Synthesis and evaluation of antitumor activity of novel N-acyllavendamycin analogues and quinoline-5,8-diones

A series of 7-N-acyllavendamycins with zero, one or two substituents at the C-2′, C-3′, and C-11′ were synthesized through short and efficient methods. Pictet–Spengler condensation of 7-N-acylamino-2-formylquinoline-5,8-diones with tryptamine or tryptophans produced the desired lavendamycins. Screening data on a panel of three ras oncogene-transformed cell lines and the non-transformed parent cell line showed that a significant number of these analogues are potent antitumor agents and appear to be particularly active against K-ras transformed cells. Compared with the corresponding quinolinediones, these novel lavendamycins are much more inhibitory toward the transformed cells indicating that the β-carboline moiety of the lavendamycin analogues plays an important role in its potency and selective toxicity.

Efficient syntheses of lavendamycins and quinoline-5,8-diones are described. Several lavendamycins showed potent selective activity against ras transformed cells, particularly the K-ras line. Toxicity toward normal cells, 3LL cells, and mice was low.Figure optionsDownload as PowerPoint slide