Triterpenoids from Momordica balsamina: Reversal of ABCB1-mediated multidrug resistance. Issue 21 (1st November 2016)

• Record Type: Journal Article
• Authors: Ramalhete, Cátia; Mulhovo, Silva; Molnar, Joseph; Ferreira, Maria-José U.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 21(2016)
• Page Start: 5061
• Page End: 5067
• Publication Date: 2016-11-01
• Subjects: FDINJVUVNVFMKX-NGPVLLJVSA-N -- AVFNYXHRDYAHNF-HEVJPHJFSA-N -- LJWAEAIXBCCHLR-ITWKNSBQSA-N -- XIQPIAMRFKEZPL-IQOYCCEYSA-N -- NBZHVWXCQLFQNW-ATYSFEEYSA-N -- NBZHVWXCQLFQNW-ATYSFEEYSA-N -- HTVYFULXCNCIQP-RWAKPREXSA-N -- WKIUWXJRQZRPNJ-HCBDOCHMSA-N -- CUZSOMMGOJSRQM-QGHMFDTNSA-N -- LAMQCISFLOCMTF-KHSSJYCYSA-N -- WFULNIMUTJQIKF-HCLZVIJHSA-N -- OSNWCRUHKQXEMA-KOBRMIIQSA-N -- HSJCULHTPJTWAJ-SOKCMQJFSA-N -- BZKMSMPQWDQSDS-UHFFFAOYSA-N -- GCSGWQIIVZDSSY-DUZPDYNRSA-N -- WLDPKTWPLRBAMQ-IXDFPWEYSA-N -- LONNOTBMXUGTQD-PRQXAQKWSA-N -- NNEMUGGPIKMKLT-ALWVRWBGSA-N -- JIOLTRNVUAVONZ-HWKWHLNMSA-N -- VDZGTDUEYLQIJL-ALWVRWBGSA-N -- ZHSMTCYBAFZWCQ-HWKWHLNMSA-N -- NPGBXYSTOACVFB-CUYRHMAMSA-N -- BRDXQCIICDEATJ-NHAZGLRPSA-N -- BADJBPVQMUKJIM-VNRYDHMRSA-N -- OWTBJGHVHPDXKD-WQRJNEJNSA-N -- YVHJVAYWUJTPKD-DKOHYKDJSA-N -- DDYLMCUWYQBWNK-GYORKWDMSA-N -- CBPYGZZVJLABTM-MXHWHTTGSA-N -- GXSSFBXVARVYOU-JJYLABBESA-N -- YZSQZWRORUCEKK-UQOSRIHBSA-N; ABC ATP binding cassette -- ABCB1 ATP-binding cassette, sub-family B -- CI combination index -- FAR fluorescence activity ratio -- FL-1 mean fluorescence intensity -- MDR multidrug resistance -- MDR1 multidrug resistance gene 1 -- L5178Y-MDR MDR1 transfected L5178Y mouse T-lymphoma cells -- L5178Y-PAR parental L5178Y mouse T-lymphoma cells; Momordica balsamina -- Cucurbitane -- Triterpenes -- Multidrug resistance -- ABCB1 -- P-glycoprotein -- MDR reversers; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.08.022
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: Thirty natural and semi-synthetic triterpenoids were evaluated as ABCB1 modulators. Most of the natural compounds displayed strong MDR reversing activity. Some of the most active modulators synergistically interact with doxorubicin. Balsaminols B and C are among the most promising modulators. Substitution patterns in the molecule play important role in ABCB1 reversal activity. 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, and29, 30 ) were previously obtained from the African medicinal plant Momordica balsamina, through both isolation (1 –15 ) and molecular derivatization (16 –26 and29, 30 ). Compounds27 –28 are two new karavilagenin C (34 ) derivatives having succinic acid moieties. Apart from4, 6, 8, 10 and11, 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, compounds2 and7 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, excepting15, 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.