title: Characterization of tropane alkaloid aromatic esters that reverse the multidrug-resistance phenotype.
abstract: P-Glycoprotein (Pgp) associated multidrug-resistance (MDR) is a significant factor that can lead to the failure of cancer chemotherapy. Several new tropane alkaloid aromatic esters obtained from extracts of Erythroxylum pervillei Baillon (Erythroxylaceae) (1-8) and Erythroxylum rotundifolium Lunan (Erythroxylaceae) (9-12) by means of bioassay-directed fractionation were found to restore vinblastine sensitivity with cultured multidrug-resistant KB-VI cells. With this model, growth was not inhibited by addition of vinblastine (1 microg/ml) to the culture medium, but in combination with tropane alkaloids, inhibition was observed with IC50 values categorized as: low (ranging from 0.17-0.62 microM) for 1 [3alpha-phenylacetoxy-6beta-(3,4,5-trimethaxycinnamoyloxy)-tropane], 3 [3alpha-(3,4,5-trimethoxybenzoyloxy)-6beta-(3,4,5-trimethoxycinnamoyloxy)tropane], 4 [3alpha-(3,4,5-trimethoxybenzoyloxy)-6beta-(3,4,5-trimethoxycinnamoyloxy)-7beta-hydroxytropane], 5 [3alpha,6beta-di-(3,4,5-trimethoxycinnamoyloxy)tropane], 6 [3alpha,6beta-di-(3,4,5-trimethoxycinnamoyloxy)-7beta-hydroxytropane] and 9 [6beta-benzoyloxy-3alpha-(3,4,5-trimethoxycinnamoyloxy)tropane]; medium (2.0-3.7 microM) for 2 [3alpha-(3-hydroxyphenylacetoxy)-6beta-(3,4,5-trimethoxycinnamoyloxy)tropane] and 10 [7beta-acetoxy-6beta-benzoyloxy-3alpha-(3,4,5-trimethoxycinnamoyloxy)tropane]; or high (9.8 microM) for 11 [6beta-benzoyloxy-3alpha-(3,4,5-trimethoxycinnamoyloxy)tropane-7beta-ol]. Compounds 7 (tropane-3alpha,6beta,7beta-triol 3-phenylacetate), 8 (1alphaH, 5alphaH-tropan-3alpha-yl 3,4,5-trimethoxybenzoate) and 12 (6beta-(3,4,5-trimethoxybenzoyloxy)-3alpha-(3,4,5-trimethoxycinnamoyloxy)tropane-7beta-ol) were not active. Among the active compounds, 1 and 3-6 were further tested with drug-resistant CEM/VLB100 cells. In the presence of modulator, sensitivity to vinblastine increased by 50-5,000-fold. Treatment of KB-V1 cells with 1 or 3-6 enhanced the intracellular accumulation of fluorescence dye (rhodamine 123). Visualization by confocal microscopy confirmed the intracellular accumulation of rhodamine 123 in drug-resistant KB-V1 cells was significantly less than drug-sensitive KB-3 cells, while treatment of KB-V1 cells with 10 microM 4 significantly increased intracellular accumulation. The molecular characteristics of the isolates were then determined and compared with their potential to reverse drug resistance. ClogP and molar refractivity were weakly correlated with their potential to reverse MDR
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 60612 USA.
authors.forename: Qiuwen
authors.initials: Q
authors.lastname: Mi
authors.forename: Baoliang
authors.initials: B
authors.lastname: Cui
authors.forename: Daniel
authors.initials: D
authors.lastname: Chávez
authors.forename: Heebyung
authors.initials: H
authors.lastname: Chai
authors.forename: Haiyuan
authors.initials: H
authors.lastname: Zhu
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Cordell
authors.forename: Sam
authors.initials: S
authors.lastname: Hedayat
authors.forename: A Douglas
authors.initials: AD
authors.lastname: Kinghorn
authors.forename: John M
authors.initials: JM
authors.lastname: Pezzuto
mesh_terms: D018432:Drug Resistance, Multiple; D004357:Drug Synergism; D030921:Erythroxylaceae / Q000737:chemistry*; D004952:Esters / Q000737:chemistry / Q000494:pharmacology; D006131:Growth Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007624:KB Cells; D007945:Leukemia, Lymphoid / Q000188:drug therapy / Q000378:metabolism; D018613:Microscopy, Confocal; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000737:chemistry / Q000494:pharmacology*; D014747:Vinblastine / Q000494:pharmacology
chemical_list: D004952:Esters; D006131:Growth Inhibitors; D010936:Plant Extracts; D014326:Tropanes; D020112:Rhodamine 123; D014747:Vinblastine