N-Substituted piperazine derivatives as potential multitarget agents acting on histamine H3 receptor and cancer resistance proteins |
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| Affiliation: | 1. Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland;2. Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Dóm tér 10, 6720 Szeged, Hungary;3. Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Düsseldorf, Universitaetsstr. 1, 40225 Düsseldorf, Germany;1. Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, United States;2. Department of Biochemistry and Molecular Biology and Center for Tropical and Emerging Global Diseases (CTEGD), University of Georgia, 120 Green Street, Athens, GA 30602, United States;1. Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan;2. Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoinkawara-cho, Sakyo-ku, Kyoto 606-8507, Japan;1. Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, Punjab, India;2. Institut de Recherche en Infectiologie (IRIM) de Montpellier, CNRS, UMR 9004 Université de Montpellier, France;3. INSERM, IRIM, 34293 Montpellier, France;4. School of Chemistry and Physics, University of KwaZulu-Natal, P/Bag X54001, Westville, Durban, South Africa;1. Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, Viet Nam;2. College of Pharmacy, Chungbuk National University, 194-31, Osongsaengmyung-1, Heungdeok, Cheongju, Chungbuk 28160, Republic of Korea;3. Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Chungbuk, Republic of Korea;4. Faculty of Pharmacy, PHENIKAA University, Hanoi 12116, Viet Nam;5. PHENIKAA Institute for Advanced Study (PIAS), PHENIKAA University, Hanoi 12116, Viet Nam;1. Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China;2. University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China;3. Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China;4. School of Life and Technology, Harbin Institute of Technology, Harbin 150001, China;5. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA;6. Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, China;7. Department of Analytical Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China;8. Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), 1 Wenhai Road, Aoshanwei, Jimo, Qingdao 266237, China;1. Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, India;2. Department of Biotechnology, Indian Institute of Technology Madras, Chennai 600 036, India |
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| Abstract: | Taking into account that multidrug resistance (MDR) is the main cause for chemotherapeutic failure in cancer treatment, the ability of novel histamine H3 receptor ligands to reverse the cancer MDR was evaluated, using the ABCB1 efflux pump inhibition assay in mouse MDR T-lymphoma cells. The most active compounds displayed significant cytotoxic and antiproliferative effects as well as a very potent MDR efflux pump inhibitory action, 3–5-fold stronger than that of reference inhibitor verapamil. Although these compounds possess weak antagonistic properties against histamine H3 receptors, they are valuable pharmacological tools in the search for novel anticancer molecules. Furthermore, for the most active compounds, an insight into mechanisms of action using either, the luminescent Pgp-Glo™ Assay in vitro or docking studies to human Pgp, was performed. |
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| Keywords: | Piperazine Cancer Antiproliferative MDR efflux pumps ABCB1 |
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