Synthesis Of Genetic Code Origin Model Compounds And Novel Pro-drug Of Nucleoside Analogues

Life's origin has been recognized as one of three important frontier topics (sphere's evolvement, life's origin, basic particle's theory), also one of the most difficult scientific puzzles. Phosphorus was even chose as a probe for searching of life in space. Todd said, 'Where there is life, there is phosphorus '. Many experiment results have showed that phosphorus plays an important role in the formation of biomolecules such as amino acids, nucleotides, peptides, oligonucleotides and nucleic acids in prebiotic conditions. In this paper, N-phosphoryl amino acids could be considered as a model to study many processes of life origin. Based on the literature information, a structural model "the specific amino acid: ribonucleotide conjugated compound" ("3 to 1" model) could be built as a new theory model to explain chemical characteristics of the origin of primordial genetic code.For decades, phosphorus chemistry has quickly developed in organic chemistry and medical chemistry. Westheimer expounded on the question of why nature chose the phosphodiester linkage as the backbone of the nucleic acid from the viewpoint of organic chemistry. Research results showed that nucleoside analogues of phosphoryl-ation such as AZT/d4T have emerged as efficient drugs against human immunodeficiency virus (HIV). Therefore, it is very important to develop a new method to synthesize some new nucleoside analogues.The research results of this dissertation are showed bellow:1. A series of nucleoside 5'-N-phosphoramidates were synthesized through a convenient and efficient approach. First, one-pot synthesis of hydrogen phosphonate derivatives of protected nucleoside by reacting protected nucleoside with PCl₃, followed by alcoholysis with benzyl alcohol. O-alkyl-5'-H-phosphonates of protected nucleoside derivatives were obtained in reasonable yields. Then the L/D amino acid methyl ester 5'-phosphoramidates of nucleoside were synthesized in the presence of Et₃N and CCl₄ in 88% yields by Atherton-Todd reaction. In the final step, benzyl was deoxidized by H₂ and 10% Pd/C. The synthetic route can be used to synthesize other nucleoside 5'-phosphoramidates.The ESI-MS(-) results indicated that two novel rearrangement were found, which are useful for the structural elucidation of amino acid methyl ester 5'-phosphoramidate of nucleosides.2. The NOE effect of these compounds were confirmed, It was found that for L/D amino acid methyl ester derivations of 5'-phosphoramidates of nucleoside, the bases were in syn-conformation, while the often simple amine derivation were in anti-conformation. It was deduced that amino acids might choose nucleotide through the week interaction (hydrogen bond) between amino acid and base on the nucleotide. Their relative formation potentials model were built up by Gaussion 03. It is significantly that the calculation results of hydrogen bond seem related to their corresponding genetic code, consequently, "co-evolution of protein and nucleic acid" was proposed.3. In order to promote their passive diffusion through cell membranes, decrease their toxic side-effects and increase their bioavailability, a series of diaryl esters and diamidates of phosphate, phosphorothioate and phosphoroselenoate 5'-derivatives of AZT and d4T were synthesized. And their anti-HIV activity of these compounds were being evaluated.4. Pyridin-4-ylmethanol as a phosphor's protecting group could be cleaved with Mg and CH3COOH under mild conditions. By this method, nucleoside 5'-phosphoramidates and O-aryl-O-nucleoside-5'-phosphate were synthesized.