Synthesis and anti-HIV evaluation of hybrid-type prodrugs conjugating HIV integrase inhibitors with d4t by self-cleavable spacers containing an amino acid residue.
In an attempt to combine the anti-HIV inhibitory capacity of reverse transcriptase (RT) inhibitors (NRTIs) and integrase (IN) inhibitors (INIs), several heterodimer analogues of the previously reported [d4T]-PABC-[INI] and [d4T]-OABC-[INI] prototypes have been prepared. In these novel series, we wished to extend our results to conjugates which incorporated an enzymatically labile aminoacid unit (L-alanine) connected to d4T through a self-immolative para- or ortho-aminobenzyl carbonate (PABC or OABC) spacer. Among the novel heterodimers, several derivatives show a potent anti-HIV-1 activity, which proved comparable to that of the [L-708,906]-PABC-[d4T] Heterodimer A prototype. However, although the compounds proved inhibitory to HIV-1, they were less potent than the parent compounds from which they were derived.
Centre d'Etudes et de Recherche sur le Médicament de Normandie, U.F.R. des Sciences Pharmaceutiques, 5, Rue Va,ubénard, F-14032, Caen Cedex, France. christine.fossey@unicaen.fr
Christine
C
Fossey
Ngoc-Trinh
NT
Huynh
Anh-Hoang
AH
Vu
Anamaria
A
Vidu
Irina
I
Zarafu
Daniel
D
Laduree
Sylvie
S
Schmidt
Geraldine
G
Laumond
Anne-Marie
AM
Aubertin
D000409:Alanine / Q000737:chemistry*; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D019281:Dimerization; D006678:HIV / Q000187:drug effects*; D019428:HIV Integrase Inhibitors / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry*; D018119:Stavudine / Q000737:chemistry*
D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D011355:Prodrugs; D018894:Reverse Transcriptase Inhibitors; D018119:Stavudine; D000409:Alanine