RESUMO
Novel thieno[2,3-d]pyrimidines containing a cyclohexane ring fused with a six- or five-membered heterocyclic moiety along with a benzylic nitrile were designed as potential inhibitors of PDE4. Expeditious synthesis of these compounds was carried out via a multi-step sequence consisting of a few key steps such as Gewald reaction, Dieckmann type cyclisation and Krapcho decarboxylation. This newly developed strategy involved construction of the thienopyrimidine ring followed by the cyclohexanone moiety and subsequently the fused heterocyclic ring. A number of thieno[2,3-d]pyrimidine based derivatives were synthesized using this method some of which showed promising PDE4B inhibitory properties. One of them was tested for PDE4D inhibition in vitro and dose dependent inhibition of TNF-α. A few selected molecules were docked into the PE4B protein the results of which showed good overall correlations to their observed PDE4B inhibitory properties in vitro. The crystal structure analysis of representative compounds along with hydrogen bonding patterns and molecular arrangement present within the molecule is described.
Assuntos
Pirimidinas/química , Tiofenos/química , Animais , Linhagem Celular , Cristalografia por Raios X , Cicloexanonas/química , Humanos , Ligação de Hidrogênio , Camundongos , Modelos Moleculares , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Tiofenos/síntese química , Tiofenos/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/química , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Regioselective construction of a fused 2-ylidene chromene ring was achieved for the first time by using AlCl(3)-induced C-C bond formation followed by Pd/C-Cu mediate coupling-cyclization strategy. A number of chromeno[4,3-b]quinoxaline derivatives were prepared by using this strategy. Single crystal X-ray diffraction study of a representative compound e.g. 6-(2,2-dimethylpropylidene)-4-methyl-6H-chromeno[4,3-b]quinoxalin-3-ol confirmed the presence of an exocyclic C-C double bond with Z-geometry. The crystal structure analysis and hydrogen bonding patterns of the same compound along with its structure elaboration via propargylation followed by Sonogashira coupling of the resulting terminal alkyne is presented. A probable mechanism for the formation of 2-ylidene chromene ring is discussed. Some of the compounds synthesized showed anticancer properties when tested in vitro.
Assuntos
Benzopiranos/química , Quinoxalinas/síntese química , Ciclização , Ligação de Hidrogênio , Modelos Moleculares , EstereoisomerismoRESUMO
A regioselective route to novel mono triazolyl substituted quinolines has been developed via copper-catalyzed azide-alkyne cycloaddition (CuAAC) of 2,4-diazidoquinoline with terminal alkynes in DMF. The reaction provided bis triazolyl substituted quinolines when performed in water in the presence of Et(3)N. A number of the compounds synthesized showed promising anti-proliferative properties when tested in vitro especially against breast cancer cells.
Assuntos
Alcinos/química , Antineoplásicos/química , Azidas/química , Cobre/química , Quinolinas/química , Solventes/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ciclização , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos MolecularesRESUMO
Molecular iodine facilitated the reaction of 5,5-dimethyl-1,3-cyclohexanedione with aromatic aldehydes in iso-propanol affording a variety of 1,8-dioxo-octahydroxanthenes in high yields. Most of the compounds synthesized showed good anti-proliferative properties in vitro against three cancer cell lines and 9-(2-hydroxyphenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione possessing a 2-hydroxy phenyl group at C-9 position was found to be promising. Further structure elaboration of the same compound and the crystal structure analysis and hydrogen bonding patterns of another compound that is, 9-(4-methoxyphenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione prepared by using this methodology is presented.
Assuntos
Antineoplásicos/síntese química , Iodo/química , Xantenos/síntese química , Aldeídos/química , Antineoplásicos/farmacologia , Catálise , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Cicloexanos/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Estrutura Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Xantenos/farmacologiaRESUMO
A one-pot Yb(III)-mediated cascade reaction has been developed leading to small molecules based on a novel structural motif, i.e. quinazolin-4-one moiety fused with an isoquinoline ring, for potential inhibition of TNF-α.
Assuntos
Mesilatos/química , Compostos Organometálicos/química , Quinazolinonas/química , Quinazolinonas/síntese química , Catálise , Quinazolinonas/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
Concurrent construction of five and six membered fused N-heretocyclic ring was achieved via a conceptually new three-component reaction affording 6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-diones as novel inhibitors of TNF-αin vitro. This represents one of the few examples of direct TNF-α inhibition by small molecules.