Synthesis, biological evaluation, and physicochemical property assessment of 4-substituted 2-phenylaminoquinazolines as Mer tyrosine kinase inhibitors. Issue 13 (1st July 2016)

• Record Type: Journal Article
• Authors: Wang, Sheng-Biao; Cui, Mu-Tian; Wang, Xiao-Feng; Ohkoshi, Emika; Goto, Masuo; Yang, De-Xuan; Li, Linna; Yuan, Shoujun; Morris-Natschke, Susan L.; Lee, Kuo-Hsiung; Xie, Lan
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 13(2016)
• Page Start: 3083
• Page End: 3092
• Publication Date: 2016-07-01
• Subjects: PXQXFGCRWHTVBD-UHFFFAOYSA-N -- NRYHKDJEPGDAGX-UHFFFAOYSA-N -- IWPFYKIFKHNHAS-UHFFFAOYSA-N -- XMKZPZBUKQMHNF-UHFFFAOYSA-N -- AFNWKIKMTQIWHU-UHFFFAOYSA-N -- QGEAHLONJRLMKZ-UHFFFAOYSA-N -- ZEXOTOJJEIBRDN-UHFFFAOYSA-N -- HMMJKDJDJCYCBK-UHFFFAOYSA-N -- RMRSKURFSGCSFM-UHFFFAOYSA-N -- HKIFQJOVGYXXBB-UHFFFAOYSA-N -- RQKOQBFNLXPPSW-UHFFFAOYSA-N -- IJLDJEASLDJCDS-UHFFFAOYSA-N -- RANDQPGUBTWPSC-UHFFFAOYSA-N -- ZVIBISIIUYWHAM-UHFFFAOYSA-N -- HUZKIRAWCBJPAF-UHFFFAOYSA-N -- PEBCBFJYPZBCNX-UHFFFAOYSA-N -- QDFNTPGVPJPEHU-UHFFFAOYSA-N -- QXDLEVGKYBDDKC-UHFFFAOYSA-N -- MJCJKFFVCHBTSF-UHFFFAOYSA-N -- NKKKHNIEVNYMCR-UHFFFAOYSA-N -- FHJDQALLIXLBIE-UHFFFAOYSA-N -- WXYDWXCNFYMYCG-UHFFFAOYSA-N -- STNFPRBCLKSHGJ-UHFFFAOYSA-N; ALL acute lymphocytic leukemia -- ADMET absorption, distribution, metabolism, elimination and toxicity -- A549 human lung cancer cell line -- DU145 prostate cancer cell line -- GI50 effective concentration for 50% cell growth inhibition -- HTCL human tumor cell lines -- IC50 effective concentration that inhibits 50% Mer tyrosine kinase -- K562 human chronic myelogenous leukemia cell line -- KB nasopharyngeal carcinoma cell line -- KB-vin vincritstine-resistant KB subline cell line -- Mer TK Mer tyrosine kinase -- MV4-11 acute leukemia cell line -- PDB protein data base -- SAR structure–activity relationship; 4-Substituted 2-phenylaminoquinazolines -- Mer tyrosine kinase inhibitors -- Antiproliferative -- Physicochemical properties -- Molecular modeling; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.05.025
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Current results identified 4-substituted 2-phenylaminoquinazoline compounds as novel Mer tyrosine kinase (Mer TK) inhibitors with a new scaffold. Twenty-one 2, 4-disubstituted quinazolines (series4 –7 ) were designed, synthesized, and evaluated against Mer TK and a panel of human tumor cell lines aimed at exploring new Mer TK inhibitors as novel potential antitumor agents. A new lead, 4b, was discovered with a good balance between high potency (IC50 0.68 μM) in the Mer TK assay and antiproliferative activity against MV4-11 (GI50 8.54 μM), as well as other human tumor cell lines (GI50 < 20 μM), and a desirable druglike property profile with low log P value (2.54) and high aqueous solubility (95.6 μg/mL). Molecular modeling elucidated an expected binding mode of4b with Mer TK and necessary interactions between them, thus supporting the hypothesis that Mer TK might be a biologic target of this kind of new active compound.