6-Substituted amiloride derivatives as inhibitors of the urokinase-type plasminogen activator for use in metastatic disease - Details

author：

Indexed by：

Scopus

Abstract：

The　oral　K+-sparing　diuretic　amiloride　shows　anti-cancer　side-activities　in　multiple　rodent　models.　These　effects　appear　to　arise,　at　least　in　part,　through　moderate　inhibition　of　the　urokinase-type　plasminogen　activator　(uPA,　Ki　=　2.4　µM),　a　pro-metastatic　trypsin-like　serine　protease　that　is　upregulated　in　many　aggressive　solid　malignancies.　In　applying　the　selective　optimization　of　side-activity　(SOSA)　approach,　a　focused　library　of　twenty　two　6-substituted　amiloride　derivatives　were　prepared,　with　multiple　examples　displaying　uPA　inhibitory　potencies　in　the　nM　range.　X-ray　co-crystal　structures　revealed　that　the　potency　increases　relative　to　amiloride　arise　from　increased　occupancy　of　uPA＇s　S1β　subsite　by　the　appended　6-substituents.　Leading　compounds　were　shown　to　have　high　selectivity　over　related　trypsin-like　serine　proteases　and　no　diuretic　or　anti-kaliuretic　effects　in　rats.　Compound　15　showed　anti-metastatic　effects　in　a　xenografted　mouse　model　of　late-stage　lung　metastasis.　©　2019　Elsevier　Ltd

Keyword：

Amiloride; Anti-metastatic; Cancer; Metastasis; Selective optimisation of side-activity; Trypsin-like serine protease; uPA; Urokinase plasminogen activator

Community：

[ 1 ] [Buckley, B.J.]School of Chemistry and Molecular Bioscience, University of WollongongNSW 2522, Australia
[ 2 ] [Buckley, B.J.]Illawarra Health and Medical Research InstituteNSW 2522, Australia
[ 3 ] [Buckley, B.J.]Molecular Horizons, University of WollongongNSW 2522, Australia
[ 4 ] [Majed, H.]School of Chemistry and Molecular Bioscience, University of WollongongNSW 2522, Australia
[ 5 ] [Majed, H.]Illawarra Health and Medical Research InstituteNSW 2522, Australia
[ 6 ] [Majed, H.]Molecular Horizons, University of WollongongNSW 2522, Australia
[ 7 ] [Aboelela, A.]School of Chemistry and Molecular Bioscience, University of WollongongNSW 2522, Australia
[ 8 ] [Aboelela, A.]Illawarra Health and Medical Research InstituteNSW 2522, Australia
[ 9 ] [Aboelela, A.]Molecular Horizons, University of WollongongNSW 2522, Australia
[ 10 ] [Minaei, E.]Illawarra Health and Medical Research InstituteNSW 2522, Australia
[ 11 ] [Minaei, E.]Molecular Horizons, University of WollongongNSW 2522, Australia
[ 12 ] [Jiang, L.]National Joint Biomdical Engineering Research Centre on Photodynamic Technologies, Fuzhou University, Fuzhou, 350116, China
[ 13 ] [Fildes, K.]Illawarra Health and Medical Research InstituteNSW 2522, Australia
[ 14 ] [Fildes, K.]Graduate School of Medicine, University of WollongongNSW 2522, Australia
[ 15 ] [Cheung, C.-Y.]Department of Microbiology and Immunology, University of Otago, Otago, 9016, New Zealand
[ 16 ] [Johnson, D.]Tri-institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer CenterNY 10065, United States
[ 17 ] [Bachovchin, D.]Tri-institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer CenterNY 10065, United States
[ 18 ] [Bachovchin, D.]Chemical Biology Program, Memorial Sloan Kettering Cancer CentreNY 10065, United States
[ 19 ] [Cook, G.M.]Department of Microbiology and Immunology, University of Otago, Otago, 9016, New Zealand
[ 20 ] [Huang, M.]National Joint Biomdical Engineering Research Centre on Photodynamic Technologies, Fuzhou University, Fuzhou, 350116, China
[ 21 ] [Ranson, M.]School of Chemistry and Molecular Bioscience, University of WollongongNSW 2522, Australia
[ 22 ] [Ranson, M.]Illawarra Health and Medical Research InstituteNSW 2522, Australia
[ 23 ] [Ranson, M.]Molecular Horizons, University of WollongongNSW 2522, Australia
[ 24 ] [Kelso, M.J.]School of Chemistry and Molecular Bioscience, University of WollongongNSW 2522, Australia
[ 25 ] [Kelso, M.J.]Illawarra Health and Medical Research InstituteNSW 2522, Australia
[ 26 ] [Kelso, M.J.]Molecular Horizons, University of WollongongNSW 2522, Australia

Reprint 's Address：

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

Email：

mranson@uow.edu.au

Show more details

Related Keywords：

Source ：

Bioorganic and Medicinal Chemistry Letters

ISSN： 0960-894X

Year： 2019

Issue： 24

Volume： 29

2 . 5 7 2

JCR@2019

2 . 5 0 0

JCR@2023

ESI HC Threshold：184

JCR Journal Grade：2

CAS Journal Grade：3

Cited Count：

WoS CC Cited Count： 0

SCOPUS Cited Count： 19

ESI Highly Cited Papers on the List： 0 Unfold All

WanFang Cited Count：

Chinese Cited Count：

30 Days PV： 1

Affiliated Colleges：

Get Fulltext

DOI Library Discovery Baidu Scholar Search SCOPUS

Type
Departments

All Years Choose Year From to