Identification of a Novel Substrate-Derived Spermine Oxidase Inhibitor

被引：8

作者：

Dunston, T. T. ^{[1
]}

Khomutov, M. A. ^{[2
]}

Gabelli, S. B. ^{[1
,3
,4
]}

Stewart, T. M. ^{[1
]}

Foley, J. R. ^{[1
]}

Kochetkov, S. N. ^{[2
]}

Khomutov, A. R. ^{[2
]}

Casero, R. A., Jr. ^{[1
]}

机构：

[1] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Sch Med, Baltimore, MD 21287 USA

[2] Russian Acad Sci, Engelhardt Inst Mol Biol, Moscow 119991, Russia

[3] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA

[4] Johns Hopkins Univ, Dept Oncol, Sch Med, Baltimore, MD 21287 USA

来源：

ACTA NATURAE | 2020年 / 12卷 / 03期

基金：

俄罗斯科学基金会; 美国国家卫生研究院;

关键词：

Spermine oxidase; inhibitors; MDL72527; spermine analogues; 2,11-Met(2)-Spm; POLYAMINES; CANCER;

D O I：

10.32607/actanaturae.10992

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Homeostasis of the biogenic polyamines spermine (Spm) and spermidine (Spd), present in mu M-mM concentrations in all eukaryotic cells, is precisely regulated by coordinated activities of the enzymes of polyamine synthesis, degradation, and transport, in order to sustain normal cell growth and viability. Spermine oxidase (SMOX) is the key and most recently discovered enzyme of polyamine metabolism that plays an essential role in regulating polyamine homeostasis by catalyzing the back-conversion of Spm to Spd. The development of many types of epithelial cancer is associated with inflammation, and disease-related inflammatory stimuli induce SMOX. MDL72527 is widely used in vitro and in vivo as an irreversible inhibitor of SMOX, but it is also potent towards AP-acetylpolyamine oxidase. Although SMOX has high substrate specificity, Spm analogues have not been systematically studied as enzyme inhibitors. Here we demonstrate that 1,12-diamino-2,11-bis(methylidene)-4,9-diazadodecane (2,11-Met(2)-Spm) has, under standard assay conditions, an IC50 value of 169 mu M towards SMOX and is an interesting instrument and lead compound for studying polyamine catabolism.

引用

页码：140 / 144

页数：5

共 20 条

[1] α-vinylic amino acids:: occurrence, asymmetric synthesis, and biochemical mechanisms [J].

Berkowitz, David B. ;

Charette, Bradley D. ;

Karukurichi, Kannan R. ;

McFadden, Jill M. .

TETRAHEDRON-ASYMMETRY, 2006, 17 (06) :869-882

[2] N-2,3-BUTADIENYL-1,4-BUTANEDIAMINE DERIVATIVES - POTENT IRREVERSIBLE INACTIVATORS OF MAMMALIAN POLYAMINE OXIDASE [J].

BEY, P ;

BOLKENIUS, FN ;

SEILER, N ;

CASARA, P .

JOURNAL OF MEDICINAL CHEMISTRY, 1985, 28 (01) :1-2

[3] Polyamine metabolism and cancer: treatments, challenges and opportunities [J].

Casero, Robert A., Jr. ;

Stewart, Tracy Murray ;

Pegg, Anthony E. .

NATURE REVIEWS CANCER, 2018, 18 (11) :681-695

[4] Spermine Oxidase Mediates the Gastric Cancer Risk Associated With Helicobacter pylori CagA [J].

Chaturvedi, Rupesh ;

Asim, Mohammad ;

Romero-Gallo, Judith ;

Barry, Daniel P. ;

Hoge, Svea ;

de Sablet, Thibaut ;

Delgado, Alberto G. ;

Wroblewski, Lydia E. ;

Piazuelo, M. Blanca ;

Yan, Fang ;

Israel, Dawn A. ;

Casero, Robert A., Jr. ;

Correa, Pelayo ;

Gobert, Alain P. ;

Polk, D. Brent ;

Peek, Richard M., Jr. ;

Wilson, Keith T. .

GASTROENTEROLOGY, 2011, 141 (05) :1696-U255

[5] Cancer pharmacoprevention: Targeting polyamine metabolism to manage risk factors for colon cancer [J].

Gerner, Eugene W. ;

Bruckheimer, Elizabeth ;

Cohen, Alfred .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2018, 293 (48) :18770-18778

[6] Increased spermine oxidase expression in human prostate cancer and prostatic intraepithelial neoplasia tissues [J].

Goodwin, Andrew C. ;

Jadallah, Sana ;

Toubaji, Antoun ;

Lecksell, Kristen ;

Hicks, Jessica L. ;

Kowalski, Jeanne ;

Bova, G. Steven ;

De Marzo, Angelo M. ;

Netto, George J. ;

Casero, Robert A., Jr. .

PROSTATE, 2008, 68 (07) :766-772

[7] Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis [J].

Goodwin, Andrew C. ;

Shields, Christina E. Destefano ;

Wu, Shaoguang ;

Huso, David L. ;

Wu, XinQun ;

Murray-Stewart, Tracy R. ;

Hacker-Prietz, Amy ;

Rabizadeh, Shervin ;

Woster, Patrick M. ;

Sears, Cynthia L. ;

Casero, Robert A., Jr. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (37) :15354-15359

[8]

Goodwin AC, 2011, METHODS MOL BIOL, V720, P173, DOI 10.1007/978-1-61779-034-8_10

[9] Synthesis of 2,11-bis(methylidene)spermine, a new inhibitor of spermine oxidase [J].

Grigorenko, N. A. ;

Khomutov, M. A. ;

Simonian, A. R. ;

Kochetkov, S. N. ;

Khomutov, A. R. .

RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY, 2016, 42 (04) :423-427

[10] Dual inhibitors of LSD1 and spermine oxidase [J].

Holshouser, Steven ;

Dunworth, Matthew ;

Murray-Stewart, Tracy ;

Peterson, Yuri K. ;

Burger, Pieter ;

Kirkpatrick, Joy ;

Chen, Huan-Huan ;

Casero, Robert A., Jr. ;

Woster, Patrick M. .

MEDCHEMCOMM, 2019, 10 (05) :778-790

← 1 2 →