The Study On The Synthetic Methods And Biological Activities Of Novel Nucleoside-Phospholipid (-Phosphate) Conjugates Containing Heteroatomic Function Groups

Nucleosides and its analogs were widely used as antitumor and antiviral drugs in clinical, but there were some major problems associated with them, such as bone marrow toxicity, poor substrates for cellular kinases. In order to improve their activities, decrease their toxicities, structure modification has been being a focus of attention all the times. Phospholipids had broad physiological activities and numerous phospholipid analogs had been synthesized and proved to possess excellent anticancer activities. As a efficient drug-carrier, phospholipid have a remarkable capacity to localize in a variety of tumors. Organoselenium and organosulphur also have good anticancer activities.To obtain a high-activity low-toxicity antitumor drug, we designed a series of novel tegafur-phospholipid(or -phosphate) conjugates containing heteroatomic function groups. But till now, the methods of introduction of function groups into nucleoside-phospholipid(or -phosphate) conjugates bore lots of shortcomings, for example laborious procedure, low yield, and so on. Here, we made it into reality successfully through the nucleophilic ring-openning of 1,3,2-dioxaphsopholane and cyclic glycerothiophospholipid conjugate.By the use of phthalimidoethanol as a starting material which was cheap and easily to access, 2-phahalimidoethyl-2-thio-1,3,2-dioxaphsopholane (1) and 2-phahal-imidoethyl-4-hexadecyloxymethylene-2-thio-1,3,2-dioxaphsopholane (9) were synthesized at first. And then based on these model-compounds, the selectivity and condition of nucleophilic ring-openning with the heteroatomic function groups were intensively explored.Under room temperature, NaN3 in the solvent of actone/water and PhSeSePh/ NaBH4 in the solvent of absolute ethanol could reacted with compound (1) to produce O-2-phahalimidoethyl-O-2-azidoethylthiophosphate (3) and O-2-phahalimidoethyl-O-2-phenylselenoethylthiophosphate (5) respectively. It was also under room temperature that p-MeC4H4SH/KOH in the solvent of i-propanol/water could achieve the ring-openning of compound (9) to give sn-l-hexadecyloxy-3-p-methylthiophenyl-2-thio-phosphatidyl phahalimidoethanol (11).These results suggested that soft base with strong nucleophilicity could realize the opening of 1,3,2-dioxaphsopholane with selectivity. And this sort of reaction had the advantages of mild conditions, high yields, easy separation and purification et al.On the basis of the model-reaction above, O-2-(N3-tegafur)ethyl-O-2-phenyl-selenoethylthiophosphate (8) and sn-l-hexadecyloxy-3-phenylseleno-2-thiopho-sphatidyl hydroxyethyltegafur (14) were obtained respectively by the means of nucleophilic ring-openning with sodium phenylselenide of 2-(N3-tegafur)ethyl-2-thio-1,3,2-dioxaphsopholane (6) and 2-(N3-tegafur)ethyl-4-hexadecyloxymethylene-2-thio-1,3,2-dioxaphsopholane (12). sn-l-Hexadecyloxy-3-p-methylthiophenyl-2-thiopho-sphatidyl hydroxyethyltegafur (13) could also be accessed when potassium benzene-thiolate coexisted with compound (12) in the solvent of i-propanol/water.The physical chemical properties of gained novel target molecule (8) (13) (14) had been greatly improved in comparison with the corresponding cyclic tegafur-phospholipid(or -phosphate) conjugates. High bioavailability was expected for these compounds for the sake of the coexistence of hydrophility and lipophilicity in each molecule.It was indicated through in vitro biologic assays using MTT that compound (8) had fine inhibitory effect on the malignant proliferation of bladder cancer cell T-24; compound (14) exhibited better inhibitory effect than tegafur on stomach cancer cell BGC-823(ID50=4.0ug/mL) and bladder cancer cell T-24(ID50=llug/mL), but on the other hand it showed more toxicity on the normal liver epithelial cell L-02.