Synthesis and biological evaluation of sulfonamide analogues of the phosphatidylinositol 3-kinase inhibitor ZSTK474

Swarna A Gamage; Anna C Giddens; Kit Y Tsang; Jack U Flanagan; Jackie D Kendall; Woo-Jeong Lee; Bruce C Baguley; Christina M Buchanan; Stephen M F Jamieson; Peter R Shepherd; William A Denny; Gordon W Rewcastle

doi:10.1016/j.bmc.2017.09.025

Synthesis and biological evaluation of sulfonamide analogues of the phosphatidylinositol 3-kinase inhibitor ZSTK474

Bioorg Med Chem. 2017 Oct 15;25(20):5859-5874. doi: 10.1016/j.bmc.2017.09.025. Epub 2017 Sep 20.

Affiliations

¹ Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
² Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
³ Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
⁴ Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
⁵ Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
⁶ Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: g.rewcastle@auckland.ac.nz.

PMID: 28958845
DOI: 10.1016/j.bmc.2017.09.025

Abstract

Replacement of one of the morpholine groups of the phosphatidylinositol 3-kinase (PI3K) inhibitor ZSTK474 (1) with sulfonamide containing substituents produced a new class of active and potent PI3Kα inhibitors. Solubility issues prevented all but the 6-amino derivative 17 from being evaluated in vivo, but the clear activity of this compound demonstrated that this class of PI3K inhibitor shows great promise.

Keywords: PI3K; Phosphatidylinositol 3-kinase; ZSTK474; p110α.

MeSH terms

Cell Line, Tumor
Enzyme Activation / drug effects
Humans
Molecular Structure
Phosphoinositide-3 Kinase Inhibitors*
Solubility
Sulfonamides / chemical synthesis*
Sulfonamides / chemistry
Sulfonamides / pharmacology*
Triazines / chemistry*
Triazines / pharmacology

Substances

Phosphoinositide-3 Kinase Inhibitors
Sulfonamides
Triazines
ZSTK474