Synthesis and antitumor activities of novel rhein α-aminophosphonates conjugates |
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| Institution: | 1. State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Pharmaceutical Science of Guangxi Normal University, Guilin 541004, PR China;2. College of Pharmacy, Guilin Medical University, Guilin 541004, PR China;3. Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China;1. Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China;2. Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China;1. Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China;2. State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, PR China;1. College of Pharmacy, Guangxi Medical University, Nanning, Guangxi, 530021, PR China;2. Guangxi Institute for Cancer Research, Nanning, Guangxi, 530021, PR China;1. Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, 62209 Cuernavaca, Morelos, Mexico;2. Departamento de Química Orgánica, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), Universidad de Zaragoza-CSIC, 50009 Zaragoza, Spain;1. Center for Drug Discovery and Translational Research, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA;2. Divisions of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA;3. Nephrology and Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA;4. Hematology-Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA |
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| Abstract: | Several rhein α-aminophosphonates conjugates (5a–5q) were synthesized and evaluated for in vitro cytotoxicity against HepG-2, CNE, Spca-2, Hela and Hct-116 cell lines. Some compounds showed relatively high cytotoxicity. Especially, compound 5i exhibited the strongest cytotoxicity against Hct-116 cells (IC50 was 5.32 μM). All the synthesized compounds exhibited low cytotoxicity against HUVEC cells. The mechanism of compound 5i was preliminarily investigated by Hoechst 33258 staining, JC-1 mitochondrial membrane potential staining and flow cytometry, which indicated that the compound 5i induced apoptosis in Hct-116 cancer cells. Cell cycle analysis showed that these compound 5i mainly arrested Hct-116 cells in G1 stage. The effects of 5i on the activation of caspases expression indicated that 5i might induce apoptosis via the membrane death receptor pathways. In addition, the binding properties of a model analog 5i to DNA were investigated by methods (UV–vis, fluorescence, CD spectroscopy and FRET-melting) in compare with that of rhein. Results indicated that 5i showed moderate ability to interact ct-DNA. |
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| Keywords: | Rhein α-Aminophosphonates Synthesis Cytotoxicity Apoptosis DNA binding |
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