Author's personal copy
European Journal of Medicinal Chemistry 45 (2010)1211–1219
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European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
6-Substituted 2-(N-triﬂuoroacetylamino)imidazopyridines induce cell cycle arrest and apoptosis in SK-LU-1 human cancer cell line
´ ´ ´ Miguel Angel Martınez-Urbina a, *, Alejandro Zentella b, Miguel Angel Vilchis-Reyes a, AngelGuzman a, b a b a, * ´ ´ ´ ´ Omar Vargas , Marıa Teresa Ramırez Apan , Jose Luis Ventura Gallegos , Eduardo Dıaz
´ ´ ´ ´ ´ Instituto de Quımica, Universidad Nacional Autonoma de Mexico, Circuito Exterior, Ciudad Universitaria, Mexico 04510, D. F., Mexico ´ ´ ´ ´ ´ Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico, Circuito Exterior, Ciudad Universitaria,Mexico 04510, D. F., Mexico
a r t i c l e i n f o
Article history: Received 9 March 2009 Received in revised form 19 November 2009 Accepted 23 November 2009 Available online 11 December 2009 Keywords: Imidazo[1,2-a]pyridine derivatives Cell cycle CDKs Apoptosis
a b s t r a c t
A series of 6-substituted 2-(N-triﬂuoroacetylamino)imidazopyridines have been synthesized and their bioactivities wereevaluated. Compounds 6a, 6c, and 11a were the most active compounds with modest cytotoxic activity against six human cancer cell lines U251 (glioma), PC-3 (prostate), K-562 (leukemia), HCT-15 (colon), MCF7 (breast) and SK-LU-1 (lung). The cell cycle analysis showed that compounds 6a, 6c, and 11a induce a G2/M phase cell cycle arrest on SK-LU-1 cell line where inhibition of CDK-1 and CDK-2 may beimplicated. Ó 2009 Elsevier Masson SAS. All rights reserved.
1. Introduction Advances in molecular and cellular biology through the last decades have revealed some of the many process implicated in cancer approach. However, at the present time the prognosis against of most human malignancies has not been improved signiﬁcantly. The continuous search for novel agents which target pathologicalprocesses of human carcinogenesis has lead to the synthesis of small molecules which may modulate cell cycle and apoptotic pathways . Special interest has been focused on molecules that can arrest cell cycle mechanism by the inhibition effect for cyclin-dependent kinases (CDK) family, because perturbation of the cell cycle has been related to human neoplastic diseases . From various subtypes ofCDKs, the most important explored targets in cancer therapy have been CDK-1, -2, and -4 . Nitrogen-bridgehead fused heterocycles containing an imidazole ring have been shown as a common structural moiety in pharmacologically important molecules, displaying a wide range of activities and spreading on diverse number of targets. Probably the most widely used heterocyclic system from this group isimidazo[1,2-a]pyridine . Imidazo[1,2-a]pyridines shown anticytomegalo-zoster and antivaricella-zoster virus , antibacterial , hypnoselective, and
* Corresponding authors. Tel.: þ52 55 56 22 44 21; fax: þ52 55 56 16 22 17. ´ E-mail addresses: firstname.lastname@example.org (M.A. Martınez-Urbina), ´ email@example.com (E. Dıaz). 0223-5234/$ – see front matter Ó 2009 Elsevier Masson...