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Design and synthesis of the novel oleanolic acid-cinnamic acid ester derivatives and glycyrrhetinic acid-cinnamic acid ester derivatives with cytotoxic properties
Affiliation:1. Marine College, Shandong University, Weihai 264209, China;2. Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, B-3001 Heverlee, Belgium;3. Zhong Yuan Academy of Biological Medicine, Liaocheng People’s Hospital/Affiliated Liaocheng Hospital, Taishan Medical University, Liaocheng, China;4. School of Marine Science and Technology, Harbin Institute of Technology at Weihai, Weihai 264209, China;1. Bursa Uludag University, Faculty of Science and Arts, Department of Biology, 16059 Bursa, Turkey;2. Istanbul University, Aziz Sancar Experimental Medicine Research Institute, Molecular Medicine, 34093 Istanbul, Turkey;3. N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Lavrent''ev Ave., 9, 630090 Novosibirsk, Russia;4. Istinye University, Faculty of Medicine, Department of Medical Biochemistry, 34010 Istanbul, Turkey;1. CONACYT – Facultad de Medicina Veterinaria y Zootecnia, Universidad Autónoma de Yucatán, Km 15.5 Carretera Mérida-Xmatkuil, CP 97100, Mérida, Yucatán, Mexico;2. Facultad de Medicina Veterinaria y Zootecnia, Universidad Autónoma de Yucatán, Km 15.5 Carretera Mérida-Xmatkuil, CP 97100, Mérida, Yucatán, Mexico;3. Centro de Investigación Científica de Yucatán, Calle 43 No. 130 × 32 Colonia Chuburná de Hidalgo, CP 97205, Mérida, Yucatán, Mexico;1. LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal;2. Pharmaceutical Chemistry Laboratory, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal;3. CIEPQPF Centre for Chemical Processes Engineering and Forest Products, University of Coimbra, 3030-790 Coimbra, Portugal;1. Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal;2. Center for Neuroscience and Cell Biology, Coimbra, Portugal;3. Michigan State University, Department of Pharmacology and Toxicology, Life Science Building 1355, Bogue St Room 430, USA;4. CHEM4PHARMA, Biocant - Parque Tecnológico de Cantanhede, Núcleo 4, Lote 14, 3060-197, Cantanhede, Portugal;5. CICS-UBI – Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506, Covilhã, Portugal;1. Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China;2. College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, 116600, China;3. School of Environment and Chemical Engineering, Dalian Jiaotong University, Dalian, 116028, China;4. Dalian Medical University, Dalian, 116044, China;5. Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, China
Abstract:Oleanolic acid (OA) and glycyrrhetinic acid (GA) are natural products with anticancer effects. Cinnamic acid (CA) and its derivatives also exhibited certain anticancer activity. In order to improve the anticancer activity of OA and GA, we designed and synthesized a series of novel OA-CA ester derivatives and GA-CA ester derivatives by using molecular hybridization approach. The 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay was used to assess their in vitro cytotoxicity on three cell lines (HeLa (cervical cancer), MCF-7 (breast cancer) and L-O2 (a normal hepatic cell)). Among the evaluated compounds, 3o presented the strongest selective cytotoxicity on HeLa cells (IC50 = 1.35 μM) and showed no inhibitory activity against MCF-7 cells (IC50 > 100 μM) and L-O2 cells (IC50 > 100 μM), and 3e presented the strongest selective inhibition of the MCF-7 cells (IC50 = 1.79 μM). What’s more, compound 2d also showed very strong selective inhibitory activity against HeLa cells (IC50 = 1.55 μM). The further research using Hoechst 33342, AO/EB dual-staining, flow cytometric analysis and DCFH-DA fluorescent dye staining assay presented that 2d and 3o could induce HeLa cells apoptosis and autophagy.
Keywords:Cytotoxicity  Oleanolic acid-cinnamic acid ester derivatives  Glycyrrhetinic acid-cinnamic acid ester derivatives  Apoptosis  ROS  Autophagy
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