Combination of 4-anilinoquinazoline,arylurea and tertiary amine moiety to discover novel anticancer agents |
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| Institution: | 1. Department of Medicinal Chemistry, School of Pharmacy, Xi’an Jiaotong University, Xi’an, Shaanxi 710061, PR China;2. Department of Pharmacology, School of Basic Medical Science, Xi’an Jiaotong University, Xi’an, Shaanxi 710061, PR China;1. Department of Pharmacy—Center for Drug Research, Pharmaceutical Biology, University of Munich, Butenandtstrasse 5-13, 81377 Munich, Germany;2. Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland;1. Jagiellonian University Medical College, Faculty of Pharmacy, Department of Technology and Biotechnology of Drugs, Medyczna 9, 30-688 Kraków, Poland;2. Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University, Universitaetsstr. 1, 40225 Duesseldorf, Germany;3. Institute of General and Ecological Chemistry, Technical University of ?ód?, ?eromskiego 116 Str., 90-924 ?ód?, Poland;1. Department of Chemistry and Biochemistry, University of Arizona, 1306 E. University Boulevard, Tucson, AZ 85721, USA;2. Department of Pharmacology, University of Arizona, Tucson, AZ 85721, USA;1. Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland;2. Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Sm?tna Street, 31-343 Krakow, Poland;3. Department of Clinical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland;4. Department of Pharmaceutical Biochemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland;5. Department of Drug Development, Institute of Pharmacology, Polish Academy of Sciences, 12 Sm?tna Street, 31-343 Krakow, Poland;6. Department of Pharmacobiology, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland;1. Univ Lille Nord de France, F-59000 Lille, France;2. Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), UDSL, EA4481, F-59006 Lille, France;1. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China;2. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China |
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| Abstract: | In present study, 4-anilinoquinazolines scaffold, arylurea and tertiary amine moiety were combined to design, synthesize gefitinib analogs and discover novel anticancer agents. A series of 4-anilinoquinazoline derivatives (1, 2, 3 and 4) bearing arylurea and tertiary amine moiety at its 6-position were synthesized. Their antiproliferative activities in vitro were evaluated via MTT assay against A431 cell and A549 cell. The SAR of the title compounds was discussed. The compounds 2d, 2i and 2j with potent antiproliferative activities were evaluated their inhibitory activity against EGFR-TK. Compound 2j displayed potent inhibitory activity against EGFR-TK. In addition, compound 2j, at 50 mg/kg, can completely inhibit cancer growth in established nude mouse A549 xenograft model in vivo. These results suggest that the 4-anilinoquinazoline derivatives bearing diarylurea and tertiary amino moiety at its 6-position can serve as anticancer agents and EGFR inhibitors. |
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| Keywords: | Gefitinib Diaryl urea Tertiary amine EGFR-TK inhibitor Anticancer agent |
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