title: Design, synthesis, and in vitro antiproliferative and kinase inhibitory effects of pyrimidinylpyrazole derivatives terminating with arylsulfonamido or cyclic sulfamide substituents.
abstract: A novel series of substituted pyrimidine compounds bearing N-phenylpyrazole and terminating with aryl and cyclic sulfonamido moiety were designed, synthesized, and evaluated in vitro as antiproliferative agents against a panel of 53 cell lines of different tissues at the NCI. Among them, compound 1d with p-chlorobenzenesulfonamido terminal moiety, ethylene spacer, and 4-chloro-3-methoxyphenyl ring at position 3 of the pyrazole nucleus showed the highest mean percentage inhibition value over the whole cancer cell line panel at 10 μM concentration. It showed broad-spectrum antiproliferative activity over many cell lines of different cancer types. For instance, compound 1d inhibited the growth of HL-60 (TB), SR leukemia, and T-47D and MCF-7 breast cancer cell line by 135.92%, 119.44%, 95.32%, and 82.03% at 10 μM, respectively. And it inhibited the growth of COLO 205 colon, HT29 colon, BT-549 breast, and ACHN renal cancer cell lines by more than 80% at the same test concentration. However, testing compound 1d upon determining its IC50against the most sensitive cell lines showed to good extent selectivity against HT29 colon cancer cell line than HL-60 leukemia and MRC-5 lung fibroblasts (normal cells). Compound 1d was further tested against 12 kinases of different kinase families, and the highest inhibitory effect was exerted against RAF1, V600E-B-RAF, and V600K-B-RAF kinases.
authors.affiliation: a Center for Biomaterials, Korea Institute of Science and Technology , Seoul , Republic of Korea.|b Department of Biomolecular Science , University of Science and Technology , Daejeon , Republic of Korea.|c Pharmaceutical and Drug Industries Research Division, National Research Centre , Dokki-Giza , Egypt.
authors.forename: Mahmoud M
authors.initials: MM
authors.lastname: Gamal El-Din
authors.affiliation: d Department of Medicinal Chemistry , College of Pharmacy, University of Sharjah , Sharjah , United Arab Emirates.|e Sharjah Institute for Medical Research, University of Sharjah , Sharjah , United Arab Emirates.|f Department of Medicinal Chemistry , Faculty of Pharmacy, University of Mansoura , Mansoura , Egypt.
authors.forename: Mohammed I
authors.initials: MI
authors.lastname: El-Gamal
authors.affiliation: a Center for Biomaterials, Korea Institute of Science and Technology , Seoul , Republic of Korea.|b Department of Biomolecular Science , University of Science and Technology , Daejeon , Republic of Korea.|c Pharmaceutical and Drug Industries Research Division, National Research Centre , Dokki-Giza , Egypt.
authors.forename: Mohammed S
authors.initials: MS
authors.lastname: Abdel-Maksoud
authors.affiliation: g Chemical Kinomics Research Center, Korea Institute of Science and Technology , Seoul , Republic of Korea , and.
authors.forename: Kyung Ho
authors.initials: KH
authors.lastname: Yoo
authors.affiliation: h Department of Chemistry , Hanseo University , Seosan , Republic of Korea.
authors.forename: Daejin
authors.initials: D
authors.lastname: Baek
authors.affiliation: h Department of Chemistry , Hanseo University , Seosan , Republic of Korea.
authors.forename: Jungseung
authors.initials: J
authors.lastname: Choi
authors.affiliation: h Department of Chemistry , Hanseo University , Seosan , Republic of Korea.
authors.forename: Huiseong
authors.initials: H
authors.lastname: Lee
authors.affiliation: a Center for Biomaterials, Korea Institute of Science and Technology , Seoul , Republic of Korea.|b Department of Biomolecular Science , University of Science and Technology , Daejeon , Republic of Korea.
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; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D013449:Sulfonamides; C000614129:pyrimidinylpyrazole; D011494:Protein Kinases
keywords: 1,3,4-triarylpyrazole; Antiproliferative activity; RAF kinases; arylsulfonamide