Synthesis and structure elucidation of novel fused 1,2,4-triazine derivatives as potent inhibitors targeting CYP1A1 activity

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• 作者：Abdel Moneim EL Massry^a ; ^c ; ^&dagger ; ; Ahmed Mosaad Asal^b ; Sherine Nabil Khattab^c ; ^&dagger ; ; Nesreen Saied Haiba^b ; ^&dagger ; ; Hala A. Awney^d ; ; Mohamed Helmy^e ; ^f ; Vratislav Langer^g ; Adel Amer^c ; ^&dagger ; ; ^{aamer@sci.alex.edu.eg}
• 关键词：Triazine ; Triazolotriazine ; Triazinotetrazine ; NMR ; X-ray ; Aryl hydrocarbons hydroxylase ; CYP1A1 ; Docking
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：15 April, 2012
• 卷：20
• 期：8
• 页码：2624-2637
• 文件大小：1497 K

摘要

Synthesis and structure elucidation of new series of novel fused 1,2,4-triazine derivatives 3a-3f, 4a-4i and 6a-6b and their inhibitory activities are presented. Molecular structures of the synthesized compounds were confirmed by ¹H NMR, ¹³C NMR, MS spectra and elemental analyses. X-ray crystallographic analysis was performed on 2-acetyl-8-(N,N-diacetylamino)-6-(4-methoxybenzyl)-3-(4-methoxy-phenyl)-7-oxo-2,3-dihydro-7H-[1,2,4]triazolo[4,3-b][1,2,4]triazine 3d and 2-acetyl-8-(N-acetylamino)-6-benzyl-3-(4-chlorophenyl)-3-methyl-7-oxo-2,3-dihydro-7H-[1,2,4]triazolo[4,3-b][1,2,4]triazine 4e to secure their structures. The inhibitory effect of these compounds toward the CPY1A1 activity was screened to determine their potential as promising anticancer drugs. Our data showed that compounds 4e, 5a, 5b and 6b possess the highest inhibitory effects among all tested compounds. Furthermore, analysis of triazolotriazine derivatives docking showed that these compounds bind only at the interface of substrate recognition site 2 (SRS2) and (SRS6) at the outer surface of the protein. Amino-acids ASN214, SER216 and ILE462 participate in the binding of these compounds through H-bonds.