RESUMO
Deoxyelephantopin is a sesquiterpene lactone that was reported to be as effective in the treatment of mammary tumours and lung metastasis as taxol based on a murine orthotopic cancer model. Its germacrene skeleton harbours three Michael acceptors that can potentially engage a target covalently. Its strained 10-membered ring is densely functionalised and represents an important synthetic challenge. We herein describe our studies towards deoxyelephantopins using a ring-closing metathesis approach and report some unexpected observations.
Assuntos
Antibióticos Antineoplásicos/síntese química , Lactonas/síntese química , Sesquiterpenos/síntese química , Indicadores e Reagentes , Conformação MolecularRESUMO
Covalent inhibitors are re-emerging as pharmacologically interesting entities with several candidates having received recent approval for therapeutic intervention. Nature has embraced this strategy and many natural products possess mildly electrophilic moieties able to covalently engage a target protein. This review surveys recent case studies for the identification of the target proteins of natural products. While sesquiterpene lactones represent a vast repertoire of covalent inhibitors, they can also be found in other classes of natural products, with sometimes unusual mechanisms to unmask the electrophilic moieties. These examples ought to be inspiring for the development of new biochemical probes and tomorrow's first-in-class drugs.
Assuntos
Produtos Biológicos/farmacologia , Descoberta de Drogas , Sesquiterpenos/farmacologiaRESUMO
There is a resurging interest in compounds that engage their target through covalent interactions. Cysteine's thiol is endowed with enhanced reactivity, making it the nucleophile of choice for covalent engagement with a ligand aligning an electrophilic trap with a cysteine residue in a target of interest. The paucity of cysteine in the proteome coupled to the fact that closely related proteins do not necessarily share a given cysteine residue enable a level of unprecedented rational target selectivity. The recent demonstration that a lysine's amine can also be engaged covalently with a mild electrophile extends the potential of covalent inhibitors. The growing database of protein structures facilitates the discovery of covalent inhibitors while the advent of proteomic technologies enables a finer resolution in the selectivity of covalently engaged proteins. Here, we discuss recent examples of discovery and design of covalent inhibitors.
Assuntos
Descoberta de Drogas/métodos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Sequência de Aminoácidos , Animais , Produtos Biológicos/química , Produtos Biológicos/farmacologia , HumanosRESUMO
Herbal extracts containing sesquiterpene lactones have been extensively used in traditional medicine and are known to be rich in α,ß-unsaturated functionalities that can covalently engage target proteins. Here we report synthetic methodologies to access analogues of deoxyelephantopin, a sesquiterpene lactone with anticancer properties. Using alkyne-tagged cellular probes and quantitative proteomics analysis, we identified several cellular targets of deoxyelephantopin. We further demonstrate that deoxyelephantopin antagonizes PPARγ activity in situ via covalent engagement of a cysteine residue in the zinc-finger motif of this nuclear receptor.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Lactonas/farmacologia , PPAR gama/antagonistas & inibidores , Sesquiterpenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Cisteína/metabolismo , Humanos , Lactonas/análise , Lactonas/síntese química , Lactonas/uso terapêutico , Terapia de Alvo Molecular/métodos , Neoplasias/tratamento farmacológico , PPAR gama/metabolismo , Proteômica/métodos , Proteínas Recombinantes/metabolismo , Sesquiterpenos/análise , Sesquiterpenos/síntese química , Sesquiterpenos/uso terapêutico , Dedos de Zinco/efeitos dos fármacosRESUMO
The asymmetric total synthesis of the diastereomers of stylopsal establishes the absolute configuration of the first reported sex pheromone of the twisted-wing parasite Stylops muelleri as (3R,5R,9R)-trimethyldodecanal. The key steps for the diastereo- and enantiodivergent introduction of the methyl groups are two different types of asymmetric conjugate addition reactions of organocopper reagents to α,ß-unsaturated esters, whereas the dodecanal skeleton is assembled by Wittig reactions. The structure of the natural product was confirmed by chiral gas chromatography (GC) techniques, GC/MS and GC/electroantennography (EAD) as well as field tests. An investigation into the biosynthesis of the pheromone revealed that it is likely to be produced by decarboxylation of a 4,6,10-trimethyltridecanoic acid derivative, which was found in substantial amounts in the fat body of the female, but not in the host bee Andrena vaga. This triple-branched fatty acid precursor thus seems to be biosynthesized de novo through a polyketide pathway with two consecutive propionate-propionate-acetate assemblies to form the complete skeleton. The simplified, motionless and fully host-dependent female exploits a remarkable strategy to maximize its reproductive success by employing a relatively complex and potent sex pheromone.