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

• Published in: Bioorganic & medicinal chemistry Vol. 15; no. 1; pp. 495 - 510
• Main Authors: Behforouz, Mohammad, Cai, Wen, Mohammadi, Farahnaz, Stocksdale, Mark G., Gu, Zhengxiang, Ahmadian, Mohammad, Baty, Darric E., Etling, Michele R., Al-Anzi, Charmaine H., Swiftney, Tyson M., Tanzer, Lee R., Merriman, Ronald L., Behforouz, Nancy C.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.01.2007
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Antitumor; Cell Line, Tumor; Cell Proliferation - drug effects; Female; Lavendamycins; Mice; Mice, Inbred C57BL; Mice, Nude; Molecular Structure; Neoplasms - drug therapy; Quinoline-5,8-diones; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; ras; Rats; Stereoisomerism; Streptonigrin - administration & dosage; Streptonigrin - analogs & derivatives; Streptonigrin - chemical synthesis; Streptonigrin - pharmacology; Structure-Activity Relationship; Xenograft Model Antitumor Assays; Lavendamycins; ras; Quinoline-5,8-diones; Antitumor
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2006.09.039

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. 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.