Natural products as aromatase inhibitors: Identification and structure-activity aspects.

摘要

Estrogens play an important role in the development and progression of breast cancer. Aromatase inhibition (AI) decreases estrogen production, with clinically available agents reducing estrogen production to nearly undetectable levels, having significant effect on the development and progression of hormone-responsive breast cancers. Improved AIs are needed due to associated side-effects and resistance. This research focused on breast cancer therapy and/or prevention by identifying and evaluating new plant-derived natural product AIs.;Extracts and pure compounds isolated from edible, medicinal, and randomly collected plant species of various structural classes were screened using a noncellular, enzyme-based microsomal aromatase assay. Fifteen compounds inhibited aromatase, with the most active compounds being two xanthones, gamma-mangostin and garcinone D, isolated from Garcinia mangostana L. (mangosteen), a chalcone, 2,4,2',4'-tetrahydroxy-3'-prenychalcone, and a flavone, broussoflavonol F, from Broussonetia papyrifera Vent. Two compounds strongly inhibited aromatase in SK-BR-3 hormone-independent human breast cancer cells including gamma-mangostin and a chalcone, isoliquiritigenin from Glycyrrhiza glabra L. (licorice) and Dipteryx odorata Willd. (tonka bean).;Natural product drug discovery efforts frequently utilize noncellular screening assays. Fatty acids are common in natural product extracts and can interfere with some noncellular assays. Several pure fatty acids were tested using a noncellular AI assay. Unsaturated analogs showed strong inhibitory activity, while saturated analogs were inactive. Unsaturated fatty acids were further tested against SK-BR-3 breast cancer cells and were inactive. In natural product screening efforts, extracts active in noncellular bioassays should be dereplicated for fatty acids prior to large-scale bioassay-guided fractionation.;Brassaiopsis glomerulata (Blume) Regel (Araliaceae) leaves, collected in Indonesia, significantly inhibited aromatase. Six compounds were isolated from the hexane extract of the steroid and triterpenoid classes, of which 6beta-hydroxy-stigmasta-4-en-3-one was moderately active (cell-based AI assay). Seven compounds were isolated from the ethyl acetate extract of the modified peptide, fatty acid, monoterpenoid, and benzenoid classes. Three compounds were active including linoleic acid (enzyme-based AI assay), (--)-dehydrololiolide (cell-based AI assay), and N-benzoyl-L-phenylalanine methyl ester (cell-based AI assay). The absolute stereochemistry of three modified peptides was determined using Marfey's analysis, with all residues having the L configuration. N-benzoyl- L-phenylalanine methyl ester was a new natural product, not previously isolated from natural sources.