Characterization of tropane alkaloid aromatic esters that reverse the multidrug-resistance phenotype.
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
Mi
Qiuwen
Q
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 60612 USA.
Cui
Baoliang
B
Chávez
Daniel
D
Chai
Heebyung
H
Zhu
Haiyuan
H
Cordell
Geoffrey A
GA
Hedayat
Sam
S
Kinghorn
A Douglas
AD
Pezzuto
John M
JM
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
D004952:Esters; D006131:Growth Inhibitors; D010936:Plant Extracts; D014326:Tropanes; D020112:Rhodamine 123; D014747:Vinblastine