Design,synthesis, and biological activity of Plastoquinone analogs as a new class of anticancer agents |
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| Institution: | 1. Chemistry Department, Engineering Faculty, Istanbul University-Cerrahpasa, Avcilar, 34320 Istanbul, Turkey;2. Chemistry Department, Gebze Technical University, Gebze 41400, Kocaeli, Turkey;3. Department of Drug Discovery, Science Farm Ltd., Kumamoto 860-0802, Japan;4. Department of Bioorganic Medicinal Chemistry, School of Pharmacy, Kumamoto University, Kumamoto 862-0973, Japan;5. Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki 12622, Cairo, Egypt;6. Research Institute for Drug Discovery, School of Pharmacy, Kumamoto University, Kumamoto 862-0973, Japan;7. Engineering Sciences Department, Engineering Faculty, Istanbul University-Cerrahpasa, Avcilar, 34320 Istanbul, Turkey;1. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia;2. Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, PO Box 35516, Mansoura, Egypt;3. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, PO Box 35516, Mansoura, Egypt;4. Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;5. Department of Pharmaceutics and Pharmaceutical Technology (Microbiology), College of Pharmacy, Taibah University, Almadinah Almunawwarah 344, Saudi Arabia;1. Chemistry Department, Engineering Faculty, Istanbul University-Cerrahpasa, Avcilar, 34320, Istanbul, Turkey;2. Chemistry Department, Gebze Technical University, Gebze, 41400, Kocaeli, Turkey;3. Pharmaceutical Microbiology Department, Pharmacy Faculty, Istanbul University, Beyazit, 34116, Istanbul, Turkey;4. Engineering Sciences Department, Engineering Faculty, Istanbul University-Cerrahpasa, Avcilar, 34320, Istanbul, Turkey;1. Medical University of Silesia in Katowice, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Department of Organic Chemistry, 4 Jagiellońska Str., 41-200 Sosnowiec, Poland;2. University of Silesia, Institute of Physics, Department of Solid State Physics, 4 Uniwersytecka Str., 40-007 Katowice, Poland;3. Silesian Center for Education and Interdisciplinary Research, University of Silesia, 41-500 Chorzów, 75 Pułku Piechoty 1 Str., Poland;4. Medical University of Silesia in Katowice, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Department of Physical Pharmacy, 4 Jagiellońska Str., 41-200 Sosnowiec, Poland;5. Medical University of Silesia in Katowice, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Department of Cell Biology, 8 Jedności Str., 41-200 Sosnowiec, Poland;6. University of Silesia, Institute of Physics, Department of Physics of Crystals, 4 Uniwersytecka Str., 40-007 Katowice, Poland;1. College of Pharmacy, Kinjo Gakuin University, 2-1723 Omori, Moriyamaku, Nagoya, Aichi 463-8521, Japan;2. Department of Medicinal Chemistry, Yokohama University of Pharmacy, 601 Matano-cho Totsuka-ku, Yokohama 245-0066 Japan;3. Environmental Safety Center, Kumamoto University, 39-1 Kurokami 2-Chome, Chuo-ku, Kumamoto 860-8555, Japan;4. Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan;5. Department of Drug Discovery, Science Farm Ltd., 1-7-30 Kuhonji, Chuo-ku, Kumamoto 862-0976, Japan;1. Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, Kumamoto 862-0973, Japan;2. Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt;3. College of Pharmacy, Kinjo Gakuin University, 2-1723 Omori, Moriyama-ku, Nagoya, Aichi 463-8521, Japan;4. Department of Drug Discovery, Science Farm Ltd., 1-7-30 Kuhonji, Chuo-ku, Kumamoto, Kumamoto 862-0976, Japan;1. Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, 54124, Greece;2. School of Health Sciences, Department of Pharmacy, Laboratory of Pharmaceutical Chemistry, University of Patras, Greece;3. Department of Medical Laboratories, School of Health and Care Professions, Alexander Technological Educational Institute of Thessaloniki, 54700, Greece;4. Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia;5. Mycological Laboratory, Department of Plant Physiology, Institute for Biological Research, Siniša Stanković, University of Belgrade, Bulevar Despota Stefana 142, 11000 Belgrade, Serbia |
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| Abstract: | In this paper, based on Plastoquinone (PQ) analogs possessing substituted aniline containing alkoxy group(s), new 2,3-dimethyl-5-amino-1,4-benzoquinones (PQ1-15) were designed and synthesized in either two steps or one-pot reaction. Specifically, the substituted amino moiety containing mono or poly alkoxy group(s) with various positions and groups were mainly explored to understand the structure-activity relationships for the cytotoxic activity against three human cancer cell lines (K562, Jurkat, and MT-2) and human peripheral blood mononuclear cells (PBMC). PQ2 was found to be most effective anticancer compound on K562 and Jurkat cell lines with IC50 values of 6.40 ± 1.73 μM and 7.72 ± 1.49 μM, respectively. Interestingly, the compound was non-cytotoxic to normal PBMC and also MT-2 cancer cells. PQ2 which showed significant selectivity in MTT assay was chosen for apoptotic/necrotic evaluation and results exhibited that it induced apoptosis in K562 cell line after 6 h of treatment. PQ2 showed anti-Abelson kinase 1 (Abl1) activity with different inhibitory profile than Imatinib in the panel of eight kinases. The binding mode of PQ2 into Abl ATP binding pocket was predicted in silico showing the formation of some key interactions. In addition, PQ2 induced Bcr-Abl1 mediated ERK pathway in human chronic myelogenous leukemia (CML) cells. Furthermore, DNA-cleaving capability of PQ2 was clearly enhanced by iron (II) complex system. Afterward, a further in silico ADMET prediction revealed that PQ2 possesses desirable drug-like properties and favorable safety profile. These results indicated that PQ2 has multiple mechanism of action and two of them are anti-Bcr-Abl1 and DNA-cleaving activity. This study suggests that Plastoquinone analogs could be potential candidates for multi-target anticancer therapy. |
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| Keywords: | Plastoquinone Aminoquinone Apoptosis Bcr-Abl DNA-cleavage Structure-activity relationship (SAR) |
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