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. (c) 2007 Elsevier Ltd. All rights reserved.