Design and synthesis of isoform-selective phospholipase D (PLD) inhibitors. Part II. Identification of the 1,3,8-triazaspiro[4,5]decan-4-one privileged structure that engenders PLD2 selectivity

被引：56

作者：

Lavieri, Robert ^{[1
]}

Scott, Sarah A. ^{[1
]}

Lewis, Jana A. ^{[1
]}

Selvy, Paige E. ^{[1
]}

Armstrong, Michelle D. ^{[1
]}

Brown, H. Alex ^{[1
,2
,4
]}

Lindsley, Craig W. ^{[1
,2
,3
,4
]}

机构：

[1] Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Dept Chem, Nashville, TN 37232 USA

[3] Vanderbilt Univ, Vanderbilt Inst Chem Biol, Vanderbilt Program Drug Discovery, Nashville, TN 37232 USA

[4] Vanderbilt Univ, Med Ctr, Vanderbilt Inst Chem Biol, Nashville, TN 37232 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 08期

关键词：

PLD; Phospholipase; Cancer; Privileged structure; HUMAN BREAST-CANCER; OVEREXPRESSION; TRANSFORMATION; DISCOVERY;

D O I：

10.1016/j.bmcl.2009.02.125

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

This Letter describes the synthesis and structure-activity relationships (SAR) of isoform-selective PLD inhibitors. By virtue of the installation of a 1,3,8-triazaspiro[4,5]decan-4-one privileged structure, PLD inhibitors with nanomolar potency and an unprecedented 40-fold selectivity for PLD2 over PLD1 were developed. Interestingly, SAR for this diverged from our earlier efforts, and dual PLD1/2 inhibitors were also discovered within this series. (c) 2009 Elsevier Ltd. All rights reserved.

引用

页码：2240 / 2243

页数：4

共 16 条

[1] Requirement of phospholipase D1 activity in H-RasV12-induced transformation [J].

Buchanan, FG ;

McReynolds, M ;

Couvillon, A ;

Kam, Y ;

Holla, VR ;

DuBois, RN ;

Exton, JH .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (05) :1638-1642

[2] Application of combinatorial chemistry science on modern drug discovery [J].

Kennedy, J. Phillip ;

Williams, Lyndsey ;

Bridges, Thomas M. ;

Daniels, R. Nathan ;

Weaver, David ;

Lindsley, Craig W. .

JOURNAL OF COMBINATORIAL CHEMISTRY, 2008, 10 (03) :345-354

[3] Development of a custom high-throughput preparative liquid chromatography/mass spectrometer platform for the preparative purification and analytical analysis of compound libraries [J].

Leister, W ;

Strauss, K ;

Wisnoski, D ;

Zhao, ZJ ;

Lindsley, C .

JOURNAL OF COMBINATORIAL CHEMISTRY, 2003, 5 (03) :322-329

[4] Allosteric modulation of kinases and GPCRs: design principles and structural diversity [J].

Lewis, Jana A. ;

Lebois, Evan P. ;

Lindsley, Craig W. .

CURRENT OPINION IN CHEMICAL BIOLOGY, 2008, 12 (03) :269-280

[5] Design and synthesis of isoform-selective phospholipase D (PLD) inhibitors. Part I: Impact of alternative halogenated privileged structures for PLD1 specificity [J].

Lewis, Jana A. ;

Scott, Sarah A. ;

Lavieri, Robert ;

Buck, Jason R. ;

Selvy, Paige E. ;

Stoops, Sydney L. ;

Armstrong, Michelle D. ;

Brown, H. Alex ;

Lindsley, Craig W. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (07) :1916-1920

[6] Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors [J].

Lindsley, CW ;

Zhao, ZJ ;

Leister, WH ;

Robinson, RG ;

Barnett, SF ;

Defeo-Jones, D ;

Jones, RE ;

Hartman, GD ;

Huff, JR ;

Huber, HE ;

Duggan, ME .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (03) :761-764

[7] Neoplastic transformation and tumorigenesis associated with overexpression of phospholipase D isozymes in cultured murine fibroblasts [J].

Min, DS ;

Kwon, TK ;

Park, WS ;

Chang, JS ;

Park, SK ;

Ahn, BH ;

Ryoo, ZY ;

Lee, YH ;

Lee, YS ;

Rhie, DJ ;

Yoon, SH ;

Hahn, SJ ;

Kim, MS ;

Jo, YH .

CARCINOGENESIS, 2001, 22 (10) :1641-1647

[8] Optimization of halopemide for phospholipase D2 inhibition [J].

Monovich, Lauren ;

Mugrage, Benjamin ;

Quadros, Elizabeth ;

Toscano, Karen ;

Tommasi, Ruben ;

LaVoie, Stacey ;

Liu, Eugene ;

Du, Zhengming ;

LaSala, Daniel ;

Boyar, William ;

Steed, Paul .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2007, 17 (08) :2310-2311

[9] Overexpression of phospholipase D1 in human breast cancer tissues [J].

Noh, DY ;

Ahn, SJ ;

Lee, RA ;

Park, IA ;

Kim, JH ;

Suh, PG ;

Ryu, SH ;

Lee, KH ;

Han, JS .

CANCER LETTERS, 2000, 161 (02) :207-214

[10] Privileged structures - An update [J].

Patchett, AA ;

Nargund, RP .

ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL 35, 2000, 35 :289-298

← 1 2 →