Design, synthesis, and biological evaluation of new diaminoquinazolines as β-catenin/Tcf4 pathway inhibitors.
More than 50 new diaminoquinazoline derivatives have been synthesized and evaluated in a colon carcinoma cell growth inhibition assay using HCT116 and SW480 cells. Twenty compounds with good cell growth inhibitory activities (<4 μM) were tested as inhibitors of the β-catenin/T cell transcription factor 4 (Tcf4) signaling pathway using a HCT116 cell-based luciferase reporter assay. Results from the biological activities as well as the comparative molecular field analysis (CoMFA) of the properties of the molecules yielded a preliminary structure-activity relationship (SAR). Three potent compounds, 74, 78, and 86, showed IC(50) values <1 μM for growth inhibition of HCT116 cells and ∼1 μM for SW480 cells, as well as IC(50) values of 1.5-2.5 μM for HCT116 cells with the luciferase reporter assay.
Department of Pharmacology, State University of New York, Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, United States.
Yongjun
Y
Mao
Nan
N
Lin
Wang
W
Tian
Xiaofeng
X
Han
Xiaobing
X
Han
Ziwei
Z
Huang
Jing
J
An
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008958:Models, Molecular; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology*
D000970:Antineoplastic Agents; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D011799:Quinazolines; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051176:beta Catenin; D008156:Luciferases