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

Abstract

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, (1)H and (13)C 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 4 g), CPA (5a) and Acr (7a and 7b) had IC(50) ranging from 1.4 to 25 microM. 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 beta-tubulin that is characterizing CEU.