tools,to explore the biological function of non B-DNA and its effectiveness as the target of antitumor drug.The exploration of DNA specific ligands could help us to understand the mechanism of action of anti-cancer drugs.So,this paper mainly focuses on the selective ligands of both A-tracts DNA and human telomeric G-quadruplex DNA,and their antitumor activity.In this thesis,59 oligocarbazole derivatives have been designed and synthesized,and have not been reported based on SciFinder.All the structures have been confirmed by 1H-NMR and HRMS.Their binding properties of these compounds with A-tracts DNA and human telomeric G-quadruplex DNA have been studied systematically.The main works in the thesis include:1.The structural characteristics of both B-DNA and non B-DNA as well as their ligands have been briefly reviewed.B-DNA is the most common double helix DNA.Non B-DNA,a research hotspot in recent years,includes A-DNA,Z-DNA,A-Tracts DNA,DNA triplex and G-quadruplex.Their different structural features as well as their ligands are introduced.The research progress of carbazole derivatives as DNA ligands are also introduced.2.The novel calix[n]carbazole have been designed and synthesized.The 1,3 alternating conformation of calix[4]carbazole is approved by UV,FL,NMR spectra and molecular simulation.3.A series of calix[4]carbazole derivatives have been synthesized.Their interactions with A-Tracts DNA are systematically studied by UV,FL,CD and NMR.Their antitumor activities in vitro have been tested.The results show that calix[4]carbazole derivative could selectively bind to the large groove of A-Tracts DNA,and stabilize A-Tracts DNA,and exhibit weak antitumor activity.4.A series of linear oligocarbazole derivatives have been designed and synthesized,and their interactions with G-quadruplex DNA are systematically studied by UV,FL spectra.Their antitumor activities in vitro are tested.The results show that the compound 40 could bind to human telomeric G-quadruplex(22AG)selectivity,which also possesses excellent antitumor activity,comparable to that of the positive control drug(fluorouracil).