Doubly Loaded cycloSaligenyl-Pronucleotides-5,5 '-Bis-(cycloSaligenyl-2 ',3 '-dideoxy-2 ',3 '-didehydrothymidine Monophosphates)

作者：Gisch Nicolas; Balzarini Jan; Meier Chris^*

来源：Journal of Medicinal Chemistry, 2009, 52(11): 3464-3473.

DOI：10.1021/jm900164g

Recently, we reported on 3,3'-bis-(cycloSaligenyl-2',3'-dideoxy-2',3'-didehydrothymidine monophosphates) (3,3'-bis-(cycloSal-d4TMPs) 4) as the first pronucleotides with a mask-to-drug ratio of 1:2 that is still a novelty in the field of pronucleotides. Here, we report on a new set of compounds of these unique type of cycloSaligenyl prodrugs 5 that bear a biaryl axis at the 5-position of the cycloSal residue. All compounds 5 showed pronounced in vitro activity against HIV-1 and HIV-2 in wild-type CEM cell cultures and better retained their antiviral activities in thymidine kinase-deficient CEM cells than the compound 4 series. Moreover, compound 5b is the first bis-(cycloSal-d4TMP) that even showed complete retention of antiviral activity in TK-deficient CEM cells. The complex hydrolysis behavior of 5 was investigated, and the proposed hydrolysis mechanism was proven by means of (31)P NMR spectroscopy and HPLC analysis.

• 出版日期2009-6-11
• 单位河北医科大学