含5-氟尿嘧啶的氨基酸衍生物的合成及其抗肿瘤活性研究

5-氟尿嘧啶乙酸对硝基苯酯和5-氟尿嘧啶丙酸对硝基苯酯与一系列氨基酸反应,制备了12个新的含5-氟尿嘧啶的氨基酸衍生物,并确定了化合物的结构。初步动物试验表明某些化合物有一定的抗肿瘤活性。

STUDY ON IMMOBILIZED THERMOLYSIN WITH CELLULOSE AS CARRIER

With cellulose as carrier, immobilized thermolysin HE Ⅰ and HE Ⅱ were prepared by diazo coupling or glutaraldehyde crosslinking reaction. Using casein as a substrate, the activity recovery of immobilized thermolysin HE Ⅰ and HE Ⅱ reach 34. 596 and 29%, respectively. Some factors which affect the activity of the immobilized thermolysin such as temperature, medium PH, EDTA and calcium acetate were studied. At the same time, the thermal stability and storage stability Of the immobilized thermolysin were also investigated.

Synthesis of Poly(Glycolide-CO-2-hydro-2-oxo-1,3,2-Dioxaphosphorinane)

A novel polyester containing glycolic acid(GA)and 2 hydro 2 oxo 1,3,2 dioxaphosphorinane(TMP)was prepared by ring opening polymerization.The composition and the structure of the titled polymer were investigated by 1H NMR, 13 C NMR,FT IR,EA,and VPO.The influence of time on total conversion and molecular weight was also studied.

Immunostimulatory Properties of a Novel Polyphosphoramidate Based on Stearyl Tyrosine

The immunostimulatory property of a synthetic polyphosphoramidate based on stearyl tyrosine (PPST) is described. The immunostimulatory activity of this negatively charged polymer was investigated in vitro through examining the effect on the mitogen induced lymphocytes proliferation by a tetrazolium based colormetric assay and also through studying the primary plaque forming cells (IgM PFC) responses of Balb/c mice after the intraperitoneal (i.p.) injection of the polymer with sheep red blood cells (SRBC). PPST exhibits specific and high immunostimulatory activity in vitro by the stimulation on lipopolysaccharide(LPS) induced murine B cells proliferation, which is probably due to the interaction between the polymer with LPS responding B lymphocytes. This polymer also makes a significant increase of single antibody producing cells. The result shows that the stimulation rate to IgM PFC responses of Balb/c mice achieved 77.9% ( p <0.01) when 160 mg/kg of PPST was injected 4 h before with SRBC.

Study on Synthesis and Herbicidal Activity of Heterocyclic Compounds Containing P-P Bond

N,N′-diphenylurea reacted with phosphorus trichloride and phenyl dichlorophosphane giving the heterocyclic compounds 1 and 2 with a direct phosphorus-phosphorus bond (P-P bond), respectively. The new compounds were characterized by elementary analysis, NMR and IR spectra. The results of preliminary bioassay showed that these heterocycles possess selective herbicidal activity at 1.5 kg/hm2.

Modified DTPA， EDTA Ligands and Their Paramagnetic Metal Complexes as Contrast Agents for MRI

Six new aminocarboxylic ligands were synthesized by reactions of EDTA (ethylenediaminetetraacetic acid) dianhydride or DTPA (dlethylenetriaminepenta-acetic acid) dianhydride and ethyl ester of serine,threonine and tyrosine. Their paramagnetic metal complexes were also synthesized.All ligands and paramagnetic metal complexes were characterized by IR spectra,IH NMR and elemental analyses.Relaxivity study showed that the metal complexes had higher relaxation effectiveness as compared to corresponding unmodified metal complexes. Imaging study of gadolinium complex of tyrosine ethyl ester modified DTPA in mice demonstrated that this metal complex could apparently increase the signal intensity of MR images.

SYNTHESIS AND DRUG RELEASE OF CROSSLINKING POLYPHOSPHATES

A new class of crosslinking polyphosphates were synthesized characterizedby IR 1HNMR, 31PNMR spectroscopy as well as elemental analysis. In vitrodegradation of the polyphosphates obtained and the release of antineoplastic drugMethotrexate (MTX) and contraceptive Levonorgestrel (LNG ) by nsing thesepolymers as matrix were studied. Zero order release rate was rkserved in the case ofLNG release.

IMMUNOMODULATION OF SYNTHESIZEDPOLYMERS CONTAINING PHOSPHORUSIN THE BACKBONE──EFFECT ON THE PROLIFERATION OF LYMPHOCYTES

The immunomodulation of several charged synthetic polymers containing phosphorus in the backbone was studied in vitro through examining their inhibition or promotion effect on the proliferation of both T and B lymphocytes. It is found that polymers based on long chain alkyl ester of tyrosine exhibit immunomodulative activity. Negatively charged polymers show stimulative activiactivity on LPS-induced B lymphocytes proliferation. Positively charged polymers exhibit inhibitory activity on both Con A-induced T lymphocytes and LPS-induced B lymphocytes proliferation.

