title: Structure-activity relationships of diverse ACGs against multidrug resistant human lung cancer cell line A549/Taxol.
abstract: Fifteen annonaceous acetogenins (ACGs) with different stereochemical structures and configuration, representing three main classes of bis-adjacent-tetrahydrofuran (THF), bis-nonadjacent-THF, and mono-THF ACGs, were selected to tested for their inhibition activity on A549/Taxol cell line, which is multidrug resistant (MDR). The present study showed that some tested compounds showed significant activity toward A549/Taxol cells, and were more potent than the positive control Verapamil. For example, squamostatin-D (14) (IC50 value=16.19μM) was 7.8 times more active than Verapamil (IC50 value=127.09μM). Those ACGs with more carbons between the THF ring and the γ-unsaturated lactone were more potent. Moreover, ACGs with stereochemical arrangement of erythro were more active than those of threo, the compounds with THF ring configuration of cis seemed to be superior to those of trans. However, if all other structural features were identical, the ACGs with more hydroxyls on the aliphatic chain were not more potent towards A549/Taxol, which was not in accordance with previous studies. Furthermore, bis-nonadjacent-THF ACGs whose molecular weight is 622, with three hydroxyl groups located at carbon 16, 19, 24 and stereochemical arrangement of erythro possibly produced notable cytotoxicity. Based on the above conclusions, we proposed a compound model that may be a promising anti-MDR cancer candidate drug in the future clinical trial.
authors.affiliation: College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210046, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Yuan
authors.affiliation: College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210046, China.
authors.forename: Ganggang
authors.initials: G
authors.lastname: Bai
authors.affiliation: College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210046, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210046, China.
authors.forename: Yunjie
authors.initials: Y
authors.lastname: Miao
authors.affiliation: College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210046, China; Jiangsu Key Laboratory for TCM Formulae Research, Nanjing 210046, China.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Chen
authors.affiliation: College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210046, China; Jiangsu Key Laboratory for Chinese Material Medica Processing, Nanjing 210029, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
mesh_terms: D054378:Acetogenins / Q000737:chemistry / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D054378:Acetogenins; D017239:Paclitaxel
keywords: A549/Taxol; ACGs; MDR; Structure–activity relationships