Lavendamycin, an antitumor antibiotic, was first isolated from the fermentation broth of Streptomyces laVendulae in 1981. 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 agent was precluded from preclinical development due to its poor aqueous solubility and its toxicity toward normal human cells. The purpose of the present study is to synthesize new lavendamycin analogues by changing the functionality, especially at C2 position of the quinoline-5,8-dione, and investigate the new moieties reactivity with the NQO1 enzyme with the goal of selectively interacting with molecular targets unique to tumor cells. The hope is to minimizing toxicity to normal cells and organs with maxing toxicity toward solid tumor cells.  This is achieved by maximizing the specificity to desired site of action and improving the drug-like properties of lavendamycin analogues for clinical trials. By synthesizing new Lavendamycin/Streptonigrin derivatives and then investigating the new moieties reactivity with the NQO1 enzyme, toxicity profile, and bioavailability, new possibilities are achieved that take us one step closer to neutralizing tumors. 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. 7-N-acetamidoquinoline-5,8-dione-2-carboxaldehyde oxime was synthesized in 7 steps from commercially available 8-hydroxy-2-methylquinolone. The results of nitrile oxide generation and 1,3-dipolar cycloaddition reaction will be discussed.

Synthesis of isoxazoles and isoxazolines as lavendamycin analogues

2019 Spring National Meeting

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