STUDY ON SYNTHESIS AND RELAXIVITY OF PARAMAGNETIC POLYESTER METAL COMPLEXES FOR MRI

Fifteen new polyester ligands were prepared by copolymerndion Of EDTA(ethylenediaminetetraacetic acid ) dianhydride or DTPA (dikthylenetriaminepenlaacetic acid) dianhydrtde and dihydric alcohol or dihydric phenol. Theirparanzagnetic metal complexes were also synthesized. All polyester ligands andmetal complexes were characterized by IHNMR, IR spectra and elemental analyses. Preliminary study showed that the polyester .metal complexes had higher relaxation effectiveness as compared to corresponding small molecular metal complexes.

Template-module assembly to prepare low-molecular-weight gene transport system with enhanced transmembrane capability

Based on specific host-guest interactions between amine-modified [3-cyclodextrin （CD-TAEA） and functional adamantane （AD） derivatives, a module-template strategy has been proposed for the construction of low-molecular-weight cationic assem- blies for gene transport. This strategy offers great flexibility in terms of the introduction of mono- or multi-functionality by the inclusion of one or more adamantane-based modules with the desired functionalities. As proof of concept, phenylboronic acid （PB） containing adamantane （PB-AD） was used as a model module in the hope of offering enhanced cytosolic delivery in con- sideration of the special affinity of PB groups with cell membranes. The physicochemical properties of the complexes formed with plasmid DNA, such as particle size, zeta potential and morphology were investigated. Confocal laser scanning microsco- py and flow cytometry experiments demonstrated the important contribution of the functional PB-AD module to the consider- ably enhanced intracellular internalization and uptake by cellular nuclei. Compared to the parent CD-TAEA, PB-AD/CD- TAEA assemblies mediated higher transfection rates, which were even comparable to that of PEI25K. In addition, PB-AD/CD- TAEA displayed much lower cytotoxicity than PEI25K in both 293T and HeLa cell lines. The encouraging results suggest that CD-TAEA can be developed as a powerful template capable of readily accommodating various AD-based modules giving versatile functionalities for improved transfection.

Current progress of polymeric gene vectors

After over 40 years of progress,gene therapy provides great opportunities for treating diseases from various genetic disorders,infections and cancers.The success of gene therapy largely depends on the availability of suitable gene vectors. As an attractive alternative to virus-based gene therapy,

Redox-Responsive Molecular Gels Based on Camptothecin Prodrug with Disulfide Linkage for Controlled and Sustained Drug Release

A novel camptothecin （CPT） prodrug was successfully synthesized by conjugating CPT to adamantanecarboxylic acid （AD） via a cleavable disulfide linkage. The resulting CPT-ss-AD prodrug could act as a low molecular weight gelator to form molecular gels in water/water-miscible organic solvent mixture. Meanwhile, biode- gradable amphiphilic block copolymer mPEG-b-P （MAC-co-DTC） （PPMD） was also employed as an organic framework together with CPT-ss-AD to form gel structure. CPT-ss-AD/PPMD gel exhibited less compact molecular arrangement but much more stability than CPT-ss-AD gel. The two kinds of gels could effectively release the original CPT under reductive condition at a near-constant rate without any initial burst. As compared to CPT-ss-AD single-component gel, the two-component gel, CPT-ss-AD/PPMD, had a significantly higher release rate of CPT, while 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide （MTT） assays also indicated highly potent cytotoxic activity against HeLa cells.

A Three-drug co-Delivery System Based on Reduction-sensitive Polymeric Prodrug to Effectively Reverse Multi-drug Resistance

In the present study, we prepared a multi-drug delivery system based on reduction-sensitive paclitaxel （PTX） polymeric prodrug（PEG-b-PMPMC-g-PTX, PMP） polymersomes to co-deliver PTX, doxorubicin hydrochlo- ride（DOX.HC1） and the P-glycoprotein（P-gp） inhibitor Tariquidar（TQR） to effectively reverse drug resistance by inhibiting the expression of P-gp and improving the accumulation of the encapsulated anticancer drugs. The PTX was linked to the backbone by reduction-sensitive disulphide, making the polymersomes prone to collapse in the reductive environment and to release the drugs. Transmission electron microscope（TEM） was used to confirm the morphology of polymeric assemblies. Moreover, the rupture process of polymersomes was verified by dynamic light scattering （DLS）. The results of confocal laser scanning microscopy（CLSM） and flow cytometry indicate that the PMP/DOX.HCl/TQR three-drug-loaded polymersomes show the strongest fluorescence intensity for DOX-HC1 compared with PMP/DOX-HC1 polymersomes and free DOX-HCl in drug-resistant MCF-7/ADR cells. More importantly, the PMP/DOX.HCl/TQR multi-drug co-delivery system shows a greater growth-inhibitory effect on tumour cells than the other two samples, including PMP/DOX.HC1 nanoparticles without the TQR component and free DOX-HCl, when co-incubated with either nonresistant HeLa cells or drug-resistant MCF-7/ADR cells. This growth-inhibitory effect was especially evident in drug-resistant cells. These results imply that the co-delivery of PTX, DOX-HCl and TQR based on reduction-sensitive polymeric prodrug may be promising for overcoming multi-drug resistance in tumour treatments.