Epoxylathyrol Derivatives Modulation of ABCB1-Mediated Multidrug Resistance in Human Colon Adenocarcinoma and Mouse T-Lymphoma Cells /
Epoxyboetirane A (1), a macrocyclic diterpene that was found to be inactive as an ABCB1 modulator, was submitted to several chemical transformations, aimed at generating a series of compounds with improved multidrug resistance (MDR)-modifying activity. Overall, 23 new derivatives were prepared, in a...
Elmentve itt :
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| Dokumentumtípus: | Cikk |
| Megjelent: |
2015
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| Sorozat: | JOURNAL OF NATURAL PRODUCTS
78 No. 9 |
| doi: | 10.1021/acs.jnatprod.5b00370 |
| mtmt: | 2951177 |
| Online Access: | http://publicatio.bibl.u-szeged.hu/10421 |
| Tartalmi kivonat: | Epoxyboetirane A (1), a macrocyclic diterpene that was found to be inactive as an ABCB1 modulator, was submitted to several chemical transformations, aimed at generating a series of compounds with improved multidrug resistance (MDR)-modifying activity. Overall, 23 new derivatives were prepared, in addition to the already reported epoxylathyrol (2) and methoxyboetirol (3). Their anti-MDR potential was assessed through both functional and chemosensitivity assays on resistant human colon adenocarcinoma and human ABCB1-gene transfected L5178Y mouse lymphoma cells. Structure-activity relationship analysis showed that different substitution patterns led to distinct ABCB1 inhibitory activities, although intrinsic cellular characteristics seemed to influence the modulatory behavior. A considerable enhancement in MDR-modifying activity was observed for aromatic compounds in both cell lines, particularly in 3,17-disubstituted esters derived from 3, a Payne-rearranged Michael adduct of 2. All compounds tested were revealed to interact synergistically with doxorubicin, and ATPase inhibition by three representative MDR-modifying compounds was also investigated. On account of its outstanding ABCB1 inhibitory activity at 0.2 muM and overall remarkable bioactive profile, methoxyboetirane B (22) was found to be a new promising lead for MDR-reversing anticancer drug development. |
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| Terjedelem/Fizikai jellemzők: | 2215-2228 |
| ISSN: | 0163-3864 |