Design and Synthesis of Formononetin-dithiocarbamate Hybrids That Inhibit Growth and Migration of PC-3 cells Via MAPK/Wnt Signaling Pathways

Overview

Journal Eur J Med Chem

Specialty Chemistry

Date 2016 Dec 31

PMID 28038329

Citations 15

Authors

Dong-Jun Fu

Li Zhang

Jian Song

Ruo-Wang Mao

Ruo-Han Zhao

Ying-Chao Liu

Yu-Hui Hou

Jia-Huan Li

Jia-jia Yang

Cheng-Yun Jin

Ping Li

Xiao-Lin Zi

Hong-Min Liu

Sai-Yang Zhang

Yan-Bing Zhang

Affiliations

Soon will be listed here.

Abstract

A series of novel formononetin-dithiocarbamate derivatives were designed, synthesized and evaluated for antiproliferative activity against three selected cancer cell line (MGC-803, EC-109, PC-3). The first structure-activity relationship (SAR) for this formononetin-dithiocarbamate scaffold is explored in this report with evaluation of 14 variants of the structural class. Among these analogues, tert-butyl 4-(((3-((3-(4-methoxyphenyl)-4-oxo-4H-chromen-7-yl)oxy)propyl)thio)carbonothioyl)piperazine-1-carboxylate (8i) showed the best inhibitory activity against PC-3 cells (IC = 1.97 μM). Cellular mechanism studies elucidated 8i arrests cell cycle at G1 phase and regulates the expression of G1 checkpoint-related proteins in concentration-dependent manners. Furthermore, 8i could inhibit cell growth via MAPK signaling pathway and inhibit migration via Wnt pathway in PC-3 cells.

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References

Mu H, Bai Y, Wang S, Zhu Z, Zhang Y . Research on antioxidant effects and estrogenic effect of formononetin from Trifolium pratense (red clover). Phytomedicine. 2008; 16(4):314-9. DOI: 10.1016/j.phymed.2008.07.005. View

Veeman M, Axelrod J, Moon R . A second canon. Functions and mechanisms of beta-catenin-independent Wnt signaling. Dev Cell. 2003; 5(3):367-77. DOI: 10.1016/s1534-5807(03)00266-1. View

Fu D, Zhang S, Liu Y, Zhang L, Liu J, Song J . Design, synthesis and antiproliferative activity studies of novel dithiocarbamate-chalcone derivates. Bioorg Med Chem Lett. 2016; 26(16):3918-22. DOI: 10.1016/j.bmcl.2016.07.012. View

Li T, Zhao X, Mo Z, Huang W, Yan H, Ling Z . Formononetin promotes cell cycle arrest via downregulation of Akt/Cyclin D1/CDK4 in human prostate cancer cells. Cell Physiol Biochem. 2014; 34(4):1351-8. DOI: 10.1159/000366342. View

Bienz M, Clevers H . Linking colorectal cancer to Wnt signaling. Cell. 2000; 103(2):311-20. DOI: 10.1016/s0092-8674(00)00122-7. View

Islam M, Park S, Song C, Kadi A, Kwon Y, Rahman A . Fluorescein hydrazones: A series of novel non-intercalative topoisomerase IIα catalytic inhibitors induce G1 arrest and apoptosis in breast and colon cancer cells. Eur J Med Chem. 2016; 125:49-67. DOI: 10.1016/j.ejmech.2016.09.004. View

Kyriakis J, Avruch J . Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update. Physiol Rev. 2012; 92(2):689-737. DOI: 10.1152/physrev.00028.2011. View

Li R, Wang H, Li Y, Wang Z, Wang X, Wang Y . Discovery and optimization of novel dual dithiocarbamates as potent anticancer agents. Eur J Med Chem. 2015; 93:381-91. DOI: 10.1016/j.ejmech.2015.02.030. View

Cragg G, Newman D . Natural products: a continuing source of novel drug leads. Biochim Biophys Acta. 2013; 1830(6):3670-95. PMC: 3672862. DOI: 10.1016/j.bbagen.2013.02.008. View

10.

Wang X, Xu H, Guo L, Zheng J, Xu B, Guo X . Synthesis and in vitro antitumor activity of new butenolide-containing dithiocarbamates. Bioorg Med Chem Lett. 2011; 21(10):3074-7. DOI: 10.1016/j.bmcl.2011.03.029. View

11.

Altintop M, Sever B, Ciftci G, Kucukoglu K, Ozdemir A, Soleimani S . Synthesis and evaluation of new benzodioxole-based dithiocarbamate derivatives as potential anticancer agents and hCA-I and hCA-II inhibitors. Eur J Med Chem. 2016; 125:190-196. DOI: 10.1016/j.ejmech.2016.09.035. View

12.

Zheng Y, Duan Y, Ma J, Xu R, Zi X, Lv W . Triazole-dithiocarbamate based selective lysine specific demethylase 1 (LSD1) inactivators inhibit gastric cancer cell growth, invasion, and migration. J Med Chem. 2013; 56(21):8543-60. PMC: 3881423. DOI: 10.1021/jm401002r. View

13.

Duan Y, Ma Y, Zhang E, Shi X, Wang M, Ye X . Design and synthesis of novel 1,2,3-triazole-dithiocarbamate hybrids as potential anticancer agents. Eur J Med Chem. 2013; 62:11-9. DOI: 10.1016/j.ejmech.2012.12.046. View

14.

Nusse R . Wnt signaling in disease and in development. Cell Res. 2005; 15(1):28-32. DOI: 10.1038/sj.cr.7290260. View

15.

Gafner S, Bergeron C, Villinski J, Godejohann M, Kessler P, Cardellina J . Isoflavonoids and coumarins from Glycyrrhiza uralensis: antibacterial activity against oral pathogens and conversion of isoflavans into isoflavan-quinones during purification. J Nat Prod. 2011; 74(12):2514-9. DOI: 10.1021/np2004775. View

16.

Kyriakis J, Avruch J . Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev. 2001; 81(2):807-69. DOI: 10.1152/physrev.2001.81.2.807. View

17.

Ren J, Xu H, Cheng H, Xin W, Chen X, Hu K . Synthesis and antitumor activity of formononetin nitrogen mustard derivatives. Eur J Med Chem. 2012; 54:175-87. DOI: 10.1016/j.ejmech.2012.04.039. View

18.

Stamos J, Weis W . The β-catenin destruction complex. Cold Spring Harb Perspect Biol. 2012; 5(1):a007898. PMC: 3579403. DOI: 10.1101/cshperspect.a007898. View

19.

Matsushime H, Roussel M, Ashmun R, Sherr C . Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle. Cell. 1991; 65(4):701-13. DOI: 10.1016/0092-8674(91)90101-4. View

20.

Schwartz G, Shah M . Targeting the cell cycle: a new approach to cancer therapy. J Clin Oncol. 2005; 23(36):9408-21. DOI: 10.1200/JCO.2005.01.5594. View