Dihydropyridines and Multidrug Resistance: Previous Attempts, Present State, and Future Trends

Abstract

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 Ca 2+ 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.

Cytotoxic and multidrug resistance reversal activities of novel 1,4-dihydropyridines against human cancer cells

“…DHPs have also shown a broad range of other pharmacological effects such as antioxidant, anticonvulsant, anti-inflammatory, antidiabetic and antitubercular properties Moghadam et al, 2006;Saini et al, 2008). MDR reversal has also been reported as one of the important pharmacological potentials of DHPs (Carosati et al, 2012;Zarrin et al, 2010). In 1980, Tsuruo et al (1983 reported for the first time that DHPs demonstrated MDR reversal effects on cancer cell lines.…”

Synthesis and assessment of the cytotoxic effect of some of 1,4-dihydropyridine derivatives which contain azole moiety

“…The potential uses of the DHPs scaffolds in the chemotherapy are well-documented and stem from their suitability for reversing the drug resistance in the treatment of cancer. 14,15 Calcium channel blockers like verapamil 16 and nicardipine, 17 among others have been reported to successfully overcome drug resistance.…”

Green synthesis, molecular docking and anticancer activity of novel 1,4-dihydropyridine-3,5-Dicarbohydrazones under grind-stone chemistry

“…It is quite interesting to note that the 1,4-dihydropyridine and hydrazine derivatives have gained prominence in the recent years for cancer chemotherapy (24)(25)(26)(27)(28)(29)(30). 1,4-Dihydropyridines have been proved to be a new class of multidrug resistance (MDR) reversals in cancer treatment (31).…”