N-4-iodophenyl-N′-2-chloroethylurea, a novel potential anticancer agent with colon-specific accumulation: radioiodination and comparative in vivo biodistribution profiles

Abstract

In a search for more selective anticancer drugs, we have designed nitrogen mustard and nitrosourea conjugates leading to a series of N-4-aryl-N'-2-chloroethylureas (CEUs). The iodinated derivative N-4-iodophenyl-N'-2-chloroethylurea (4-ICEU) has demonstrated significant antineoplastic and antiangiogenic potency in preclinical evaluations. In this study, 4-ICEU was radiolabelled with [(125)I]iodide in order to carry out a comparative study of its in vivo behavior profile. 4-[(125)I]-ICEU was synthesized by direct electrophilic radioiodination with 80% radiochemical yield and 97% radiopurity. Three different routes of administration (intraperitoneal (ip), intravenous (iv) and intratumoral (it)) were tested in mice bearing subcutaneously implanted CT-26 murine colon carcinoma. The results clearly established that 4-ICEU was more stable to biotransformation than previously studied CEUs congeners. It was readily bioavailable and reached the CT-26 colorectal tumor regardless of the route of administration. Additionally, the colon mucosa was an important target tissue where 4-ICEU accumulated and remained largely untransformed. In conclusion, these results justify further investigations for developing 4-ICEU as a new chemotherapeutic agent for colorectal cancer.

Diabetes mellitus drug discovery: insights into targeting feline and human amylin with small molecules

“…Chloroethylurea follows the rule of five and remains stable in the tissue after administration, exhibiting good bioavailability (Mounetou et al. 2010 ). Furthermore, the investigators found that the compound primarily concentrates in organs of the digestive system upon intraperitoneal or intravenous injection (Mounetou et al.…”

“…Furthermore, the investigators found that the compound primarily concentrates in organs of the digestive system upon intraperitoneal or intravenous injection (Mounetou et al. 2010 ). Work by Radhakrishnan et al.…”

Intramolecular cyclization of N-phenyl N′(2-chloroethyl)ureas leads to active N-phenyl-4,5-dihydrooxazol-2-amines alkylating β-tubulin Glu198 and prohibitin Asp40

“…New CEUs will be synthesized to elucidate this interesting point concerning the alkylation process of Glu and Asp residues and to enhance our knowledge about the specific interactions occurring in the colchicine-binding site. From a biological point of view, previous in vivo data did not allow detecting oxazolinic forms or dechlorinated CEUs in urines of mice treated with tBCEU [31], while some unidentified metabolites were found in blood, tumors and colon of mice treated with ICEU [32]. In vivo investigations will be pursued to identify these metabolites and to determine precisely the active forms of CEUs or Oxas.…”

Transdermal diffusion, spatial distribution and physical state of a potential anticancer drug in mouse skin as studied by diffusion and spectroscopic techniques

“…Phenylchloroethylurea derivatives (CEUs) are promising alkylating anticancer drugs, alkylating notably beta tubulin and prohibitin-1 [7][8][9][10][11]. CEUs were initially designed from the pharmacophoric moiety of aliphatic 2-chloroethylnitrosoureas such as carmustine and the biofunctional moiety of aromatic nitrogen mustards such as chlorambucil.…”