Abstract
Unsymmetrically N-substituted and N,N’-disubstituted 5,12-dihydrodibenzo [b,f][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[b]thieno[3,4-f][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[b,f][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[b,f][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.
Highlights
Modern medicinal chemistry is mainly based on the design of novel, biologically active compounds containing diverse heterocyclic scaffolds, including privileged structures
Modified benzene-1,2-diamines and properly prepared phthalic esters. To our knowledge, such derivatives containing modified and substituted eight-membered dilactam knowledge, such containing eight-membered dilactam have rings have not yetderivatives been described in themodified literatureand so substituted far
Our syntheticofefforts leading to the fused diazocine-2,5-diones, diazocine-2,5-diones, started from synthesis
Summary
Modern medicinal chemistry is mainly based on the design of novel, biologically active compounds containing diverse heterocyclic scaffolds, including privileged structures. Tricyclic heterocyclic scaffolds, possessing two non-polar phenyl rings separated by a seven-membered heterocycle, and their structural analogues, are challenging synthetic targets for organic chemists [2,3,4,5]. The development of a wide range of novel synthetic methods has led to Molecules 2020, 25, 2855; doi:10.3390/molecules25122855 www.mdpi.com/journal/molecules. Molecules 2020, 25, 2855 phenyl rings separated by a seven-membered heterocycle, and their structural analogues, are challenging synthetic targets for organic chemists [2,3,4,5]. The development of a wide range of novel synthetic methods has led to the of synthesis of a broad variety of derivatives with significant biological the synthesis of a broad variety derivatives with significant biological activity, where the tricyclic activity, wheredrugs the tricyclic drugs focused most attention [6].development. Our the own research on the of novel the development of novel therapeutic agents, based on tricyclic benzodiazepine derivatives, resulted therapeutic agents, based on tricyclic benzodiazepine derivatives, resulted in the development of in the development unique agents 1 a(Figure
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