19 research outputs found
Unsymmetrically-Substituted 5,12-dihydrodibenzo[b,f][1,4]diazocine-6,11-dione ScaffoldâA Useful Tool for Bioactive Molecules Design
Unsymmetrically N-substituted and N,Nâ-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 (EUFA30âhuman fibroblasts) and three tumor cells (U87âhuman primary glioblastoma, HeLaâcervix adenocarcinoma, BICR18âlaryngeal 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
Unsymmetrically Substituted Dibenzo[b,f][1,5]-diazocine-6,12(5H,11H)dioneâA Convenient Scaffold for Bioactive Molecule Design
A novel approach for the synthesis of unsymmetrically substituted dibenzo[b,f][1,5]diazocine-6,12(5H,11H)diones has been developed. This facile three-step method uses variously substituted 1H-benzo[d][1,3]oxazine-2,4-diones (isatoic anhydrides) and 2-aminobenzoic acids as a starting materials. The obtained products were further transformed into N-alkyl-, N-acetyl- and dithio analogues. Developed procedures allowed the synthesis of unsymmetrical dibenzo[b,f][1,5]diazocine-6,12(5H,11H)diones and three novel heterocyclic scaffolds: benzo[b]naphtho[2,3-f][1,5]diazocine-6,14(5H,13H)dione, pyrido[3,2-c][1,5]benzodiazocine-5,11(6H,12H)-dione and pyrazino[3,2-c][1,5]benzodiazocine-6,12(5H,11H)dione. For 11 of the compounds crystal structures were obtained. The preliminary cytotoxic effect against two cancer (HeLa, U87) and two normal lines (HEK293, EUFA30) as well as antibacterial activity were determined. The obtained dibenzo[b,f][1,5]diazocine(5H,11H)6,12-dione framework could serve as a privileged structure for the drug design and development
Improved HDAC Inhibition, Stronger Cytotoxic Effect and Higher Selectivity against Leukemias and Lymphomas of Novel, Tricyclic Vorinostat Analogues
Histone deacetylase (HDAC) inhibitors are a class of drugs used in the cancer treatment. Here, we developed a library of 19 analogues of Vorinostat, an HDAC inhibitor used in lymphomas treatment. In Vorinostat, we replaced the hydrophobic phenyl group with various tricyclic âcapsâ possessing a central, eight-membered, heterocyclic ring, and investigated the HDAC activity and cytotoxic effect on the cancer and normal cell lines. We found that 3 out of the 19 compounds, based on dibenzo[b,f]azocin-6(5H)-one, 11,12-dihydrodibenzo[b,f]azocin- 6(5H)-one, and benzo[b]naphtho[2,3-f][1,5]diazocine-6,14(5H,13H)-dione scaffolds, showed better HDACs inhibition than the referenced Vorinostat. In leukemic cell line MV4-11 and in the lymphoma cell line Daudi, three compounds showed lower IC50 values than Vorinostat. These compounds had higher activity and selectivity against MV4-11 and Daudi cell lines than reference Vorinostat. We also observed a strong correlation between HDACs inhibition and the cytotoxic effect. Cell lines derived from solid tumours: A549 (lung carcinoma) and MCF-7 (breast adenocarcinoma) as well as reference BALB/3T3 (normal murine fibroblasts) were less susceptible to compounds tested. Developed derivatives show improved properties than Vorinostat, thus they could be considered as possible agents for leukemia and lymphoma treatment
Unsymmetrically Substituted Dibenzo[b,f][1,5]-diazocine-6,12(5H,11H)dioneâA Convenient Scaffold for Bioactive Molecule Design
A novel approach for the synthesis of unsymmetrically substituted dibenzo[b,f][1,5]diazocine-6,12(5H,11H)diones has been developed. This facile three-step method uses variously substituted 1H-benzo[d][1,3]oxazine-2,4-diones (isatoic anhydrides) and 2-aminobenzoic acids as a starting materials. The obtained products were further transformed into N-alkyl-, N-acetyl- and dithio analogues. Developed procedures allowed the synthesis of unsymmetrical dibenzo[b,f][1,5]diazocine-6,12(5H,11H)diones and three novel heterocyclic scaffolds: benzo[b]naphtho[2,3-f][1,5]diazocine-6,14(5H,13H)dione, pyrido[3,2-c][1,5]benzodiazocine-5,11(6H,12H)-dione and pyrazino[3,2-c][1,5]benzodiazocine-6,12(5H,11H)dione. For 11 of the compounds crystal structures were obtained. The preliminary cytotoxic effect against two cancer (HeLa, U87) and two normal lines (HEK293, EUFA30) as well as antibacterial activity were determined. The obtained dibenzo[b,f][1,5]diazocine(5H,11H)6,12-dione framework could serve as a privileged structure for the drug design and development
