ABSTRACT
Studies have advanced a stereocontrolled pathway for the synthesis of australifungin. Elaboration of the trans-fused IMDA product 4 led to the cis-diol 15, which produced the α-hydroxyenone 19 upon oxidation. Computational studies on model systems indicate that the keto-enol tautomer shown for 19 is higher in energy than the keto-enol tautomer represented by the natural product 1. The reactivity of 19 does not permit mild isomerization and subsequent deprotection to yield 1. These findings raise new questions regarding the synthesis and bioactivity of australifungin and related natural products.
Subject(s)
Tetrahydronaphthalenes/chemical synthesis , Ascomycota/chemistry , Biological Products/chemistry , Molecular Structure , Stereoisomerism , Tetrahydronaphthalenes/chemistryABSTRACT
Inhibition of the mitogen-activated protein kinase (MAPK) pathway by targeting the commonly occurring mutated B-Raf in melanoma has become a practical method for the development of drugs and drug candidates. In order to expand upon the currently reported structural scaffolds used to target the MAPK pathway, molecular docking studies led to the installation an α,ß-unsaturated ketone side chain, related to the cucurbitacin class of natural products, on to an estrone core via an aldol condensation reaction, along with installation of the Δ(9,11) olefin to assemble what has been defined as a pseudo-cis configuration at the B/C ring juncture. Combination of these cucurbitacin-like features resulted in a compound with an enhanced biological profile against the A-375 mutant B-Raf cell line, in regards to their cytotoxicity and inhibitory activity toward phosphorylated extracellular-signal-regulated kinase (ERK).
Subject(s)
Cucurbitacins/chemistry , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Binding Sites , Biological Products/chemistry , Biological Products/metabolism , Biological Products/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Cucurbitacins/metabolism , Cucurbitacins/pharmacology , Humans , Hydrogen Bonding , Molecular Docking Simulation , Protein Structure, Tertiary , Proto-Oncogene Proteins B-raf/metabolismABSTRACT
Functionalized estrogen analogs have received interest due to their unique and differing biological activity compared to their parent compounds. The synthesis of a new class of 3-methoxyestrone analogs functionalized at the C17 position possessing both alkyl and aryl substituted α,ß-unsaturated ketones is described, along with their thiophenol conjugate addition products.
Subject(s)
Alkenes/chemistry , Estrone/analogs & derivatives , Estrone/chemical synthesis , Ketones/chemistry , Phenols/chemistry , Sulfhydryl Compounds/chemistry , Chemistry Techniques, Synthetic , Estrone/chemistry , Models, Molecular , Molecular ConformationSubject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Lactones/chemistry , Biological Products/chemical synthesis , Biological Products/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Cyclization , Dicarboxylic Acids/chemistry , Kinetics , Lactones/chemical synthesis , StereoisomerismABSTRACT
A modification of the Sonogoshira coupling reaction employing an amidine base and a substoichiometric amount of water generates symmetrical and unsymmetrical bisarylethynylenes in one pot through in situ deprotection of trimethylsilylethynylene-added intermediates.