RESUMO
Efficient racemic synthesis of two antibacterial and antimalarial natural products, cordypyridones A and B, was achieved from inexpensive, commercially available starting materials in an overall yield of 15% (8% and 7%, respectively). This convergent synthesis utilizes a key coupling step of two fragments and the subsequent functional group transformations lead to the target compounds and their 8-epi-analogues.
Assuntos
Produtos Biológicos/síntese química , Piridonas/síntese química , Produtos Biológicos/química , Catálise , Cordyceps/química , Estrutura Molecular , Piridonas/química , EstereoisomerismoRESUMO
Despite their structural similarities, the natural products chelerythrine ( 5) and sanguinarine ( 6) target different binding sites on the pro-survival Bcl-X L protein. This paper details the synthesis of phenanthridine-based analogues of the natural products that were used to probe this difference in binding profiles. The inhibitory constants for these compounds were then measured in a fluorescence polarization assay against Bcl-X L and the tagged Bak-BH3 peptide. The results led to structure-activity relationship studies, which identified the structural motifs required for binding-site specificity as well as inhibitory activity. We also identified synthetic analogues of the natural products that display similar binding modes but with more potent IC 50 values.
Assuntos
Fenantridinas/síntese química , Fenantridinas/farmacologia , Proteína bcl-X/antagonistas & inibidores , Simulação por Computador , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Mutação/genética , Fenantridinas/química , Relação Estrutura-Atividade , Proteína bcl-X/genética , Proteína bcl-X/metabolismoRESUMO
A concise formal total synthesis of the cytotoxic bisnaphthazarin derivative hybocarpone has been completed through the development of routes to the synthetic precursor, 3-ethyl-2-hydroxy-5,7,8-trimethoxy-6-methyl-1,4-naphthoquinone. The oxidation of 3-ethyl-1,2,4,5,7,8-hexamethoxy-6-methylnaphthalene under Rapoport conditions gave 3-ethyl-2-hydroxy-5,7,8-trimethoxy-6-methyl-1,4-naphthoquinone in modest yields after basic hydrolysis. In addition, treatment of 3-ethyl-1,2,4,5,7,8-hexamethoxy-6-methylnaphthalene with boron tribromide provided access to the naturally occurring naphthazarin, boryquinone. The analogous oxidative demethylation of 3,6-dimethyl-1,2,4,5,7,8-hexamethoxynaphthalene and 3-ethyl-1,2,4,5,7,8-hexamethoxynaphthalene resulted in the synthesis of 2,5,7,8-tetrahydroxy-3,6-dimethyl-1,4-naphthoquinone (aureoquinone) and 3-ethyl-2,5,7,8-tetrahydroxy-1,4-naphthoquinone, respectively. An alternative selective synthetic route to 3-ethyl-2-hydroxy-5,7,8-trimethoxy-6-methyl-1,4-naphthoquinone was also developed utilizing an intramolecular Claisen condensation of methyl 2-butyryl-3,5,6-trimethoxy-4-methylphenylacetate with concomitant in situ aerial oxidation.
