Dihydropyridines and multidrug resistance: previous attempts, present state, and future trends

Multidrug resistance is defined as the resistance of a tumor cell to the cytotoxic action of divergent drugs used in chemotherapy. Dihydropyridines are a class of calcium channel antagonists that were discovered to have a multidrug resistance reversing effect and prompted investigations resulting in the synthesis of hundreds of new derivatives. Most of the investigators tried to achieve two goals: a decrease in Ca²(+) channel-blocking activity and an increase in the multidrug resistance reversing effect. Most of the synthesized compounds failed in the later stages of studies especially in clinical trials because of pharmacokinetic or pharmacodynamic limitations. Therefore, it will be necessary to include new methods, such as combinatorial synthesis, and, more importantly, to apply computational methods based on global structure-activity relationship models that consider all problems. Moreover, some compounds should be synthesized that are effective on several multidrug resistance targets.