title: Synthesis and biochemical characterization of new phenothiazines and related drugs as MDR reversal agents.
abstract: Chemotherapy is one of the most important methods in the treatment of cancer. However, development of drug resistance during chemotherapy is the leading cause of treatment failure and decreased survival in cancer patients. Multidrug resistance (MDR) is one of the extensively studied forms of drug resistance for more than 30 years. The members of ATP-binding cassette protein family are responsible for multidrug resistance with P-glycoprotein as most representative transporter. To overcome multidrug resistance, pharmacological modulation of the transporters by efflux pump inhibitors seem to be the first choice, but preclinical studies did not lead to clinical applications. Therefore, a systematical research for pharmacophor structures is a promising strategy to increase the efficacy of those drugs still influencing multidrug resistance. In this study a range of phenothiazine derivatives was synthesizied with systematical variation of three molecule domains. The biochemical determination of multidrug resistance reversal activity was achieved with the crystalviolet assay on LLC-PK1/MDR1 cells. The results will be discussed considering of hypotheses in the literature directed to new structure-acitivity relationships to overcome drug resistance in the future.
authors.affiliation: Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany. matthias.schmidt@pharmazie.uni-halle.de
authors.forename: Matthias
authors.initials: M
authors.lastname: Schmidt
authors.forename: Marlen
authors.initials: M
authors.lastname: Teitge
authors.forename: Marianela E
authors.initials: ME
authors.lastname: Castillo
authors.forename: Tobias
authors.initials: T
authors.lastname: Brandt
authors.forename: Bodo
authors.initials: B
authors.lastname: Dobner
authors.forename: Andreas
authors.initials: A
authors.lastname: Langner
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D018374:LLC-PK1 Cells; D010640:Phenothiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D000970:Antineoplastic Agents; D010640:Phenothiazines