Design and synthesis of photoactivatable aryl diketo acid-containing HIV-1 integrase inhibitors as potential affinity probes.
Aryl diketo acids (ADKs) represent an important new class of HIV-1 integrase (IN) inhibitors. In order to facilitate examination of the structural basis underlying IN?ADK interaction, biphenyl ketone and phenyl azide photophores were incorporated into ADK structures. Of particular note is the novel dual utilization of azide and phenyketone moieties for both enzyme recognition and for crosslinking. The resulting analogues maintained low micromolar inhibitory potency against IN in recombinant in vitro assays. These potential HIV-1 integrase photoaffinity labels may provide useful tools for studying enzyme interactions of the ADK inhibitor class.
Laboratory of Medicinal Chemistry, Center for Cancer Research, NCI-Frederick, PO Box B, Bldg. 376 Boyles Street, Frederick, MD 21702-1201, USA.
Xuechun
X
Zhang
Christophe
C
Marchand
Yves
Y
Pommier
Terrence R
TR
Burke
D015195:Drug Design; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D007651:Keto Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D008027:Light
D019428:HIV Integrase Inhibitors; D007651:Keto Acids; D019427:HIV Integrase