Discovery of aromatic amides with triazole-core as potent reversal agents against P-glycoprotein-mediated multidrug resistance |
| |
| Affiliation: | 1. Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, PR China;2. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China;3. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China;1. Department of Plant Anatomy, Institute of Biology, Eötvös Loránd University, Pázmány Péter sétány 1/C, Budapest 1117, Hungary;2. Department of Pharmaceutical Chemistry, Semmelweis University, Hőgyes Endre utca 7, Budapest 1092, Hungary;3. Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Gellért tér 4, Budapest 1111, Hungary;4. Department of Analytical Chemistry, Institute of Chemistry, Eötvös Loránd University, Pázmány Péter sétány 1/A, Budapest 1117, Hungary;5. Department of Pharmacognosy, Semmelweis University, Üllői út 26, Budapest 1085, Hungary;1. Key Laboratory of Natural Medicinal Chemistry and Resources Evaluation of Hubei Province, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, 13# Hangkong Road, Wuhan 430030, PR China;2. First Clinical School, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, PR China;3. Synergy Innovation Center of Biological Peptide Antidiabetics of Hubei Province, School of Life Science, Wuchang University of Technology, Wuhan 430223, PR China |
| |
| Abstract: | P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a major impediment for clinical cancer therapy. 19 novel aromatic amides with triazole-core as MDR reversal agents were designed and synthesized via click chemistry to reverse MDR. Among them, compound 42 was identified as the most promising candidate with high potency (EC50 = 78.1 ± 5.4 nM), low cytotoxity (SI > 1282) and persistent duration in reversing doxorubicin (DOX) resistance in K562/A02 cells. 42 also enhanced the potency of other P-gp associated cytotoxic agents with different structures. In further study, remarkably increased intracellular accumulation of Rh123 and DOX in K562/A02 cells was achieved by compound 42, while CYP3A4 activity had no change by compound 42. These results indicate that compound 42 as a relatively safe modulator of P-gp-mediated MDR has good potential for further development. |
| |
| Keywords: | P-glycoprotein Multidrug resistance Reversal agents Click chemistry ABC" },{" #name" :" keyword" ," $" :{" id" :" k0030" }," $$" :[{" #name" :" text" ," _" :" ATP binding cassette P-gp" },{" #name" :" keyword" ," $" :{" id" :" k0040" }," $$" :[{" #name" :" text" ," _" :" P-glycoprotein MDR" },{" #name" :" keyword" ," $" :{" id" :" k0050" }," $$" :[{" #name" :" text" ," _" :" multidrug resistance TMD" },{" #name" :" keyword" ," $" :{" id" :" k0060" }," $$" :[{" #name" :" text" ," _" :" transmembrane domain NBD" },{" #name" :" keyword" ," $" :{" id" :" k0070" }," $$" :[{" #name" :" text" ," _" :" nucleotide binding domain TKI" },{" #name" :" keyword" ," $" :{" id" :" k0080" }," $$" :[{" #name" :" text" ," _" :" tyrosine kinase inhibitor SAR" },{" #name" :" keyword" ," $" :{" id" :" k0090" }," $$" :[{" #name" :" text" ," _" :" structure-activity relationship HPLC" },{" #name" :" keyword" ," $" :{" id" :" k0100" }," $$" :[{" #name" :" text" ," _" :" high performance liquid chromatography DOX" },{" #name" :" keyword" ," $" :{" id" :" k0110" }," $$" :[{" #name" :" text" ," _" :" doxorubicin RF" },{" #name" :" keyword" ," $" :{" id" :" k0120" }," $$" :[{" #name" :" text" ," _" :" reversal fold SI" },{" #name" :" keyword" ," $" :{" id" :" k0130" }," $$" :[{" #name" :" text" ," _" :" selective index VRP" },{" #name" :" keyword" ," $" :{" id" :" k0140" }," $$" :[{" #name" :" text" ," _" :" verapamil PTX" },{" #name" :" keyword" ," $" :{" id" :" k0150" }," $$" :[{" #name" :" text" ," _" :" paclitaxel VLB" },{" #name" :" keyword" ," $" :{" id" :" k0160" }," $$" :[{" #name" :" text" ," _" :" vinblastine DNR" },{" #name" :" keyword" ," $" :{" id" :" k0170" }," $$" :[{" #name" :" text" ," _" :" daunorubicin CTX" },{" #name" :" keyword" ," $" :{" id" :" k0180" }," $$" :[{" #name" :" text" ," _" :" cyclophosphamide PBS" },{" #name" :" keyword" ," $" :{" id" :" k0190" }," $$" :[{" #name" :" text" ," _" :" phosphate buffered saline Rh123" },{" #name" :" keyword" ," $" :{" id" :" k0200" }," $$" :[{" #name" :" text" ," _" :" rhodamine 123 MFI" },{" #name" :" keyword" ," $" :{" id" :" k0210" }," $$" :[{" #name" :" text" ," _" :" mean fluorescence intensity DMSO" },{" #name" :" keyword" ," $" :{" id" :" k0220" }," $$" :[{" #name" :" text" ," _" :" dimethyl sulfoxide TFA" },{" #name" :" keyword" ," $" :{" id" :" k0230" }," $$" :[{" #name" :" text" ," _" :" trifluoroacetic acid TLC" },{" #name" :" keyword" ," $" :{" id" :" k0240" }," $$" :[{" #name" :" text" ," _" :" thin layer chromatography DCM" },{" #name" :" keyword" ," $" :{" id" :" k0250" }," $$" :[{" #name" :" text" ," _" :" dichloromethane MTT" },{" #name" :" keyword" ," $" :{" id" :" k0260" }," $$" :[{" #name" :" text" ," _" :" 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide HUVEC" },{" #name" :" keyword" ," $" :{" id" :" k0270" }," $$" :[{" #name" :" text" ," _" :" Human Umbilical Vein Endothelial Cells FBS" },{" #name" :" keyword" ," $" :{" id" :" k0280" }," $$" :[{" #name" :" text" ," _" :" fetal bovine serum |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
