title: Synthesis and antiproliferative activity of two diastereomeric lignan amides serving as dimeric caffeic acid-l-DOPA hybrids.
abstract: Two new diastereomeric lignan amides (4 and 5) serving as dimeric caffeic acid-l-DOPA hybrids were synthesized. The synthesis involved the FeCl3-mediated phenol oxidative coupling of methyl caffeate to afford trans-diester 1a as a mixture of enantiomers, protection of the catechol units, regioselective saponification, coupling with a suitably protected l-DOPA derivative, separation of the two diastereomers thus obtained by flash column chromatography and finally global chemoselective deprotection of the catechol units. The effect of hybrids 4 and 5 and related compounds on the proliferation of two breast cancer cell lines with different metastatic potential and estrogen receptor status (MDA-MB-231 and MCF-7) and of one epithelial lung cancer cell line, namely A-549, was evaluated for concentrations ranging from 1 to 256μM and periods of treatment of 24, 48 and 72h. Both hybrids showed interesting and almost equipotent antiproliferative activities (IC50 64-70μM) for the MDA-MB-231 cell line after 24-48h of treatment, but they were more selective and much more potent (IC50 4-16μM) for the MCF-7 cells after 48h of treatment. The highest activity for both hybrids and both breast cancer lines was observed after 72h of treatment (IC50 1-2μM), probably as the result of slow hydrolysis of their methyl ester functions.
authors.affiliation: Laboratory of Synthetic Organic Chemistry, Department of Chemistry, University of Patras, 26504 Patras, Greece. Electronic address: magoulas@upatras.gr.
authors.forename: George E
authors.initials: GE
authors.lastname: Magoulas
authors.affiliation: Laboratory of Synthetic Organic Chemistry, Department of Chemistry, University of Patras, 26504 Patras, Greece.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rigopoulos
authors.affiliation: Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece; Foundation for Research and Technology-Hellas (FORTH)/Institute of Chemical Engineering Sciences (ICE-HT), Patras, Greece.
authors.forename: Zoi
authors.initials: Z
authors.lastname: Piperigkou
authors.affiliation: Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece; Lund University, Department of Laboratory Medicine, Malmö University Hospital, Malmö, Sweden.
authors.forename: Chrysostomi
authors.initials: C
authors.lastname: Gialeli
authors.affiliation: Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece; Foundation for Research and Technology-Hellas (FORTH)/Institute of Chemical Engineering Sciences (ICE-HT), Patras, Greece. Electronic address: n.k.karamanos@upatras.gr.
authors.forename: Nikos K
authors.initials: NK
authors.lastname: Karamanos
authors.affiliation: Department of Biological Applications and Technology, University of Ioannina, Ioannina 45110, Greece.
authors.forename: Panteleimon G
authors.initials: PG
authors.lastname: Takis
authors.affiliation: Department of Biological Applications and Technology, University of Ioannina, Ioannina 45110, Greece.
authors.forename: Anastassios N
authors.initials: AN
authors.lastname: Troganis
authors.affiliation: Laboratory of Theoretical Chemistry, Department of Chemistry, University of Patras, 26504 Patras, Greece.
authors.forename: Athanassios
authors.initials: A
authors.lastname: Chrissanthopoulos
authors.affiliation: Laboratory of Theoretical Chemistry, Department of Chemistry, University of Patras, 26504 Patras, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Maroulis
authors.affiliation: Laboratory of Synthetic Organic Chemistry, Department of Chemistry, University of Patras, 26504 Patras, Greece.
authors.forename: Dionissios
authors.initials: D
authors.lastname: Papaioannou
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002109:Caffeic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007980:Levodopa / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017705:Lignans / Q000737:chemistry / Q000494:pharmacology*; D061986:MCF-7 Cells; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D002109:Caffeic Acids; D017705:Lignans; D007980:Levodopa
keywords: A-549; Amides; Antiproliferative activity; Lignans; MCF-7; MDA-MB-231; Phenol oxidative coupling; l-DOPA