Abstract:
Lavendamycin is a quinoline-5,8-dione antibiotic and antitumor agent with a pentacyclic
structure including the 7-aminoquinoline-5,8-dione and the indolopyridine (β-carboline) moieties.
Despite the interest in lavendamycin as an antitumor agent, this agent was precluded from
preclinical development due to its poor aqueous solubility and its toxicity toward normal human
cells. Lavendamycin has been the focus of several synthetic studies to elucidate the structural
features that are required for its cytotoxic activity and to develop improved analogues with potent
antitumor properties and lower animal toxicity.
The purpose of the present study is to synthesize new lavendamycin analogues by changing
the functionality, at the C2 position of the quinoline-5,8-dione, and investigate the new analogues’
reactivity with the NQO1 enzyme. Therefore, 7-N-acylamidoquinoline-5,8-dione-2-
carboxaldehyde oximes were synthesized in 7 steps from commercially available 8-hydroxy-2-
methyl quinoline. 7-N-(acetamido, propionamido, butyramido and isobutyramido)-5,8-dione
VII
aldehyde, and finally oxime formation. Several 3-(7-N-acylamido-5,8-quinolinedion-2-yl)-5-tbutylisoxazoline
and 3-(7-N-acylamido-5,8-quinolinedion-2-yl)-5-methoxymethylisoxazole
derivatives were synthesized in good to excellent yields. The new analogues were characterized
by 1H-NMR, 13C-NMR and IR spectroscopy.
