Synthesis and Antimitotic and Tubulin Interaction Profiles of Novel Pinacol Derivatives of Podophyllotoxins

详细信息    查看全文

• 作者：Andr茅s Abad ; Jos茅 L. L贸pez-P茅rez ; Esther del Olmo ; Luis F. Garc铆a-Fern谩ndez ; Andr茅s Francesch ; Chiara Trigili ; Isabel Barasoain ; Jos茅 M. Andreu ; J. Fernando D铆az ; Arturo San Feliciano
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：August 9, 2012
• 年：2012
• 卷：55
• 期：15
• 页码：6724-6737
• 全文大小：800K
• 年卷期：v.55,no.15(August 9, 2012)
• ISSN：1520-4804

文摘

Several pinacol derivatives of podophyllotoxins bearing different side chains and functions at C-7 were synthesized through reductive cross-coupling of podophyllotoxone and several aldehydes and ketones. While possessing a hydroxylated chain at C-7, the compounds retained their respective hydroxyl group with either the 7伪 (podo) or 7尾 (epipodo) configuration. Along with pinacols, some C-7 alkylidene and C-7 alkyl derivatives were also prepared. Cytotoxicities against neoplastic cells followed by cell cycle arrest and cellular microtubule disruption were evaluated and mechanistically characterized through tubulin polymerization inhibition and assays of binding to the colchicine site. Compounds of the epipodopinacol (7尾-OH) series behaved similarly to podophyllotoxin in all the assays and proved to be the most potent inhibitors. Significantly, 7伪-isopropyl-7-deoxypodophyllotoxin (20), without any hydroxyl function, appeared as a promising lead compound for a novel type of tubulin polymerization inhibitors. Experimental results were in overall agreement with modeling and docking studies performed on representative compounds of each series.