Triterpenoids from Momordica balsamina: Reversal of ABCB1-mediated multidrug resistance.

Abstract

The ability as P-glycoprotein (P-gp, ABCB1) modulators of thirty (1-30) triterpenoids of the cucurbitane-type was evaluated on human L5178 mouse T-lymphoma cell line transfected with the human MDR1 gene, through the rhodamine-123 exclusion assay. Compounds (1-26, and 29, 30) were previously obtained from the African medicinal plant Momordica balsamina, through both isolation (1-15) and molecular derivatization (16-26 and 29, 30). Compounds 27-28 are two new karavilagenin C (34) derivatives having succinic acid moieties. Apart from 4, 6, 8, 10 and 11, most of the isolated compounds (1-15) displayed strong MDR reversing activity in a dose-dependent mode, exhibiting a many-fold activity when compared with verapamil, used as positive control. At the lowest concentration tested, compounds 2 and 7 were the most active. However, a decrease of activity was found for the acyl derivatives (16-30). In a chemosensitivity assay, the MDR reversing activity of some of the most active compounds (1-3, 5, 7, 12-15) was further assessed on the same cell model. All the tested compounds, excepting 15, corroborated the results of the transport assay, revealing to synergistically interact with doxorubicin. Structure-activity relationship studies, taking into account previous results, showed that different substitution patterns, at both the tetracyclic nucleus and the side chain, play important role in ABCB1 reversal activity. An optimal lipophilicity was also recognized.

• Authors: Cátia Ramalhete, Silva Mulhovo, Joseph Molnar, Maria-José U Ferreira
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 24 Issue 21 Pg. 5061-5067 (11 01 2016) ISSN: 1464-3391 [Electronic] England
• PMID: 27591010 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• Antineoplastic Agents, Phytogenic
• Triterpenes

Topics

• ATP Binding Cassette Transporter, Subfamily B (antagonists & inhibitors)
• Animals
• Antineoplastic Agents, Phytogenic (chemistry, isolation & purification, pharmacology)
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Resistance, Multiple (drug effects)
• Drug Screening Assays, Antitumor
• Humans
• Mice
• Molecular Conformation
• Momordica (chemistry)
• Structure-Activity Relationship
• Triterpenes (chemistry, isolation & purification, pharmacology)
• Tumor Cells, Cultured