cycloSal-PMEA and cycloAmb-PMEA: potentially new phosphonate prodrugs based on the cycloSal-pronucleotide approach.
Two new classes of lipophilic prodrugs of the antiviral active phosphonate 9-[2-phosphonomethoxyethyl]adenine (PMEA 1) have been prepared and were studied with regard to their hydrolysis properties and biological activity. A first series of compounds was prepared on the basis of the cycloSal nucleotide approach. Because of the surprisingly low hydrolysis stability of these cycloSal-PMEA derivatives, more stable derivatives have to be developed. Instead of using salicyl alcohol, in cycloAmb-PMEA derivatives 2-aminobenzyl alcohols were attached to PMEA 1. The latter compounds showed a considerably higher stability compared to the cycloSal counterparts. Stability studies revealed that all lipophilic prodrugs delivered PMEA selectively by chemical means. All compounds proved to be noninhibiting to acetyl- and butyrylcholinesterase, and some of the phosphonate diesters were found to be more active against HIV compared to the parent PMEA.
Meier
Chris
C
Institute of Organic Chemistry, University of Hamburg, Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany. chris.meier@chemie.uni-hamburg.de
Görbig
Ulf
U
Müller
Christian
C
Balzarini
Jan
J
D000110:Acetylcholinesterase / Q000737:chemistry; D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001592:Benzyl Alcohols / Q000737:chemistry*; D002091:Butyrylcholinesterase / Q000737:chemistry; D002460:Cell Line; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D006868:Hydrolysis; D009682:Magnetic Resonance Spectroscopy; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D001592:Benzyl Alcohols; D002800:Cholinesterase Inhibitors; D063065:Organophosphonates; D011355:Prodrugs; C072332:2-aminobenzyl alcohol; C053001:adefovir; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; C010631:salicyl alcohol; D000225:Adenine