Synthesis And Bioactivity Study Of DNA Bisintercalators Containing Sugar Skelecton And Dibutyltin Carboxylates Of Aminoglucosyl Derivatives

This dissertation was divided into three parts,the first part is study on thesynthesis of DNA intercalators containing sugar skelecton and their DNA bindingproperties;the second part is the synthesis of novel dibutyltin carboxylates ofaminoglucosyl derivatives and their anti-tumor activity and myelotoxicity study;thethird part is the design and synthesis of curcumin derivatives containing sugarhybrids.DNA is the carrier of genetic information and plays an important role in thecourse of genetic,which is the main target molecule that exists in anticancer andantiviral therapies.Small molecules that interact with DNA through recognition,binding,modification and cleavage have attracted great interests in the healthcarefield.Intercalators are the most important group of compounds that interact reversiblywith the DNA double helix.In recent years,synthese of various bisintercalators hasbeen popularly studied for their higher DNA-binding capacity and substantialsequence selectivity.Monosaccharides have long been known as biologically relevantscaffolds.Advantages of using saccharides are that they display a high density offunctional groups,are available as single enantiomers and contain multiple sites forattachment of recognition groups.Carbohydrate also exists in many antitumorantibiotics which targeting in DNA helix,including Anthracyclines family andEnediyne antibiotics.And it has been found that the carbohydrate part in thesemoleculars play a crucial role in the DNA recognition and sequence selectivity.According to this,we design and synthesis three series of DNA bisintercalators containing D-glucose,2-deoxy-2-amino-D-glucose and D-glucopyranuronic acidscatffold.For the chromophore part,we choose quinoline,quinoxaline,acridine andindol[3,2-b]quinoline ring as the intercalating agents.In the first series of compounds,8-hydroxy-quinoline is linked to the 6-CH₂OH group of glucose and the 1-OH groupof glucose was connected with different linkers including quinol,glycol andtriethylene glycol.The second series of the intercalators is based on the 2-aminoglucose which the amino group is coupled with terephthaloyl chloride and the 1-OHof the sugar is connected with different chromophores including 8-OH quinoline,9-hydroxyethyl acridine and indol[3,2-b]quinolin.The third part is the analogues ofEchinomycin based on D-glucopyranuronic acid which contains the macrocycles andquinoxaline group.All the synthesized compounds are characterized by ¹H NMR,¹³CNMR,MS and HR-MS.Also their interactions with calf thymus DNA (CT-DNA)were also investigated with UV-absorption,fluorescence spectroscopy and EBdisplacement analysis.The primary results suggest that the binding mode betweensome compounds and calf thymus DNA might be intercalation.D-amino glucose(2-amino-2-deoxy-D-glucose) is one of the most importantmonosaccharides in the glycosylprotein of higher animals and present in almost alltissues of human body.One of its interesting biological properties is that itsderivatives such as chitosan and glucosamine derivatives could kill the tumor cellswhile being less toxic to normal cells in human body.To take the advantage of thepositive biological properties of organotin (â…£) compounds and D-amino glucose,wedesigned two dibutyltin complexes of aminoglucosyl derivative compoundsbis-{cis-4-[N-(1′,3′,4′,6′-tetra-O-benzoyl-2-deoxy-glucopyranosyl)imido]-4-oxo-2-butenoic acid]-di-n-butyltin} carboxylate (35b) and bis-{o-[N-(1′,3′,4′,6′-tetra-O-benzoyl-2-deoxy-glucopyranosyl) carbamoyl]benzoic acid]-di-n-butyltin}carboxylate(36b).These two compounds were then characterized by IR,NMR and MS.In vitrotests showed that both compounds have high cytotoxicity to four tumor cell lines(P388,HL-60,A549 and BEL-7402) while compound (36b) is more efficient to P388and HL-60 (IC₅₀=0.06μM).Clonogenic assays demonstrated that both compounds (35b) and (36b) have hematopoietic cell toxicity at 2.06μM.This indicates thatcompound 36b could be a potential leading compound for antitumor drugs.Curcumin has attracted considerable attention due to its wide range of anticancerproperties,definitely curative effect and low toxicity.But poor water and plasmasolubility and easy decompose in water Caused by curcumin structure extremelylimited the use of curcumin.It has been found that whcn modified by carbohydrates,the lead compounds show lower toxicity and side effects,improved bioavailability.According to this,a series of carbohydrate modified compounds based on curcuminskelecton were designed and synthesized.And 4-methylene of the curcumin wassubstituted by 1-O-bromoethoxy glucose and the function groups in the two benzenerings are various.We postulated that the glycosylecurcuminoids derivatives mayincrease their stability,antitumor activity and water solubility.All the eightcompounds are novel and the structures are confirmed by ¹H NMR,¹³C NMR,ESI-MS and HR-MS.The screening of their bioactivities is underway.