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不对称取代的5,12-二氢二苯并[,][1,4]二氮杂䓬-6,11-二酮骨架——生物活性分子设计的有用工具。

Unsymmetrically-Substituted 5,12-dihydrodibenzo[,][1,4]diazocine-6,11-dione Scaffold-A Useful Tool for Bioactive Molecules Design.

作者信息

Bieszczad Bartosz, Garbicz Damian, Trzybiński Damian, Dudek Marta K, Woźniak Krzysztof, Grzesiuk Elżbieta, Mieczkowski Adam

机构信息

Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warszawa, Poland.

Biological and Chemical Research Centre, University of Warsaw, 02-089 Warszawa, Poland.

出版信息

Molecules. 2020 Jun 20;25(12):2855. doi: 10.3390/molecules25122855.

DOI:10.3390/molecules25122855
PMID:32575784
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7356613/
Abstract

Unsymmetrically -substituted and -disubstituted 5,12-dihydrodibenzo [,][1,4]diazocine-6,11-diones were synthesized in the new protocol. The desired modifications of the dibenzodiazocine scaffold were introduced at the stages of proper selection of building blocks as well as post-cyclization modifications with alkylation or acylation agents, expanding the structural diversity and possible applications of synthesized molecules. The extension of developed method resulted in the synthesis of novel: tricyclic 5,10-dihydrobenzo[]thieno[3,4-][1,4]diazocine-4,11-dione scaffold and fused pentacyclic framework possessing two benzodiazocine rings within its structure. Additionally, the unprecedented rearrangement of 5,12-dihydrodibenzo[,][1,4]diazocine-6,11-diones to 2-(2-aminophenyl)isoindoline-1,3-diones was observed under the basic conditions in the presence of sodium hydride for secondary dilactams. The structures of nine synthesized products have been established by single-crystal X-ray diffraction analysis. Detailed crystallographic analysis of the investigated tri- and pentacyclic systems has shed more light on their structural features. One cell line derived from non-cancerous cells (EUFA30-human fibroblasts) and three tumor cells (U87-human primary glioblastoma, HeLa-cervix adenocarcinoma, BICR18-laryngeal squamous cell carcinoma) were used to determine the cytotoxic effect of the newly synthesized compounds. Although these compounds showed a relatively weak cytotoxic effect, the framework obtained for 5,12-dihydrodibenzo[,][1,4]diazocine-6,11-dione could serve as a convenient privilege structure for the design and development of novel bioactive molecules suitable for drug design, development and optimization programs.

摘要

采用新方案合成了不对称取代和二取代的5,12 - 二氢二苯并[,][1,4]二氮杂辛 - 6,11 - 二酮。在合适的构建块选择阶段以及用烷基化或酰化试剂进行环化后修饰阶段引入了对二苯并二氮杂辛支架所需的修饰，扩大了合成分子的结构多样性和可能的应用。所开发方法的扩展导致合成了新型的：三环5,10 - 二氢苯并[]噻吩并[3,4 - ][1,4]二氮杂辛 - 4,11 - 二酮支架以及在其结构中具有两个苯并二氮杂辛环的稠合五环骨架。此外，在氢化钠存在的碱性条件下，观察到5,12 - 二氢二苯并[,][1,4]二氮杂辛 - 6,11 - 二酮发生了前所未有的重排，生成2 - (2 - 氨基苯基)异吲哚啉 - 1,3 - 二酮用于二级双内酰胺。通过单晶X射线衍射分析确定了九种合成产物的结构。对所研究的三环和五环体系进行的详细晶体学分析进一步揭示了它们的结构特征。使用一种源自非癌细胞的细胞系（EUFA30 - 人成纤维细胞）和三种肿瘤细胞（U87 - 人原发性胶质母细胞瘤、HeLa - 宫颈腺癌、BICR18 - 喉鳞状细胞癌）来测定新合成化合物的细胞毒性作用。尽管这些化合物显示出相对较弱的细胞毒性作用，但5,12 - 二氢二苯并[,][1,4]二氮杂辛 - 6,11 - 二酮所获得的骨架可作为一种方便的优势结构，用于设计和开发适用于药物设计、开发和优化计划的新型生物活性分子。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a0f/7356613/78e9ce6f99ea/molecules-25-02855-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a0f/7356613/5f33f9415336/molecules-25-02855-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a0f/7356613/a2266e48f00e/molecules-25-02855-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a0f/7356613/106a94c27772/molecules-25-02855-sch002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a0f/7356613/64928558117d/molecules-25-02855-sch003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a0f/7356613/4e4ad73d9f69/molecules-25-02855-sch004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a0f/7356613/870f9a6216cf/molecules-25-02855-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a0f/7356613/8630bb6ab230/molecules-25-02855-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a0f/7356613/384bac82d93b/molecules-25-02855-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a0f/7356613/112a67ecc228/molecules-25-02855-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a0f/7356613/78e9ce6f99ea/molecules-25-02855-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a0f/7356613/5f33f9415336/molecules-25-02855-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a0f/7356613/a2266e48f00e/molecules-25-02855-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a0f/7356613/106a94c27772/molecules-25-02855-sch002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a0f/7356613/64928558117d/molecules-25-02855-sch003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a0f/7356613/4e4ad73d9f69/molecules-25-02855-sch004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a0f/7356613/870f9a6216cf/molecules-25-02855-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a0f/7356613/8630bb6ab230/molecules-25-02855-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a0f/7356613/384bac82d93b/molecules-25-02855-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a0f/7356613/112a67ecc228/molecules-25-02855-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a0f/7356613/78e9ce6f99ea/molecules-25-02855-g006.jpg

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