ABSTRACT
The lignan 7'-hydroxymatairesinol (1), extracted from the knotwoods of fir (Abies alba), spruce (Picea abies), and Douglas fir (Pseudotsuga menziesii), exhibited unexpected reactivity when esterification reactions were attempted on the hydroxy group at position C-7'. To circumvent the rapid intramolecular cyclization procedure, leading quantitatively to the lignan conidendrin (7), a simple strategy for 7'-esterification of 1 under mild conditions (three steps, up to 80% overall yield) was developed. Compared to hydroxymatairesinol (1) (log K'w = 1.49), the derivatives (2-5) had increased lipophilicity with log K'w > 3.1, as determined by a UHPLC method. Compounds 1-5 exhibited potent antioxidant properties in the same range as the standards ascorbic acid and α-tocopherol (IC50 = 20-25 µM) and higher than that of BHT using a DPPH radical-scavenging assay.
Subject(s)
Antioxidants/chemistry , Antioxidants/pharmacology , Lignans/chemistry , Lignans/pharmacology , Picea/chemistry , Pinus/chemistry , Tetrahydronaphthalenes/chemistry , Tetrahydronaphthalenes/pharmacology , Biphenyl Compounds/pharmacology , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Picrates/pharmacology , Stereoisomerism , alpha-TocopherolSubject(s)
Capsaicin , Fluorine Compounds , TRPV Cation Channels/metabolism , Animals , Capsaicin/chemical synthesis , Capsaicin/metabolism , Fluorine Compounds/chemical synthesis , Fluorine Compounds/metabolism , Ganglia, Spinal/cytology , Halogenation , Humans , Molecular Conformation , Molecular Structure , Neurons/cytology , Neurons/physiology , Rats , Rats, Sprague-Dawley , StereoisomerismABSTRACT
In continuing research that led us to identify chromanone derivatives (J. Med. Chem. 2003, 46, 2125) as P-glycoprotein inhibitors, we obtained analogues able to modulate multidrug resistance (MDR) mediated by the breast cancer resistance protein (BCRP). The linkage of 5-hydroxybenzopyran-4-one to piperazines or phenalkylamines affords highly potent inhibitors of BCRP. By using sensitive (HCT116) and resistant colon cancer cells expressing BCRP, we evaluated the effect of 14 benzopyranone (chromone) derivatives on the accumulation and the cytotoxic effect of the anticancer drug, mitoxantrone. At 10 microM, three compounds increased both intracellular accumulation and cytotoxicity of mitoxantrone in HCT116/R cells with a comparable rate as fumitremorgin C and Gleevec used as reference inhibitors. The most potent molecules 5b and 5c are still active at 1 microM, whereas FTC shows weak inhibition. These molecules do not induce cell death as shown by the cell cycle distribution study, which makes them potential candidates for in vivo studies.
