title: Design, synthesis, in vitro antiproliferative evaluation, and kinase inhibitory effects of a new series of imidazo[2,1-b]thiazole derivatives.
abstract: Design and synthesis of a new series of 5,6-diarylimidazo[2,1-b]thiazole derivatives possessing terminal aryl sulfonamide moiety are described. Their in vitro antiproliferative activities against a panel of 57 human cancer cell lines of nine different cancer types were tested at the NCI. Compounds 8a, 8b, 8n, 8q, 8t, and 8u showed the highest mean % inhibition values over the 57 cell line panel at 10 μM, and they were further tested in 5-dose testing mode to determine their IC50 values. Among the six compounds, compound 8u possessing terminal para-hydroxybenzenesulfonamido moiety and ethylene linker showed the highest potency. It demonstrated superior potency than Sorafenib against eight different cell lines, and was equipotent to Sorafenib against COLO 205 colon cancer cell line. Its IC50 values over NCI-H460 non-small cell lung cancer cell line and MCF7 breast cancer cell line were 0.845 μM and 0.476 μM, respectively. Compounds 8a, 8b, 8q, 8t, and 8u showed high selectivity indices towards cancer cells over L132 normal lung cell line. Compound 8u showed potential inhibitory effects over the components of ERK pathway. Its IC50 value over V600E-B-RAF and C-RAF kinases were 39.9 nM and 19.0 nM, respectively.
authors.affiliation: Center for Biomaterials, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea; Department of Biomolecular Science, Korea University of Science and Technology, 113 Gwahangno, Yuseong-gu, Daejeon 305-333, Republic of Korea; Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki-Giza 12622, Egypt.
authors.forename: Mohammed S
authors.initials: MS
authors.lastname: Abdel-Maksoud
authors.affiliation: Center for Biomaterials, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea; Department of Chemistry, Yonsei University, Seoul, Republic of Korea.
authors.forename: Mi-Ryeong
authors.initials: MR
authors.lastname: Kim
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt.
authors.forename: Mohammed I
authors.initials: MI
authors.lastname: El-Gamal
authors.affiliation: Center for Biomaterials, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea; Department of Biomolecular Science, Korea University of Science and Technology, 113 Gwahangno, Yuseong-gu, Daejeon 305-333, Republic of Korea; Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki-Giza 12622, Egypt.
authors.forename: Mahmoud M
authors.initials: MM
authors.lastname: Gamal El-Din
authors.affiliation: Department of Chemistry, Yonsei University, Seoul, Republic of Korea.
authors.forename: Jinsung
authors.initials: J
authors.lastname: Tae
authors.affiliation: Department of Pharmaceutical Biochemistry, College of Pharmacy, Chosun University, Gwangju, Republic of Korea.
authors.forename: Hong Seok
authors.initials: HS
authors.lastname: Choi
authors.affiliation: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea; Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Lee
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea.
authors.forename: Kyung Ho
authors.initials: KH
authors.lastname: Yoo
authors.affiliation: Center for Biomaterials, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea; Department of Biomolecular Science, Korea University of Science and Technology, 113 Gwahangno, Yuseong-gu, Daejeon 305-333, Republic of Korea. Electronic address: choh@kist.re.kr.
authors.forename: Chang-Hyun
authors.initials: CH
authors.lastname: Oh
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D013844:Thiazoles; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf
keywords: Antiproliferative activity; Arylsulfonamido; C-RAF; ERK pathway; Imidazo[2,1-b]thiazole; V600E-B-RAF