Synthesis and QSAR study of novel cytotoxic spiro[3H-indole-3,2¡ä(1¡äH)-pyrrolo[3,4-c]pyrrole]-2,3¡ä,5¡ä(1H,2¡äaH,4¡äH)-triones

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• 作者：Adel S. Girgis^a ; ^{girgisas10@yahoo.com} ; Jacek Stawinski^b ; ^{js@organ.su.se} ; Nasser S.M. Ismail^c ; Hanaa Farag^a
• 关键词：1H-pyrrole-2 ; 5-diones ; Azomethine ylides ; Spiro[3H-indole-3 ; 2&prime ; (1&prime ; H)-pyrrolo[3 ; 4-c]pyrrole] ; Anti-tumor ; QSAR
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：January, 2012
• 年：2012
• 卷：47
• 期：Complete
• 页码：312-322
• 全文大小：904 K

文摘

1,3-Dipolar cycloaddition reaction of 1-aryl-1H-pyrrole-2,5-diones 1a-e with non-stabilized azomethine ylides, generated in situ via decarboxylative condensation of isatins 2a-c and sarcosine (3) in refluxing ethanol, afforded 4¡ä-aryl-5¡äa,6¡ä-dihydro-1¡ä-methyl-spiro[3H-indole-3,2¡ä(1¡äH)-pyrrolo[3,4-c]pyrrole]-2,3¡ä,5¡ä(1H,2¡äaH,4¡äH)-triones 4a-o in good yields. Compound 4l exhibited high anti-tumor activity against HEPG2 (liver cancer) cell line (IC₅₀?=?12.16?¦ÌM) compared to that of Doxorubicin (IC₅₀?=?7.36?¦ÌM), and the other synthesized compounds revealed moderate anti-tumor properties against HCT116 (colon), MCF7 (breast) and HEPG2 (liver) human tumor cell lines. 3D-Pharmacophore modeling and quantitative structure-activity relationship (QSAR) analysis were combined to explore the structural requirements controlling the observed anti-tumor properties. It was found that the major structural factors affecting potency of these compounds were related to their basic skeleton.