Synthesis of novel arylaminoquinazolinylurea derivatives and their antiproliferative activities against bladder cancer cell line

• Published in: Bioorganic & medicinal chemistry letters Vol. 26; no. 20; pp. 5082 - 5086
• Main Authors: Kim, Jung Hun, Kwak, Yeonui, Song, Chiman, Roh, Eun Joo, Oh, Chang-Hyun, Lee, So Ha, Sim, Taebo, Choi, Jung Hoon, Yoo, Kyung Ho
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.10.2016; Elsevier
• Subjects: Antiproliferative activity; Arylaminoquinazolinylamides; Arylaminoquinazolinylureas; Bladder cancer cell line; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Drug Screening Assays, Antitumor; Enzymatic activity; FGFR3; Humans; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Physical Sciences; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinazolines - pharmacology; Science & Technology; Urea - chemical synthesis; Urea - chemistry; Urea - pharmacology; Urinary Bladder Neoplasms - pathology; Arylaminoquinazolinylureas; Antiproliferative activity; Enzymatic activity; FGFR3; Arylaminoquinazolinylamides; Bladder cancer cell line; SELECTIVE INHIBITOR; POTENT; DESIGN; FGFR1 INHIBITORS; GROWTH-FACTOR RECEPTORS; DISCOVERY
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.08.076

[Display omitted] A novel series of arylurea and arylamide derivatives 1a–z, 2a–d having aminoquinazoline scaffold was designed and synthesized. Their in vitro antiproliferative activities against RT112 bladder cancer cell line and inhibitory activities against FGFR3 kinase were tested. Most compounds showed good antiproliferative activities against RT112 bladder cancer cell line, and arylurea compounds 1a–z were more potent than arylamide compounds 2a–d. Among them, eight compounds 1a, 1d–g, 1l, 1y, and 1z showed potent activities with GI50 values below submicromolar range. Especially, arylurea compounds 1d and 1g possessing 2,3-dimethyl and 3,4-dimethyl moieties exhibited superior or similar antiproliferative activity (GI50=8.8nM and 30.2nM, respectively) to AZD4547 (GI50=29.2nM) as a reference standard.