6-Substituted Hexamethylene Amiloride (HMA) Derivatives as Potent and Selective Inhibitors of the Human Urokinase Plasminogen Activator for Use in Cancer - Details

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Abstract：

Metastasis　is　the　cause　of　death　in　the　majority　(∼90%)　of　malignant　cancers.　The　oral　potassium-sparing　diuretic　amiloride　and　its　5-substituted　derivative　5-N,N-(hexamethylene)amiloride　(HMA)　reportedly　show　robust　antitumor/metastasis　effects　in　multiple　in　vitro　and　animal　models.　These　effects　are　likely　due,　at　least　in　part,　to　inhibition　of　the　urokinase　plasminogen　activator　(uPA),　a　key　protease　determinant　of　cell　invasiveness　and　metastasis.　This　study　reports　the　discovery　of　6-substituted　HMA　analogs　that　show　nanomolar　potency　against　uPA,　high　selectivity　over　related　trypsin-like　serine　proteases,　and　minimal　inhibitory　effects　against　epithelial　sodium　channels　(ENaC),　the　diuretic　and　antikaliuretic　target　of　amiloride.　Reductions　in　lung　metastases　were　demonstrated　for　two　analogs　in　a　late-stage　experimental　mouse　metastasis　model,　and　one　analog　completely　inhibited　formation　of　liver　metastases　in　an　orthotopic　xenograft　mouse　model　of　pancreatic　cancer.　The　results　support　further　evaluation　of　6-substituted　HMA　derivatives　as　uPA-targeting　anticancer　drugs.　©　2018　American　Chemical　Society.

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[ 1 ] [Buckley, B.J.]Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia
[ 2 ] [Buckley, B.J.]Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia
[ 3 ] [Aboelela, A.]Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia
[ 4 ] [Aboelela, A.]Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia
[ 5 ] [Minaei, E.]Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia
[ 6 ] [Minaei, E.]Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia
[ 7 ] [Jiang, L.X.]National Joint Biomedical Engineering Research Centre on Photodynamic Technologies, Fuzhou University, Fujian, 350116, China
[ 8 ] [Xu, Z.]Pancreatic Research Group, South Western Sydney Clinical School, University of New South Wales, Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia
[ 9 ] [Ali, U.]Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia
[ 10 ] [Ali, U.]Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia
[ 11 ] [Fildes, K.]Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia
[ 12 ] [Fildes, K.]Graduate School of Medicine, University of Wollongong, Wollongong, NSW 2522, Australia
[ 13 ] [Cheung, C.-Y.]Department of Microbiology and Immunology, University of Otago, Otago, 9016, New Zealand
[ 14 ] [Cook, S.M.]Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia
[ 15 ] [Johnson, D.C.]Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States
[ 16 ] [Bachovchin, D.A.]Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States
[ 17 ] [Bachovchin, D.A.]Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States
[ 18 ] [Cook, G.M.]Department of Microbiology and Immunology, University of Otago, Otago, 9016, New Zealand
[ 19 ] [Apte, M.]Pancreatic Research Group, South Western Sydney Clinical School, University of New South Wales, Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia
[ 20 ] [Huang, M.]National Joint Biomedical Engineering Research Centre on Photodynamic Technologies, Fuzhou University, Fujian, 350116, China
[ 21 ] [Ranson, M.]Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia
[ 22 ] [Ranson, M.]Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia
[ 23 ] [Kelso, M.J.]Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia
[ 24 ] [Kelso, M.J.]Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia

Reprint 's Address：

[Ranson, M.]Molecular Horizons and School of Chemistry and Molecular Bioscience, University of WollongongAustralia

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mranson@uow.edu.au

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Journal of Medicinal Chemistry

ISSN： 0022-2623

Year： 2018

Issue： 18

Volume： 61

Page： 8299-8320

6 . 0 5 4

JCR@2018

6 . 9 0 0

JCR@2023

ESI HC Threshold：209

JCR Journal Grade：1

CAS Journal Grade：1

Cited Count：

WoS CC Cited Count： 0

SCOPUS Cited Count： 55

ESI Highly Cited Papers on the List： 0 Unfold All

WanFang Cited Count：

Chinese Cited Count：

30 Days PV： 0

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