RESUMO
Herein we describe a catalyst-free regioselective [3 + 3] annulation/oxidation reaction of cyclic amidines such as DBU (1,8-diazabicyclo(5.4.0)undec-7-ene) and DBN (1,5-diazabicyclo(4.3.0)non-5-ene) with activated olefins, i.e., 2-arylidenemalononitriles and 2-cyano-3-aryl acrylates, to afford tricyclic 2-pyridones and pyridin-2(1H)-imines, respectively. The mechanism has been proposed based on DFT calculations. In the reaction, the cyclic amidines serve as C,N-bisnucleophiles for the cyclization, while the olefins play a dual role by acting as both reactants and oxidants.
RESUMO
DNA alkylation damage, emanating from the exposure to environmental alkylating agents or produced by certain endogenous metabolic processes, affects cell viability and genomic stability. Fe(II)/2-oxoglutarate-dependent dioxygenase enzymes, such as Escherichia coli AlkB, are involved in protecting DNA from alkylation damage. Inspired by the natural product indenone derivatives reported to inhibit this class of enzymes, and a set of 2-chloro-3-amino indenone derivatives was synthesized and screened for their inhibitory properties against AlkB. The synthesis of 2-chloro-3-amino indenone derivatives was achieved from 2,3-dichloro indenones through addition-elimination method using alkyl/aryl amines under catalyst-free conditions. Using an in vitro reconstituted DNA repair assay, we have identified a 2-chloro-3-amino indenone compound 3o to be an inhibitor of AlkB. We have determined the binding affinity, mode of interaction, and kinetic parameters of inhibition of 3o and tested its ability to sensitize cells to methyl methanesulfonate that mainly produce DNA alkylation damage. This study established the potential of indenone-derived compounds as inhibitors of Fe(II)/2-oxoglutarate-dependent dioxygenase AlkB.
Assuntos
Alquilantes/síntese química , Reparo do DNA , Indenos/química , Alquilantes/farmacologia , Sítios de Ligação , Dano ao DNA , Desmetilação do DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Escherichia coli/enzimologia , Proteínas de Escherichia coli/antagonistas & inibidores , Proteínas de Escherichia coli/metabolismo , Humanos , Indenos/metabolismo , Indenos/farmacologia , Cinética , Oxigenases de Função Mista/antagonistas & inibidores , Oxigenases de Função Mista/metabolismo , Simulação de Acoplamento Molecular , Ligação ProteicaRESUMO
An efficient acid induced rearrangement of a tetrahalo-7,7-dimethoxybicyclo[2.2.1]heptenyl system leading to substituted indenones is reported. This domino reaction involves dehydration, olefin isomerization, ketal hydrolysis, [3,3]-sigmatropic rearrangement and dehydrohalogenation. The resultant vicinal dihalo olefin moiety in the efficiently generated indenone derivatives was utilized to transform into ninhydrin derivatives by employing Ru(III)-catalyzed oxidation.