Study Of HPMA-Coumarins Copolymer Anti-cancerdrug

My research work was mainly composed of four parts:1.In order to obtain potent and low toxicity anti-cancer drug, we report the synthesis, characterization and evaluation of two novel7-hydroxycoumarin,N-(2-hydroxypropyl) methacrylamide and7-hydroxycoumarin,N-(2-hydroxypropyl)methacrylamide, sulfadiazine copolymers conjugates for tumor drugs. Poly(HPMA)-7-hydroxycoumarin (1) and Poly(HPMA)-sulfadiazine-7-hydroxycoumarin (2) were synthesized by free radical precipitation polymerization in acetone/dimethylsulfoxide using N,N'-azobis(isobutyronitrile) as the initiator. The copolymers were characterized by1H-NMR,13C-NMR and Gel Permeation Chromatography (Mn=1.1×104, Mw/Mn=1.42; Mn=1.1×104, Mw/Mn=1.04). Also, the preliminary in vitro antitumor activities against liver cancer H22and the in vivo inhibitions of liver cancer H22demonstrated that the copolymers effectively inhibit the growth of tumor cells.2.Poly(HPMA)-FA-APMA-DTPA(HPMA:N-(2-hydroxypropyl)-methacrylamide; APMA:N-(3-aminopropyl)methacrylamide; DTPA:diethylenetriaminepentaacetic acid; FA: Folic acid) as dual targeting drug delivery system was synthesized and characterized was by1H NMR. Folic acid and HPMA copolymer were selected as the active targeting ligands and passive targeting carrier respectively, and a combination of both is expected to provide synergistic dual targeting (passive targeting and active targeting) drug delivery system.3.Two new a-diimine ligands, bis[N,N'-(2-ethyl-6-methyl-4-(1-phenylethyl)phenyl) imino]-1,2-dimethylethane (S,R)-2a and bis[N,N'-(4-chloro-2-ethyl-6-methylphenyl)imino]-1,2-dimethylethane2b, and their corresponding Ni(?) complexes{bis[N,N'-(2-ethyl-6-methyl-4-(1-phenylethyl)phenyl)imino]-1,2-dimethylethane}dibromonickel (s,R)-3a and {bis[N,N'-(4-chloro-2-ethyl-6-methylphenyl)imino]-1,2-dimethylethane}dibromonickel3b, were synthesized and characterized. The crystal structures of representative racemic ligand (S,R)-2a and its racemic complex(S,R)-3a were determined by X-ray crystallography. The asymmetric unit of chiral (S,R)-2a contains one half-molecule which exhibits a crystallographically imposed center of symmetry. The single C-C bond in1,4-diazabutadiene fragment is trans-configured and situated on inversion center. However, the trans-configured ligand can be transformed into cis-configured ligand in order to facilitate the formation of chiral complex (S,R)-3a. Complex (S,R)-3a has pseudo-tetrahedral geometry about the nickel center. Complex3c{bis[N,N'-(2-ethyl-6-methylphenyl)imino]-1,2-dimethylethane} dibromonickel was also synthesized and characterized for comparison. These complexes, activated by diethylaluminum chloride (DEAC) were tested in the polymerization of ethylene under mild conditions. Complex (S,R)-3a bearing one ethyl and one methyl in the ortho-aryl position and an electron-donating1-phenylethyl groups in the para-aryl position, activated by diethylaluminum chloride (DEAC), shows highly catalytic activity for the polymerization of ethylene [3.22×106g PE/(mol Ni·h·bar)]. Interesting, complex3b bearing one ethyl and one methyl groups in the ortho-aryl position and a strong electron-withdrawing Cl substituent group in the para-aryl position produced the more dendritic polyethylenes (branching degree:92,114and139branches/1000C at20,40and60?, respectively) under low ethylene pressure. The dendritic polyethylene particle size can be controlled in the1-20nm range, and could be expected to become the nano-targeted drug carrier after modified with water-soluble oligo (ethylene glycol)(OEG).4.Two new bulky-substituted a-diimine ligand, bis[N,N'-(2-ethyl-6-methyl-4-(1-phenyl-ethyl)-phenyl)imino]acenaphthene2a, and bis[N,N'-(4-fluoro-2-methyl-6-(1-phenyl-ethyl)-phenyl)imino]acenaphthene2b, and its corresponding racemic Ni(II) complex, bis{bis[N,N'-(2-ethyl-6-methyl-4-(1-phenyl-ethyl)-phenyl)imino]acenaphthene}dibromonicke (S,R,S,R)-3a, bis{bis[N,N'-(4-fluor-2-methyl-6-(1-phenyl-ethyl)-phenyl)imino]acenaphthene} dibromonicke (R,R)-3b, were successfully synthesized and characterized by1H NMR,13C NMR. The molecular structure of complex3a,3b were determined by single-crystal X-ray diffraction and revealed a distorted-tetrahedron geometry about the nickel center. a-Diimine ligand2c, bis[N,N'-(2-ethyl-6-methylpheny)imino]acenaphthene and bis{bis[N,N'-(2-ethyl-6-methylpheny)imino]acenaphthene}dibromonicke3c, were also synthesized and characterized for comparison. These complexes, activated by diethylaluminum chloride (DEAC) were tested in the polymerization of ethylene under mild conditions. The precatalyst3a,3b with sterically bulky p-sec-phenethyl and o-sec-phenethyl, activated by diethylaluminum chloride (DEAC) and tested in the polymerization of ethylene, were highly active [3.29×106g PE/(mol Ni·h·bar)],[3.64×106g PE/(mol Ni·h·bar)]. The state of the polyethylene obtained varied from plastic, elastomer polymers to the oil-like hyper branched polymers. Interesting, complex3b bearing one methyl and one phenethyl groups in the ortho-aryl position and a strong electron-withdrawing F substituent group in the para-aryl position produced the more dendritic polyethylenes (branching degree:81.2,102.0and127.9branches/1000C at20,40and60?, respectively).