Synthesis and biological evaluation of 4-aza-2,3-dihydropyridophenanthrolines as tubulin polymerization inhibitors |
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| Institution: | 1. Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India;2. IICT-RMIT Research Centre, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India;3. Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India;4. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India;1. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia;2. Department of Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia;3. Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia;4. College of Medicine, Alfaisal University, Riyadh, Saudi Arabia;1. Centre de recherche de l’Institut universitaire en santé mentale de Québec (CRIUSMQ), Université Laval, Québec G1J 2G3, Canada;2. Department of Psychiatry and Neuroscience, Université Laval, Québec G1V 0A6, Canada;1. Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan;2. Biological Resources and Postharvest Division, Japan International Research Center for Agricultural Science (JIRCAS), 1-1 Ohwashi, Tsukuba, Ibaraki 305-8686, Japan;3. Plant Breeding, Genetics, and Biotechnology, International Rice Research Institute, Los Baños, Laguna, Philippines;4. National Agriculture and Food Research Organization, Institute of Crop Science, 2-1-18 Kannondai, Tsukuba, Ibaraki 305-8518, Japan;5. Tropical Agricultural Research Front, JIRCAS, 1091-1 Kawarabaru, Aza Maezato, Ishigaki, Okinawa 907-002, Japan;1. Department of Biochemistry, Jawaharlal Institute of Post Graduate Medical Education and Research (JIPMER), Puducherry, India;2. Department of Medicine, Jawaharlal Institute of Post Graduate Medical Education and Research (JIPMER), Puducherry, India;3. Department of Biometrics, Jawaharlal Institute of Post Graduate Medical Education and Research (JIPMER), Puducherry, India;1. University of Oulu, Department of Electrical engineering, Optoelectronics and Measurement laboratory, Erkki Koiso-Kanttilankatu 3, Oulu, 90570, Finland;2. Tampere University of Technology, Surface Science Laboratory, Optoelectronics Research Centre, P.O. Box 692, FI-33101 Tampere, Finland |
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| Abstract: | A series of novel 4-aza-2,3-dihydropyridophenanthrolines 12(a–t) were synthesized by a one-step three component condensation of 1,10-phenanthroline amine, tetronic acid and various aromatic aldehydes. These were evaluated for their antiproliferative activity against three human cancer cell lines (MIAPACA, MCF-7 and HeLa) using SRB assay. Majority of the tested compounds exhibited significant anticancer activity on these cell lines and interestingly compounds 12h and 12i were more potent than etoposide and podophyllotoxin against all three tested cancer cell lines with GI50 values in the range of 0.01–0.5 μM. Furthermore, these compounds showed significant inhibition of tubulin polymerization which is comparable to that of podophyllotoxin and disrupted microtubule network by accumulating tubulin in the soluble fraction. The flow cytometry analysis confirmed that the synthesized compounds led to cell cycle arrest at the G2/M phase. Moreover, the structure activity relationship studies in this series are also discussed. |
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| Keywords: | 4-Azapodophyllotoxin 1 10-Phenanthroline Multicomponent reaction Cytotoxicity Tubulin polymerization |
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