Abstract:A concise chemoenzymatic synthesis of glucose-6-phosphate is described. Candida rugosa lipase was found to be an efficient catalyst for both regio-and stereoselective deacetylation of the primary hydroxyl group in the peracetylated D-glucose. In addition, we report an improved synthesis of 1,2,3,4,6-penta-O-acetyl--D-glucopyranose providing a large-scale procedure for the acetylation of -D-glucose without isomerization at the anomeric center. The high overall yield and the easy scalability makes this chemoenzymatic strategy attractive for industrial application. Furthermore, molecular modeling of phosphonate transition-state analogue for the enzymatic hydrolysis step supports the substrate selectivity observed with Candida rugosa lipase.
Phosphodiester linked conjugates of various nucleosides such as d4U, d4T, IdUrd, ddI, ddA, virazole, ara-A and ara-C containing a glucosyl moiety have been described. These compounds were designed to act as prodrugs, where the corresponding 5′-monophosphates may be generated intracellularly. The synthesis of the glycoconjugates was achieved in good yields by condensation of a glucosyl phosphoramidite 7 with nucleosides in the presence of an activating agent. It was demonstrated that the glucose-conjugates improve water solubility of the nucleoside analogues, for example up to 31-fold for ara-A conjugate compared to ara-A alone. The new conjugates were tested for their anti-HIV-1 activity in human lymphocytes. These derivatives offer a convenient design for potential prodrug candidates with the possibility to improve the physicochemical properties and therapeutic activity of nucleoside analogues.
An efficient separation of a mixture of 2Ј/3Ј-O-methyladenosine regioisomers (1 + 2; 1:1) has been developed by selective enzymatic acylation using immobilized Pseudomonas cepacia lipase (PSL-C) in combination with acetonoxime levulinate as acyl donor. The 3Ј-hydroxy group of 2Ј-O-methyladenosine (1) was acylated with high selectivity (ca. 70 %), whereas an equal amount of 3Ј-O-methyladenosine (2) in the same solution resulted in minor acylation of 5Ј-hydroxy group (ca. 8 %). The differential behavior of both regioisomers towards enzymatic acylation allowed to develop a separation protocol. Upon extraction of the acylated products, the
We have developed a simple and convenient synthetic strategy for the preparation of tetrahydropyranyl, 4-methoxytetrahydropyranyl, and tetrahydrofuranyl ethers of 2Ј-deoxynucleosides, which are useful building blocks for nucleic acid chemistry. Enzymatic benzoylation provides an efficient alternative for protecting the 5Ј-hydroxy group of the parent nucleosides in a regioselective manner. Subsequently, tetra-
An efficient synthesis protocol for the glucosyl-nucleoside phosphodiester derivatives has been developed. These mononucleotides were designed to act as pronucleotides with potential to deliver the parent compound as its monophosphate. Key step of the synthesis is the regioselective hydrolysis of peracetylated alpha-D-glucose catalyzed by Candida rugosa lipase.
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