Recent advances in the synthesis and applications of oxazolo[5,4-d]pyrimidines (microreview)
Modern methods of synthesis of oxazolo[5,4-d]-pyrimidines published over the past 10 years are reviewed in the present communication. The two main approaches include the synthesis via cyclization of pyrimidine derivatives resulted in the fused oxazole ring or by condensation of oxazole derivatives leading to fused pyrimidine rings
A Radical Route to α-Substituted Enones
International audienceA versatile strategy for the α-substitution of enones through the formal fusion between enones and unactivated alkenes is described. It relies on the formation and use of α-xanthyl-ÎČ-hydroxy ketones, which can be considered as synthetic equivalents of the high energy and difficult to tame alkenyl radicals. The process, which can often be accomplished one-pot, could be extended in one case to an α,ÎČ-unsaturated ester. α,ÎČ-Unsaturated carbonyls, and enones in particular, are of paramount importance in organic synthesis because of their exceptionally rich chemistry and their central role in the planning and execution of total syntheses of natural products. 1 Nonetheless, the facil
An Ionic-Radical Approach to Vicinally Functionalized Cyclopentanones and Cyclohexanones 1
International audienc
α-Xanthyl Cyclopentenones and Cyclohexenones: New, Highly Versatile Building Blocks
A versatile strategy to synthesize α,ÎČ-functionalized cyclopentanones and cyclohexanones is described. It takes advantage of new reagents, α-xanthyl enones, which can be prepared from the reaction of xanthate salts with epoxides under acidic conditions. ÎČ-Functionalization of these compounds can be performed by conjugate additions without affecting the xanthate moitety. This significantly expands the pool of xanthate substrates, allowing the synthesis of open chain and fused bicyclic building blocks useful in the synthesis of natural products
Photochemical C H Hydroxyalkylation of Quinolines and Isoquinolines
We report herein a visible lightâmediated CâH hydroxyalkylation of quinolines and isoquinolines that proceeds via a radical path. The process exploits the excitedâstate reactivity of 4âacylâ1,4âdihydropyridines, which can readily generate acyl radicals upon blue light absorption. By avoiding the need for external oxidants, this radicalâgenerating strategy enables a departure from the classical, oxidative Minisciâtype pattern and unlocks a unique reactivity, leading to hydroxyalkylated heteroarenes. Mechanistic investigations provide evidence that a radicalâmediated spinâcenter shift is the key step of the process. The method's mild reaction conditions and high functional group tolerance accounted for the lateâstage functionalization of active pharmaceutical ingredients and natural products
A Radical Route to 뱉Substituted Enones
A versatile strategy for the α-substitution of
enones through
the formal fusion between enones and unactivated alkenes is described.
It relies on the formation and use of α-xanthyl-ÎČ-hydroxy
ketones, which can be considered as synthetic equivalents of the high
energy and difficult to tame alkenyl radicals. The process, which
can often be accomplished one-pot, could be extended in one case to
an α,ÎČ-unsaturated ester