CycloSal-BVDUMP pronucleotides: how to convert an antiviral-inactive nucleoside analogue into a bioactive compound against EBV.
Novel cycloSal-BVDUMP triesters 2-4 5-[(E)-2-bromovinyl]-2'-deoxyuridine (BVDU, 1) have been studied with regard to their potential anti-EBV activity. In addition to the 3'-unmodified cycloSal-BVDUMP triesters 2a-f, the 3'-hydroxyl function has been esterified with different aliphatic carboxylic acids (3a-g) and alpha-amino acids having natural and nonnatural Calpha-configuration (4a-m). In addition to the synthesis of these compounds, different physicochemical properties of the new derivatives will be reported, i.e., lipophilicity and hydrolysis behavior. It could be proven that the monophosphate BVDUMP and not 3',5'-cyclic BVDUMP was delivered from most of the compounds by chemical hydrolysis in phosphate buffers at pH 6.8 and 7.3 as well as P3HR-1 cell extracts. Finally, the new compounds were tested for their anti-EBV activity. As a result, the prototype compounds and particularly triesters 2c,d exhibited pronounced anti-EBV activity making these compounds promising candidates for further development. However, the 3'-ester derivatives were devoid of any antiviral activity while the 3'-aminoacyl derivatives showed an antiviral activity dependent upon the amino acid and the Calpha-configuration
Meier
Chris
C
Institute of Organic Chemistry, University of Hamburg, Martin-Luther-King-Platz 6, Germany. chris.meier@chemie.uni-hamburg.de
Lomp
Andreas
A
Meerbach
Astrid
A
Wutzler
Peter
P
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002457:Cell Extracts; D003856:Deoxyuracil Nucleotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004952:Esters; D004854:Herpesvirus 4, Human / Q000187:drug effects*; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000998:Antiviral Agents; D002457:Cell Extracts; D003856:Deoxyuracil Nucleotides; D004952:Esters; D001973:Bromodeoxyuridine