ABSTRACT
(±)-8-Deisopropyladunctin B, the deisopropyl form of adunctin B, which was isolated from the leaves of Piper aduncum (Piperaceae) collected in Papua New Guinea, was synthesized in 0.77% overall yield in 17 steps from 5,7-dimethoxycoumarin-3-carboxylate. The key step was our original stereoconvergent skeleton transformation from 1,2,2a,8b-tetrahydro-3H-benzo[b]cyclobuta[d]pyran-3-one to 1,2,4a,9b-tetrahydrodibenzofuran-4-ol with dimethylsulfoxonium methylide.
Subject(s)
Benzofurans/chemical synthesis , Pyrans/chemistry , Benzofurans/chemistry , Dicarboxylic Acids/chemistry , Piper/chemistry , Plant Leaves/chemistry , Pyrans/chemical synthesis , Stereoisomerism , Sulfonium Compounds/chemistryABSTRACT
Cucurbitane-type triterpenes, cucurbitacins B and E, were reported to exhibit cytotoxic effects in several cell lines mediated by JAK/STAT3 signaling. However, neither compound inhibited phosphorylation of STAT3 in human leukemia (U937) cells at low concentrations. We therefore synthesized a biotin-linked cucurbitacin E to isolate target proteins based on affinity for the molecule. As a result, cofilin, which regulates the depolymerization of actin, was isolated and suggested to be a target. Cucurbitacins E and I inhibited the phosphorylation of cofilin in a concentration-dependent manner, and their effective concentrations having the same range as the concentrations at which they had cytotoxic effects in U937 cells. In addition, the fibrous-/globular-actin ratio was decreased after treatment with cucurbitacin E in HT1080 cells. These findings suggested that the inhibition of cofilin's phosphorylation increased the severing activity of cofilin, and then the depolymerization of actin was enhanced after treatment with cucurbitacin E at lower concentrations.
Subject(s)
Antineoplastic Agents/chemistry , Cofilin 1/metabolism , Triterpenes/chemistry , Actins/metabolism , Antineoplastic Agents/toxicity , Cell Line, Tumor , Cofilin 1/antagonists & inhibitors , Humans , Phosphorylation , STAT3 Transcription Factor/metabolism , Triterpenes/toxicity , U937 CellsABSTRACT
Eleven 3-substituted isocoumarins and a benzylidenephthalide were synthesized through thermal cyclization reaction of delta- and gamma-ketoamides, respectively. Subsequent deprotection of the hydroxyl groups of the resulting isocoumarin and benzylidenephthalide compounds afforded thunberginols A, B, and F, respectively, which originated from the processed leaves of Hydrangea macrophylla SERINGE var. thunbergii MAKINO. The synthesized isocoumarins and thunberginols were evaluated for their anti-allergic activity, in which thunberginol B exhibited the highest inhibitory potency on the degranulation of RBL-2H3 cells induced by antigen. Structure-activity relationship studies were carried out to determine the necessary substituents on the 3-phenylisocoumarin skeleton for inhibitory activity.
Subject(s)
Cell Degranulation/drug effects , Cell Degranulation/immunology , Isocoumarins/chemical synthesis , Antigens/immunology , Antigens/pharmacology , Cell Line , Cyclization , Dinitrobenzenes/immunology , Hydrangea/chemistry , Indicators and Reagents , Magnetic Resonance Spectroscopy , Plant Leaves/chemistry , Serum Albumin, Bovine/immunology , Serum Albumin, Bovine/pharmacology , Spectrometry, Mass, Electrospray Ionization , Spectrophotometry, Infrared , Structure-Activity RelationshipABSTRACT
The first asymmetric total synthesis of (-)-Linderol A, a potent inhibitor of melanin biosynthesis of cultured B-16 melanoma cells, has been achieved via two key reactions: a diastereoselective [2+2] photocycloaddition of a coumarin-3-carboxylate bearing a chiral auxiliary with 3-methyl-1-butene and a subsequent stereoconvergent transformation of the photoadducts with use of dimethylsulfoxonium methylide to afford a tetrahydrodibenzofuran derivative.
