Modulation of the multidrug-resistance phenotype by new tropane alkaloid aromatic esters from Erythroxylum pervillei.
Nine tropane alkaloid aromatic esters (1-9) were isolated from the roots of Erythroxylum pervillei by following their potential to reverse multidrug-resistance with vinblastine-resistant oral epidermoid carcinoma (KB-V1) cells. All isolates, including seven new structures (3-9), were evaluated against a panel of human cancer cell lines, and it was found that alkaloids 3 and 5-9 showed the greatest activity with KB-V1 cells assessed in the presence of vinblastine, suggesting that these new compounds are potent modulators of P-glycoprotein. Confirmatory results were obtained with human ovarian adenocarcinoma (SKVLB) cells evaluated in the presence of adriamycin and synergistic studies performed with several cell lines from the NCI tumor panel. The structures of the new compounds were determined using spectroscopic techniques. Single-crystal X-ray analysis was performed on the monoester, tropane-3 alpha,6 beta,7 beta-triol 3-phenylacetate (1).
Silva
G L
GL
Program for Collaborative Research in the Pharmaceutical Sciences and Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
Cui
B
B
Chávez
D
D
You
M
M
Chai
H B
HB
Rasoanaivo
P
P
Lynn
S M
SM
O'Neill
M J
MJ
Lewis
J A
JA
Besterman
J M
JM
Monks
A
A
Farnsworth
N R
NR
Cordell
G A
GA
Pezzuto
J M
JM
Kinghorn
A D
AD
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000470:Alkaloids / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D004354:Drug Screening Assays, Antitumor; D030921:Erythroxylaceae / Q000737:chemistry*; D004952:Esters / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D005260:Female; D006801:Humans; D008270:Madagascar; D008519:Medicine, Traditional; D008968:Molecular Conformation; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D010051:Ovarian Neoplasms; D018517:Plant Roots / Q000737:chemistry; D010946:Plants, Medicinal / Q000737:chemistry*; D013055:Spectrophotometry, Infrared; D013237:Stereoisomerism; D014326:Tropanes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D018435:ATP Binding Cassette Transporter, Subfamily B; D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D004952:Esters; D014326:Tropanes; D004317:Doxorubicin