Synthetic polysulfane derivatives induce cell cycle arrest and apoptotic cell death in human hematopoietic cancer cells |
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| Affiliation: | 1. Division of Bioorganic Chemistry, School of Pharmacy, Saarland University, Campus B 2.1, D-66123 Saarbruecken, Germany;2. Laboratoire de Biologie Moléculaire et Cellulaire de Cancer, Hôpital Kirchberg 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg;3. Medical Biochemistry and Molecular Biology, Saarland University, Building 44, D-66424 Homburg, Germany;4. Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea;1. College of Pharmacy, Chosun University, Gwangju 501-759, Republic of Korea;2. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea;1. Department of Organic Chemistry, Faculty of Pharmacy with Division of Medical Analytics, 4A Chodźki St., PL-20093 Lublin, Poland;2. Analytical Laboratory, Faculty of Chemistry, M. Curie-Skłodowska University, 3 M. Curie-Skłodowska Sq., PL-20031 Lublin, Poland;3. Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Faculty of Pharmacy with Division of Medical Analytics, 4A Chodźki St., PL-20093 Lublin, Poland;4. School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, FI-70211 Kuopio, Finland;1. Department of Chemistry, University of Waikato, Private Bag 3105, Hamilton 3240, New Zealand;2. Molecular Structure Facility, Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA;1. Unidad de Biofísica (CSIC, UPV/EHU), Departamento de Bioquímica y Biología Molecular, Bilbao, Spain;2. Interactions Moléculaires et Systèmes Membranaires, EA-4674, Aix-Marseille Université, Marseille, France;3. IKERBASQUE, Basque Foundation for Science, Bilbao, Spain;4. Laboratory of Molecular Neurobiology, Faculty of Medical Sciences, Biomedical Research Institute (BIOMED) UCA-CONICET, Catholic University of Argentina, Buenos Aires, Argentina;1. Department of Laboratory Diagnostics, Poznan University of Medical Sciences, Poznan, Poland;2. Department of Internal Medicine, Metabolic Disorders and Hypertension, Poznan University of Medical Sciences, Poznan, Poland |
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| Abstract: | Natural polysulfanes including diallyltrisulfide (DATS) and diallyltetrasulfide (DATTS) from garlic possess antimicrobial, chemopreventive and anticancer properties. However these compounds exhibit chemical instability and reduced solubility, which prevents their potential clinical applicability. We synthesized six DATS and DATTS derivatives, based on the polysulfane motif, expected to exhibit improved physical and chemical properties and verified their biological activity on human leukemia cells.We identified four novel cytotoxic compounds (IC50 values: compound 1, 24.96 ± 12.37 μM; compound 2, 22.82 ± 4.20 μM; compound 3, 3.86 ± 1.64 μM and compound 5, 40.62 ± 10.07 μM, compared to DATTS: IC50: 9.33 ± 3.86 μM). These polysulfanes possess excellent differential toxicity, as they did not affect proliferating mononuclear blood cells from healthy donors.We further demonstrated ability of active compounds to induce apoptosis in leukemia cells by analysis of nuclear fragmentation and of cleavage of effector and executioner caspases. Apoptosis was preceded by accumulation of cells in G2/M phase with a pro-metaphase-like nuclear pattern as well as microtubular alterations. Prolonged and persistent arrest of cancer cells in early mitosis by the benzyl derivative identifies this compound as the most stable and effective one for further mechanistic and in vivo studies. |
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| Keywords: | Polysulfanes Cancer Apoptosis Cell cycle Tubulin |
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