The Research On The Synthetic Methods And Biological Activities Of Novel 1,3-disubstituted Phoshpholipids(Phosphates) Containing Tegafur

Nucleosides analogs are widely used as anticancer and antiviral drugs in modern medicine, but there are some major problems and disadvantages, such as causing toxic side effect on normal cells; tumors can develop resistance to these drugs; a poor substrate for cellular kinases need for its activation . Nucleosides prodrugs are important part of structure modification of Nucleosides in present . Phospholipids not only have broad physiological activities but also are an efficient drug-carrier. phospholipids 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.Such conjugates are expected to show good bioavailability , readily penetrate into cells , enhance cellular uptake, expand actuation duration of nucleosides , exhibit low toxicity side effect.Up to the present, the methods of introduction of function groups into nucleoside -phospholipid(or -phosphate) conjugates bore lots of shortcomings, for example the lengthy experimental procedure and relatively low yield, and so on. Here, we made it into reality successfully through the nucleophilic ring-openning of cyclic glycerol -thiophospholipid conjugate.Our method needs short steps and get high yield.We have focused much attention on the conversion of antitumor nucleosides(we use Tegafur as the model compound) to their phopholipid derivatives. We designed and synthesized several novel glycerolthiophospholipid (phosphorothioate)–Tegafur conjugates.Firstly,2-(N3-tegafur)ethyoxyl-4-thiophenyl-2-thio- 1,3,2-dioxaphospholane (1a)and 2-(N3-tegafur)ethyoxyl-4- selenophenyl -2- thio - 1,3,2-dioxaphospholane (1b) were synthesized, these two compounds share with the same chemical structure of 2- thio -1,3,2-dioxaphospholane .Compounds 2a,2b,2c the corresponding tegafur-phospholipid(or -phosphate) conjugates were obtained respectively by the means of nucleophilic ring-openning with sodium phenylselenide and potassium benzene- thiolate of 1a,1b.Triethylamine was used as the nucleophilic agent to attack the 2- thio-1,3,2 -dioxaphospholane of 1b,1c,1d,1e respectively, we got sn-1- selenophenyl -3-triethyl amino -2-thiophosphatidyl hydroxyethyltegafur(3a,3b,3c,3d)which have chemical structure just like phosphatidylcholine in moderate yield .we design that long chain acyloxyl (alkoxy) are introduced into glyceryl phosphatide skeleton by the means of nucleophilic ring-opening of cyclic glycerolthiophospholipid conjugate,using potassium strearate (sodium alkoxide) as nucleophilic reagent.The physical chemical properties of gained novel target molecule had been greatly improved in comparison with the corresponding cyclic tegafur-phospholipid(phosphate) conjugates. High bioavailability was expected for these compounds for the sake of the coexistence of hydrophility and lipophilicity in each molecule.The longer fatty acid side chain can made nucleosides derivatives less toxic than the shorter chain length derivatives.It was indicated through in vitro biologic assays using MTT that compound 3c,3d had fine inhibitory effect on the malignant proliferation of bladder cancer cell PGA1; compound 3a,3b,3c,3d exhibited better inhibitory effect on stomach cancer cell BGC-823.