RESUMEN
The recent discovery of c-Jun NH2-terminal kinase JNK1 suppression by natural quercetagetin (1) is a promising lead for the development of novel anticancer agents. Using both X-ray structure and docking analyses we predicted that 5'-hydroxy- (2) and 5'-hydroxymethyl-quercetagetin (3) would inhibit JNK1 more actively than the parent compound 1. Notably, our drug design was based on the active enzyme-ligand complex as opposed to the enzyme's relatively open apo structure. In this paper we test our theoretical predictions, aided by docking-model experiments, and report the first synthesis and biological evaluation of quercetagetin analogues 2 and 3. As calculated, both compounds strongly suppress JNK1 activity. The IC50 values were determined to be 3.4â µM and 12.2â µM, respectively, which shows that 2 surpasses the potency of the parent compound 1 (IC50 =4.6â µM). Compound 2 was also shown to suppress matrix metalloproteinase-1 expression with high specificity after UV irradiation.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Cromonas/química , Cromonas/farmacología , Proteína Quinasa 8 Activada por Mitógenos/química , Factores Biológicos , Cromonas/metabolismo , Diseño de Fármacos , Flavonas , Humanos , Concentración 50 Inhibidora , Proteína Quinasa 8 Activada por Mitógenos/metabolismo , Rayos UltravioletaRESUMEN
The first enantioselective total syntheses of the tetrahydroxanthenone (-)-blennolideâ C (ent-4) and related γ-lactonyl chromanone (-)-gonytolideâ C (ent-3) are reported. Key to the syntheses is an enantioselective domino-Wacker/carbonylation/methoxylation reaction to set up the stereocentre at C-4a. Various chiral BOXAX ligands were investigated, including novel (S,S)-iBu-BOXAX, and allowed access to chromane 8 in an excellent enantioselectivity of 99 %. The second stereocentre at C-4 was established employing a diastereoselective Sharpless dihydroxylation. An extensive survey of (DHQ)- and (DHQD)-based ligands enabled the preparation of both the anti-isomer 14 a and the syn-isomer 14 b in very good to reasonable selectivities of 13.7:1 and 1:3.7, respectively. While 14 a was further converted to ent-3 and ent-4, 14 b was elaborated to syn-acid 25 and 2'-epi-gonytolideâ C 28.
Asunto(s)
Cromonas/síntesis química , Xantonas/síntesis química , Productos Biológicos , Catálisis , Cromonas/química , Modelos Moleculares , Estructura Molecular , Estereoisomerismo , Xantonas/químicaRESUMEN
C-C bond fragmentation of structurally diverse carbocycles has been applied to the divergent synthesis of dendrimers. The fragmentation has been paired to deprotection or thio-Michael reaction, allowing the preparation of a fourth generation dendrimer of narrow molecular weight distribution. Methodologies to increase water solubility have been examined using appended carboxylic acid or oligoether moieties. In addition, incorporation of chiral prolinol derivatives has resulted in the synthesis of dendrimers that have been shown to catalyse the α-amination of aldehydes in good yield and modest enantioselectivity.
Asunto(s)
Ácidos Carboxílicos/síntesis química , Dendrímeros/síntesis química , Pirrolidinas/química , Ácidos Carboxílicos/química , Dendrímeros/química , Estructura MolecularRESUMEN
Introduction of a ß-electron withdrawing group to cycloalkanones allows facile C-C bond fragmentation. The reaction has been demonstrated with a large range of ring sizes, bearing various leaving and electron withdrawing groups, and using a variety of nitrogen and oxygen containing nucleophiles (>30 examples). The application of fragmentation products to the preparation of substituted γ-lactones has been demonstrated. Mechanistic studies are reported which are suggestive of a Grob/Eschenmoser type reaction.
RESUMEN
A range of spirocyclic γ-lactones have been prepared exploiting a Beckwith-Dowd ring expansion cascade involving 1-, 3-, 4-, and 5-carbon expansion of cyclopentanone and cyclohexanone followed by 5-exo-trig or 5-exo-dig cyclization. This radical cascade reaction can be achieved with various substrates to provide a broad range of γ-lactones spirofused to 6- to 10-membered cycloalkanones.
Asunto(s)
Lactonas/síntesis química , Compuestos de Espiro/síntesis química , Ciclización , Lactonas/química , Conformación Molecular , Compuestos de Espiro/química , EstereoisomerismoRESUMEN
The C-C bond fragmentation of carbocycles has been developed as a new method for the divergent synthesis of dendrimers. The scope of this reaction was examined with the preparation of six first generation dendrimers from structurally diverse and readily available fragmentation precursors. By pairing the fragmentation with a thio-Michael reaction, the preparation of a [G4]-ene(24) dendrimer has been achieved.