Title of article :
Cycloalkyl-substituted aryl chloroethylureas inhibiting cell cycle progression in G0/G1 phase and thioredoxin-1 nuclear translocation
Author/Authors :
Jessica S. Fortin، نويسنده , , Marie-France Côté، نويسنده , , Jacques Lacroix، نويسنده , , Alexandre Patenaude، نويسنده , , Eric Petitclerc، نويسنده , , René C.-Gaudreault، نويسنده ,
Issue Information :
روزنامه با شماره پیاپی سال 2008
Pages :
6
From page :
3526
To page :
3531
Abstract :
1-(2-Chloroethyl)-3-(4-cyclohexylphenyl)urea (cHCEU) has been shown to abrogate the presence of thioredoxin-1 into the nucleus through its selective covalent alkylation. In the present letter we have evaluated the structure–activity relationships of the substituents at positions 3 and 4 of the phenyl ring of cHCEU derivatives on cell cycle progression and thioredoxin-1 nuclear translocation. Active CEU derivatives exhibited GI50 ranging from 1.9 to 49 μM on breast carcinoma MCF-7, skin melanoma M21, and colon carcinoma HT-29 cells. On one hand, compounds 1, 2, 9c, 10c, 13, and 14 arrested the cell cycle in G2/M phase while CEUs 3, 4, 5c, 6c, 11c, and 12c blocked the cell division in G0/G1 phase. On the other hand, CEUs 2–4, 5c, 7c, 8c, 11c, and 12c abrogated the translocation of thioredoxin-1 while the other CEU derivatives were inactive in that respect. Our results suggest that CEU substituted on the phenyl ring at position 3 or 4 by lower cycloalkyl or cycloalkoxy groups arrest cell progression in G0/G1 phase through mechanism of action different from their antimicrotubule counterparts, presumably via thioredoxin-1 alkylation and modulation of its activity. The mechanism of action of these new molecules is still undetermined. However, the significant accumulation of cells in G0/G1 phase suggests that these molecules may act similarly to known chemopreventive agents against cancers. In addition, the inhibition of Trx-1 nuclear localization also suggests the abrogation of an important chemoresistance mechanism towards a variety of chemotherapeutic agents.
Keywords :
Phenyl chloroethylurea , alkylating agents , Thioredoxin-1 , Anticancer drugs
Journal title :
Bioorganic & Medicinal Chemistry Letters
Serial Year :
2008
Journal title :
Bioorganic & Medicinal Chemistry Letters
Record number :
799591
Link To Document :
بازگشت