Epoxylathyrol Derivatives: Modulation of ABCB1-Mediated Multidrug Resistance in Human Colon Adenocarcinoma and Mouse T‑Lymphoma Cells

• Published in: Journal of natural products (Washington, D.C.) D.C.), 2015-09, Vol.78 (9), p.2215-2228
• Main Authors: Matos, Ana M, Reis, Mariana, Duarte, Noélia, Spengler, Gabriella, Molnár, Joseph, Ferreira, Maria-José U
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - isolation & purification; Antineoplastic Agents - pharmacology; ATP Binding Cassette Transporter, Sub-Family B - metabolism; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Cell Line, Tumor; Colonic Neoplasms - pathology; Combinatorial Chemistry Techniques; Diterpenes - chemistry; Diterpenes - isolation & purification; Diterpenes - pharmacology; Doxorubicin - pharmacology; Drug Resistance, Multiple - drug effects; Drug Resistance, Neoplasm - drug effects; Euphorbia - chemistry; Humans; Lymphoma, T-Cell; Mice; Molecular Structure; Structure-Activity Relationship
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/acs.jnatprod.5b00370

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.