title: Structure-activity relationship and molecular mechanisms of ethyl 2-amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (CXL017) and its analogues.
abstract: Multidrug resistance (MDR) in cancer is a phenomenon in which administration of a single chemotherapeutic agent causes cross-resistance of cancer cells to a variety of therapies even with different mechanisms of action. Development of MDR against standard therapies is a major challenge in the treatment of cancer. Previously we have demonstrated a unique ability of CXL017 (5) to selectively target MDR cancer cells and synergize with mitoxantrone (MX) in HL60/MX2 MDR cells. Here we expand its scope and demonstrate that 5 can synergize with both vincristine and paclitaxel in three different MDR cell lines (HL60/DNR, K562/HHT300, and CCRF-CEM/VLB100). We also demonstrate that 5 has potent cytotoxicity in the NCI-60 panel of cell lines with an average IC(50) of 1.04 μM. In addition, 5 has a unique mechanism of action in comparison with standard agents in the NCI database based on COMPARE analysis. Further structure-activity relationship study led to the development of a more potent analogue, compound 7d, with an IC(50) of 640 nM in HL60/MX2. Additionally, one enantiomer of 5 is 13-fold more active than the less active enantiomer. Taken together, our study has led to the discovery of a series of analogues that selectively target drug-resistant cancer cells with the potential for the treatment of drug-resistant cancers.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, 308 Harvard Street SE, Minneapolis, Minnesota 55455, USA.
authors.forename: Sonia G
authors.initials: SG
authors.lastname: Das
authors.forename: Balasubramanian
authors.initials: B
authors.lastname: Srinivasan
authors.forename: David L
authors.initials: DL
authors.lastname: Hermanson
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Bleeker
authors.forename: Jignesh M
authors.initials: JM
authors.lastname: Doshi
authors.forename: Ruoping
authors.initials: R
authors.lastname: Tang
authors.forename: William T
authors.initials: WT
authors.lastname: Beck
authors.forename: Chengguo
authors.initials: C
authors.lastname: Xing
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001578:Benzopyrans / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003630:Daunorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D045325:HCT116 Cells; D018922:HL-60 Cells; D019073:HT29 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D008942:Mitoxantrone / Q000494:pharmacology; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014750:Vincristine / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001578:Benzopyrans; C543325:ethyl 2-amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate; D014750:Vincristine; D008942:Mitoxantrone; D017239:Paclitaxel; D003630:Daunorubicin