RESUMO
DAG-lactones represent useful templates for the design of potent and selective C1 domain ligands for PKC isozymes. The ester moiety at the sn-1 position, a common feature in this template, is relevant for C1 domain interactions, but it represents a labile group susceptible to endogenous esterases. An interesting challenge involves replacing the ester group of these ligands while still maintaining biological activity. Here, we present the synthesis and functional characterization of novel diacylglycerol-lactones containing heterocyclic ring substituents at the sn-1 position. Our results showed that the new compound 10B12, a DAG-lactone with an isoxazole ring, binds PKCα and PKCε with nanomolar affinity. Remarkably, 10B12 displays preferential selectivity for PKCε translocation in cells and induces a PKCε-dependent reorganization of the actin cytoskeleton into peripheral ruffles in lung cancer cells. We conclude that introducing a stable isoxazole ring as an ester surrogate in DAG-lactones emerges as a novel structural approach to achieve PKC isozyme selectivity.
Assuntos
Diglicerídeos/farmacologia , Desenho de Fármacos , Compostos Heterocíclicos/farmacologia , Lactonas/farmacologia , Proteína Quinase C/metabolismo , Diglicerídeos/síntese química , Diglicerídeos/química , Relação Dose-Resposta a Droga , Células HeLa , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Isoenzimas/metabolismo , Lactonas/síntese química , Lactonas/química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The palladium catalyzed cross-coupling reaction of phenyltrifluoroborate with a chemoenzymatically derived bromoazidoconduritol, combined with 1,3-dipolar cycloaddition, with a variety of alkynes is described. Fourteen new compounds were synthesized in moderate to good yields. The click chemistry reaction can be effected by using sodium ascorbate and CuSO(4) · 5H(2)O as catalyst in toluene-H(2)O at room temperature.
Assuntos
Biocatálise , Química Click/métodos , Ciclitóis/química , Paládio/química , Ciclitóis/síntese química , Dioxigenases/metabolismo , Pseudomonas putida/enzimologiaRESUMO
The first syntheses of two deoxythiocyanocyclitols (4-deoxy-4-thiocyano-L-chiro-inositol and deoxythiocyanoconduritol F) and two deoxysulfonylcyclitol acetals are reported by a chemoenzymatic enantioselective route. The compounds were prepared by a sequence of enzymatic and ruthenium-catalyzed dihydroxylations, and the results were studied regarding reaction conditions and co-catalyst for different derivatives. The new compounds were included in a minilibrary of deoxygenated cyclitols and evaluated for their capacity to influence the feeding behavior of Epilachna paenulata (Coleoptera: Coccinellidae), a common pest of the Curcubitaceae crops.
Assuntos
Ciclitóis/síntese química , Ciclitóis/farmacologia , Enxofre/química , Animais , Besouros , Ciclitóis/química , Comportamento Alimentar/efeitos dos fármacos , Estrutura MolecularRESUMO
epi-Inositol was synthesized in six steps in 40% overall yield from a bacterial bromobenzene metabolite. The chemoenzymatic route involved toluene dioxygenase oxidation, substrate-directed catalytic osmylation, m-CPBA epoxidation, radical debromination, and Amberlite-catalized hydrolysis. The route described is amenable to scaleup and could allow access to cis-inositol, and deoxy derivatives of epi-inositol.