Lavendamycin is a quinoline-5,8-dione 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 molecule was precluded from preclinical development due to its poor aqueous solubility and its high 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, especially at C<sub>2 </sub>position of the quinoline-5,8-dione. 7-N-acylamidoquinoline-5,8-dione-2-carboxaldehyde oxime was synthesized in 6 to 7 steps from commercially available 8-hydroxy-2-methyl quinolone.  The aldoxime can be selectively oxidized to its corresponding nitrile oxide, which can then undergo 1,3-dipolar cycloaddition reactions with dipolarophiles to create heterocycles attached to the quinolone-5,8-dione core. The biological activities of the new moieties reactivity with the NQO<sub>1</sub> enzyme were investigated in order to compare the toxicity profile and antitumor activity.  Several of the quinoline-5,8-diones showed submicromolar activity in MDA-468 breast cancer cells. The most active compound containing a methyloxymethylisoxazole had an IC50 value of 269 nM. Three of the four N-hydroxyimino derivatives showed increased toxicity to the NQO1-transfected variant suggesting a role for this enzyme in selective toxicity.

Synthesis of quinoline-5,8-dione containing isoxazoles and isoxazolines

255th National Meeting (2018)

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