Synthesis, antiproliferative activity evaluation and structure–activity relationships of novel aromatic urea and amide analogues of N-phenyl- N′-(2-chloroethyl)ureas

• Published in: European journal of medicinal chemistry 2010-07, Vol.45 (7), p.2928-2937
• Main Authors: Fortin, Sébastien, Moreau, Emmanuel, Lacroix, Jacques, Côté, Marie-France, Petitclerc, Éric, C.-Gaudreault, René
• Format: Article
• Language: English
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - metabolism; Amides - pharmacology; Anticancer drugs; Antimitotic agents; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Aromatic amides; Aromatic ureas; Binding Sites; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - drug effects; CEU; Chemical Sciences; Colchicine - metabolism; Coordination chemistry; General aspects; Humans; Medical sciences; Medicinal Chemistry; N-phenyl- N′-(2-chloroethyl)ureas; Organic chemistry; Pharmacology. Drug treatments; Radiochemistry; Structure-Activity Relationship; Tubulin - chemistry; Tubulin - metabolism; Urea - chemical synthesis; Urea - chemistry; Urea - metabolism; Urea - pharmacology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2010.03.018

Seven subsets of aromatic urea and amide analogues of N-phenyl- N′-(2-chloroethyl)ureas (CEU) have been synthesized by nucleophilic addition of 3-chloropropylisocyanate, 2-chloroacetylisocyanate, ethylisocyanate, 2-chloroacetyl chloride, 3-chloropropanoyl chloride, 4-chlorobutanoyl chloride, and acryloyl chloride, respectively, to selected anilines or benzylamines to afford 3-chloropropylureas ( 1, CPU), 2-chloroacetylureas ( 2, CAU), ethylureas ( 3, EU), 2-chloroacetamides ( 4, CA), 3-chloropropionamides ( 5, CPA), 4-chlorobutyramides ( 6, CBA) and acrylamides ( 7, Acr). The molecular structure of these compounds has been confirmed by IR, 1H and 13C NMR, and MS spectra and their purity also confirmed by HPLC. The CEU analogues were evaluated for their antiproliferative activity against three human tumor cell lines, namely human colon carcinoma HT-29, human skin melanoma M21, and human breast carcinoma MCF-7. CAU ( 2c to 2g), CA ( 4a to 4d, 4f and 4g), CPA ( 5a) and Acr ( 7a and 7b) had IC 50 ranging from 1.4 to 25 μM. CAU, CA, CPA and Acr exhibited interesting antiproliferative activity through mechanism(s) of action unrelated to the acylation of glutamic acid at position 198 on β-tubulin that is characterizing CEU. [Display omitted]