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 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 μM and overall remarkable bioactive profile, methoxyboetirane B (22) was found to be a new promising lead for MDR-reversing anticancer drug development.
Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa , Avenida Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
Ana M
AM
Matos
Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa , Avenida Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
Mariana
M
Reis
Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa , Avenida Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
Noélia
N
Duarte
Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged , Dóm tér 10, H-6720 Szeged, Hungary.
Gabriella
G
Spengler
Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged , Dóm tér 10, H-6720 Szeged, Hungary.
Joseph
J
Molnár
Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa , Avenida Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
Maria-José U
MJ
Ferreira
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000230:Adenocarcinoma; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology; D020650:Combinatorial Chemistry Techniques; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D028481:Euphorbia / Q000737:chemistry*; D006801:Humans; D016399:Lymphoma, T-Cell; D051379:Mice; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004224:Diterpenes; D004317:Doxorubicin