Studies On The Synthesis And Properties Of Steroid-nucleoside Conjugates

Steroids are a kind of natural substances which play very important rolein the life of animals and plants. Due to their lipophilic character, lymphocytemembrane affinity, and the ability of binding to low density lipoproteins,design and synthesis of steroidal AZT prodrugs become important, as suchdrugs should have increased lipophilicty and enhanced permeability throughcell membranes, and favorable specific organ distribution. Syntheticsteroidal-nucleoside bioconjugates, which provide materials for correlatingstructure with function, may contribute to better insight into the myriadbiological functions of steroidal-nucleoside bioconjugates.In present dissertation, several series of steroid-nucleoside bioconjugateswere synthesized by improved chemical protocol, and their structures wereconfirmed by NMR and ESI-MS analysis.Inspired by the encouraging development of steroidal bioconjugates, thehydroxyl groups of the steroids were substituted by various active groups. Anoriginal approach was to develope a synthesis of the H-phosphonates,phosphonates, N-phosphoramidates and bivalent ligand-basedphosphoramidates of steroids using a diphenyl phosphite (DPP)transesterification and the Atherton-Todd reaction. These extend the diversityof steroidal type of phosphates as potential therapeutic agents. Thesteroidal-nucleoside carbonates were conveniently prepared via thetriphosgene approach. Furthermore, diamines and polyamines were coupledwith 3-hydroxyl function of the steroids in high yield, via a coupling withnucleoside H-phosphonate. In this way, series of a novel steroid-nucleosideconjugates was synthesized.The carboxyl group of the cholic acid was also modified in differentways. Deoxycholic acid-nucleoside conjugates were conveniently synthesizedvia a DCC mediated condensation. In order to mimic squalamine, two kinds ofdiamines were coupled with cholic acid. By utilizing the Atherton-Toddreaction, nucleoside H-phosphonates were joined together cholic-diamine togive a novel series of steroid-nucleoside conjugate, which can be consideredas a new type of anti-HIV prodrug candidates.The ESI-MS/MS of the synthesized steroidal phosphoramidateconjugates and dinucleoside 2-, 3-, 4-pyridylphosphonates were determinedusing positive and negative ion modes, respectively. The characteristicfragmentation pathways were found for these compounds and the resultsshould be very useful in the structural determination of bioconjugatescontaining phosphate.