4-isoxazolyl-1,4-dihydropyrirines Bind the Multidrug-resistance Transporter

Steiger, Scott, MS., May 2013, Major Medicinal Chemistry 4-Isoxazolyl-1,4-dihydropyrirines bind the multidrug-resistance transporter Chairperson: Nicholas R. Natale The development of multidrug resistance in tumor cells has been recognized as a major obstacle to successful cancer treatment. Tumor cells in vitro and in vivo can develop multidrug resistance (MDR) to the lethal effects of a variety of cytotoxic drugs used to treat cancerous tumor cells. The over expression of multiple drug resistance gene 1 has been correlated with the expression of multi drug resistance protein 1(MDR1, also known as P-glycoprotein or P-gp). MDR1's role in altering uptake, distribution and bioavailability is considered a significant factor when examining drugs for clinical administration, and represents a viable drug target for the reversal of MDR. MDR1 is driven by ATP hydrolysis and as such it shares both sequence and structural homology with proteins that are energy-dependent efflux transporters driven by ATP hydrolysis, making MDR1 a member of the ATP binding cassette (ABC) super family. Because, MDR1 transports substrates that are often toxic xenobiotics, MDR1 is thought to fulfill a cellular detoxification function. As such it is expressed in several tissues in the body such as the liver, pancreas, kidney, colon, intestinal mucosa, and in the blood brain barrier. Due to its presences in a wide variety of cells it has been suggested that MDR1 is involved in protection of the organism as a whole. Consequently, the overproduction of MDR1 is seen in cancer cells. MDR1 has been shown to transport a wide variety of lipophilic agents, of importance, MDR1 effluxes chemotherapeutics agents out of the cell resulting in a low and ineffective intracellular drug concentration. Thus, the over production of MDR1 in cancer cells can then be thought of as a protective factor for cancer cells, and as an effect causes MDR cancer cells. Therefore, understanding MDR1’s function is important for controlling the bioavailability of drugs and for improving anticancer chemotherapy. Reversal of multidrug resistance is of interest, and MDR reversing agents have been under intensive investigation. The 4-Isoxazolyl-1, 4-Dihydropyridines (IDHP’s) have been shown to exhibit inhibition of MDR1. A novel series of IDHP compounds have been prepared and found to inhibit MDR1. The synthesis, MDR1 assay results, and relevant controls will be discussed. If successful, halting the function of MDR1 will stop the outward efflux of chemotherapeutic agents. In combination with chemotherapeutic treatments IDHP agents could allow for greater effectiveness of pharmaceutical intervention. This research would give an option in the treatment of cancer that would normally never exist for MDR cancer patients, and would allow for far more effective treatment via pharmaceutical means.