4,5-Diaryl-1H-pyrrole-2-carboxylates as combretastatin A-4/lamellarin T hybrids: Synthesis and evaluation as anti-mitotic and cytotoxic agents

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• 作者：Martin G. Banwell ; Ernest Hamel ; David C.R. Hockless ; Pascal Verdier-Pinard ; Anthony C. Willis and David J. Wong
• 关键词：Anti-mitotic ; cis-Stilbene ; Combretastatin A-4 ; Cytotoxic ; Lamellarin T
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2006
• 出版时间：1 July 2006
• 年：2006
• 卷：14
• 期：13
• 页码：4627-4638
• 全文大小：390 K

文摘

The 4,5-diarylated-1H-pyrrole-2-carboxylates <strong>3strong>–<strong>8strong> have each been prepared as hybrids of the potent anti-mitotic agent combretastatin A-4 (<strong>1strong>) and the similarly active marine alkaloid lamellarin T (<strong>2strong>). The key steps involved selective lithium-for-halogen exchange at C5 within the N-PMB protected 4,5-dibromopyrrole <strong>22strong> and Negishi cross-coupling of the derived zincated species with the relevant aryl iodide. The ensuing 5-aryl-4-bromopyrrole then engaged in Suzuki–Miyaura cross-coupling with the appropriate arylboronic acid to give the 4,5-diarylated pyrroles <strong>4strong>, <strong>6strong> and <strong>8strong>. TFA-promoted removal of the N-PMB group within these last compounds then gave the N-unsubstituted congeners <strong>3strong>, <strong>5strong> and <strong>7strong>. Compounds <strong>3strong>–<strong>8strong> have all been evaluated for their anti-mitotic and cytotoxic properties and two of them, <strong>3strong> and <strong>5strong>, display useful activities although they are less potent than combretastatin A-4.