New 1,3-dioxolane and 1,3-dioxane derivatives as effective modulators to overcome multidrug resistance.
Multidrug resistance (MDR) to antitumor agents represents a major obstacle to a successful chemotherapy of cancer. Overexpression of P-glycoprotein (p-gp) seems to be the major factor responsible for MDR. A large number of chemically unrelated compounds are known to interact with p-gp resulting in a decreasing resistance. In our efforts related to structure-activity studies of new potential MDR reversal agents we synthesized a series of compounds that differ in the aromatic core structure, the linker, and the basic moiety. For our search of new aromatic core structures we synthesized novel 2,2-diphenyl-1,3-dioxolane, 2,2- diphenyl-1,3-dioxane, and 4,5-diphenyl-1,3-dioxolane derivatives. A range of lipophilic linker structures and protonable basic moieties were synthesized and investigated to optimize the structure of the potential MDR-modulators. The compounds were tested in vitro using human Caco-2 cells. Both the cytotoxicity of the synthons and their ability to resensitize the cells were determined with a MTT assay. The results show that at low concentration various substances reverse tumor cell MDR. Some of the new structures show better effects than established modulators like trifluoperazine.
Schmidt
Matthias
M
Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, D-06120 Halle, Germany. matthias.schmidt@pharmazie.uni-halle.de
Ungvári
Johannes
J
Glöde
Julia
J
Dobner
Bodo
B
Langner
Andreas
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D018938:Caco-2 Cells / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004146:Dioxanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004148:Dioxolanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D013329:Structure-Activity Relationship
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004146:Dioxanes; D004148:Dioxolanes; C025223:1,4-dioxane; C010962:formal glycol