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

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.

Improved HDAC Inhibition, Stronger Cytotoxic Effect and Higher Selectivity against Leukemias and Lymphomas of Novel, Tricyclic Vorinostat Analogues

“…In the next part of our research, we decided to synthesize the compounds of Series 3 and to use seven tricyclic ‘caps’: 5-methyl-5,12-dihydrodibenzo[ b,f ][1,4]diazocine-6,11-dione ( 11 ) [ 96 ], 2,3-dichloro-5-methyl-5,12-dihydrodibenzo[ b,f ][1,4]diazocine-6,11-dione ( 12 ) [ 96 ], 5-benzyl-5,12-dihydrodibenzo[ b,f ][1,4]diazocine-6,11-dione ( 13 ) [ 96 ], 11,12-dihydrodibenzo[ b,f ]azocin-6(5 H )-one ( 14 ) [ 98 ], 2-bromo-11-methyldibenzo[ b,f ][1,5]diazocine-6,12(5 H ,11 H )-dione ( 15 ) [ 95 ], 2,3-dimethoxy-11-methyldibenzo[ b,f ][1,5]diazocine-6,12(5 H ,11 H )-dione ( 16 ) [ 95 ], and 2-chloro-5-methylbenzo[ b ]naphtho[2,3- f ][1,5]diazocine-6,14(5 H ,13 H )-dione ( 17 ) [ 95 ] ( Scheme 2 ). Previously obtained compounds 11 – 17 were treated with ethyl 6-bromohexanoate in the presence of sodium hydride which resulted in the intermediate products 10m – t .…”

“…For years, our research group has been working on the design and synthesis of various mono- and polycyclic dilactam derivatives [ 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 ] with potential biological activity. The studies resulted in the discovery of tricyclic benzodiazepines exhibiting selective antileukemic effects [ 92 , 93 , 94 ].…”

“…These compounds could be treated as structural analogues of antitumour antibiotic Anthramycin. Recently, we focused on the development of novel synthetic methods leading to asymmetrically substituted tricylic lactam and dilactam compounds with central, eight-membered heterocyclic rings [ 95 , 96 , 97 ]. Such structures were used by us for the development of novel analogues of tricyclic drugs exhibiting significant affinity to H 1 receptors [ 98 ].…”

Novel Vorinostat Analogues with Improved HDAC Inhibition, Stronger Cytotoxic Effect and Higher Selectivity Against Leukemias and Lymphomas

“…During research on new Vorinostat analogues, compounds 2-6 having a bicyclic or tricyclic benzodiazepine ring system (Figure 1) were also obtained [85][86][87][88] exhibiting marked HDAC inhibition and selective antileucemic effect on tested cell lines. For years our research group has been working on the design and synthesis of various mono-and polycyclic dilactam derivatives [89][90][91][92][93][94][95][96][97][98] with potential biological activity. The studies resulted in the discovery of tricyclic benzodiazepines exhibiting selective antileukemic effect [92][93][94].…”

“…These compounds could be treated as structural analogues of antitumor antibiotic Anthramycin. Recently, we focused on the development of novel synthetic methods leading to asymmetrically substituted tricylic lactam and dilacam compounds with central, eight-membered heterocyclic rings [95][96][97]. Such structures were used by us for the development of novel analogues of tricyclic drugs, which exhibited significant affinity to H1 receptors [98].…”