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Syntheses And Structures Of Polynuclear Complexes Bridged By N,N’-bis(substituted)oxamides: Cytotoxicity Studies And Reactivities Towards DNA And Protein

Posted on:2013-03-31Degree:DoctorType:Dissertation
Country:ChinaCandidate:X W LiFull Text:PDF
GTID:1221330377452891Subject:Medicinal chemistry
Abstract/Summary:PDF Full Text Request
Investigations on small organic molecules and metal complexes towards DNA and protein areof current interest in connection with information about drug design and tools of molecular biology.Cisplatin (cis-[PtCl2(NH3)2]), is one of the most widely used anticancer chemotherapeutic agents.But the side-effects, which involve covalent binding to DNA, prevent its potential efficacy. On theother hand, serum albumins have been serving an important and efficient role in drug delivery dueto their remarkable binding properties. Taking into account the above facts, DNA-binding andprotein-binding investigations of polynuclear metal complexes have been an active field ofinorganic pharmaceutical chemistry studies.With the aim of finding more-efficacious, target-specific and less-toxic anticancer drugs, in thispaper, four N,N’-bis(substituted)oxamide ligands and twenty polynuclear complexes have beensynthesized and characterized. And their reactivities towards HS-DNA and BSA and in vitrocytotoxicity studies have been studied. The detail contents include four aspects as follows:1. Synthesis and structures of N,N’-bis(substituted)oxamide ligands and polynuclearcomplexes: in this paper, three dissymmetrical N,N’-bis(substituted)oxamide ligands,N-(2-aminopropyl)-N’-(2-oxidophenyl)oxalamide (H3apopoxd, L1), N-(5-chloro-2-hydroxyphenyl)-N’-[3-(dimethylamino)propyl]oxamide (H3chdpoxd, L2), N-benzoato-N’-(2-aminoethyl)oxamide(H3oxbe, L3) and one symmetrical N,N’-bis(substituted)oxamide ligands,N,N’-bis[3-(methylamino)propyl]oxamide (H2mapox, L4), have been synthesized and characterized.Three binuclear complexes,[Cu2(apopoxd)(bpy)](ClO4)·H2O (1),[Cu2(apopoxd)dabt](ClO4)·2H2O(2) and [Cu2(apopoxd)(phen)2](ClO4)(3), are synthesized using H3apopoxd (L1) as bridging ligand.By choosing H3chdpoxd (L2) as bridging ligand, nine polynuclear complexes have beensynthesized, including seven binuclear complexes,[Cu2(chdpoxd)(H2O)(Me2bpy)]·[Cu2(chdpoxd)-(CH3OH)(Me2bpy)](ClO42·CH3OH (4),[Cu2(chdpoxd)(H2O)(bpy)](ClO4)·CH3OH (5),[Ni2(chdpoxd)(bpy)2](ClO4)(6),[Cu2(chdpoxd)(H2O)(dabt)](ClO4)·H2O (7),[Cu2(chdpoxd)(H2O)-(phen)](NO3)·H2O (8),[Cu2(chdpoxd)(CH3CH2OH)(NO2phen)](NO3)(9) and Cu2(apopoxd)-(Mepy)N3(10) and two trinuclear complexes,{[Cu3(chdpoxd)2]·H2O}2·[Cu3(chdpoxd)2(H2O)2]·-2H2O (11) and [Ni3(chdpoxd)2(H2O)(DMF)](H2O)(DMF)(12). Using the mononuclear fragmentN-benzoato-N’-(2-aminoethyl)oxamidocopper(II), Na[Cu(oxbe)], as “complex ligand”, fivetetranuclear complexes [Cu4(oxbe)2(bpy)2]Cl22CH3OH (13),[Cu4(oxbe)2(bpy)2](ClO4)22H2O (14),[Cu2(oxbe)(dabt)]2(ClO42(15),[Cu2(oxbe)(dabt)]2(pic)2(16) and [Cu2(oxbe)(phen)]4(ClO44·6H2O (17) are synthesized. By choosing N,N’-bis[3-(methylamino)propyl]oxamide (H2mapox, L4) asbridging ligand, two binuclear complexes [Cu2(mapox)(bpy)2](ClO42(18) and [Cu2(mapoox)-(CH3OH)(bpy)2]2(pic)4·H2O (19) and one two-dimensional polymer [Tb2(mapoox)2-(ox)3(H2O)2]n·(4H2O)n(20) are synthesized. Their structures have been characterized by elementalanalyses, IR and single-crystal X-ray diffraction. The influence factors of the crystal structures ofthese complexes, and the effects of hydrogen bonds and π-π stacking interactions on the crystalstructures and supramolecular structures of these complexes were also discussed.2. Interactions of compounds with DNA: the DNA-binding properties of the fourN,N’-bis(substituted)oxamide ligands and twenty polynuclear complexes have been studied by theelectronic and fluorescence spectra and viscosity measurements. Besides, the influences of the typesof metal ions, terminal ligands and counter-ions on the interactions between compounds andHS-DNA were also investigated. The results reveal that liand L1, L2and L3interact with HS-DNAvia the intercalation mode, L4via the groove mode. And all of the twenty complexes interact withHS-DNA mainly via the intercalation mode, and according to the difference of the metal ions,terminal ligands and counter-ions, the bonding strength of these complexes with HS-DNA followthe order:(3)>(2)>(1),(4)>(5),(7)>(6),(9)>(8),(11)>(12),(17)>(14)>(13)>(16)≈(15),(18)>(19).3. Interactions of compounds with BSA: furthermore, the protein binding ability has beenmonitored by using UV absorption and tryptophan fluorescence quenching experiment in thepresence of the twenty-four compounds using bovine serum albumin (BSA) as model protein. Theresults reveal that all of the twenty-four compounds can interact with BSA, and the metal ions,terminal ligands and counter-ions could influence the binding abilities.4. In vitro cytotoxicity studies of compounds: the in vitro cytotoxicity studies of twenty-fourcompounds against two cancer cell lines: human hepatocellular carcinoma cell line SMMC-7721and human lung adenocarcinoma cell line A549were tested by SRB method, the results indicatethat except H2mapox (L4), the other compounds have a certain cytotoxicities against SMMC-7721and A549cell lines, with IC50values less than100μg/mL, respectively.The researches of this dissertation enrich the content of oxamide-bridged polynuclearcomplexes. And the results could be the valuable in understanding the relationship between theDNA and BSA binding properties and bioactivities of the oxamide-bridged polynuclearcomplexes.These studies could supply some valuable information for the rational design of novel,powerful antitumor agents.
Keywords/Search Tags:N,N’-bis(substituted)oxamide, Polynuclear complexes, Crystal structures, DNAinteractions, BSA interactions, Antitumor activities
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