Double-component diazeniumdiolate derivatives as anti-cancer agents |
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| Affiliation: | 1. Biodesign Center for BioEnergetics, Arizona State University, Tempe, AZ 85287, USA;2. Department of Central Laboratory, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, PR China;3. School of Medcine, Taizhou University, Taizhou, Zhejiang, PR China;1. Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, United States;2. Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, United States;1. Departments of Pharmaceutical Sciences, University of California, Irvine, CA 92697-3900, United States;2. Departments of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697-3900, United States;1. La Trobe Institute for Molecular Science, La Trobe University, Victoria 3086, Australia;2. School of Science, University of New South Wales, Canberra 2610, Australia;3. School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia;4. Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia;5. Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia;1. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China;2. The Key Laboratory for Chemical Biology of Fujian Province, MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China;3. Hangzhou Ipharmacare Co., LTD, Hangzhou, 310000, China;1. Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK;2. Vernalis (R&D) Ltd., Granta Park, Abington, Cambridge CB21 6GB, UK |
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| Abstract: | ![]()
In this study, we synthesized a series of double-component O2-aryl diazeniumdiolate (DDNO) derivatives, of which each molecule can release up to four nitric oxide molecules. These compounds showed cytotoxic activities to cancer cells, such as human leukemia, breast cancer and lung cancer. Among them, compound 1 (DDNO-1) showed the highest specific activity to human leukemia cells. It induced cell apopotosis and arrest cell cycle of G2/M phase. The JNK and p38 protein kinases were activated by compound 1 to induce cancer cell apoptosis. Compound 1 also increased pro-apoptotic Bax level, which is a same function compared to a reported NO donor, JS-K. More interestingly, it decreased the level of an anti-apoptotic member Bcl-2, which is an opposite effect compared to JS-K. Compound 1 could be developed as a new anti-cancer agent since it increases the Bax/Bcl-2 ratio to overcome the drug resistance. |
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| Keywords: | Diazeniumdiolate derivatives Nitric oxide Anti-cancer agent G2/M phase arrest Bcl-2 inhibitor Leukemia |
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