Identification of human telomerase inhibitors having the core of N-acyl-4,5-dihydropyrazole with anticancer effects

Bioorg Med Chem Lett. 2016 Mar 15;26(6):1508-1511. doi: 10.1016/j.bmcl.2016.02.025.

Xuan Xiao ¹, Yong Ni ¹, Ying-Ming Jia ², Min Zheng ¹, Han-Fei Xu ¹, Jun Xu ³, Chenzhong Liao ⁴

Affiliations

1 School of Medical Engineering, Hefei University of Technology, Hefei 230009, China.
2 School of Chemistry and Chemical Engineering, Anhui University of Technology, Maanshan 243002, China.
3 Research Center for Drug Discovery and Institute of Human Virology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
4 School of Medical Engineering, Hefei University of Technology, Hefei 230009, China. Electronic address: czliao@hfut.edu.cn.

PMID: 26883149 DOI: 10.1016/j.bmcl.2016.02.025

Abstract

Eight human Telomerase inhibitors (5a-5h) having the core of N-acyl-4,5-dihydropyrazole with Anticancer effects were identified in this study. Biological results revealed that a few compounds had potent Anticancer activities against three common tumor cell lines (SGC-7901, HepG2 and MGC-803). Among them, compound 5c, with a molecular weight of only 272.2 Da, had antiproliferative activities against SGC-7901 and MGC-803 with EC50 values of 2.06 ± 0.17 and 2.89 ± 0.62 μM, respectively, better than 5-Fluorouracil. Compound 5c inhibited the Enzyme of Telomerase with an IC50 value of 1.86 ± 0.51 μM, surpassing the control compound, ethidium bromide. Modeling study showed that this compound can reside in the binding pocket of the Telomerase/TNA:DNA hairpin complex. When the moiety of N-acyl was changed to N-sulfonyl, the gotten compounds (8a-8i) had deteriorative activities against both these three Cancer cell lines and the Enzyme of Telomerase.

Keywords

Anticancer; Dihydropyrazole; Molecular modeling; Telomerase; Telomerase inhibitor.

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