Synthesis and biological evaluation of novel phosphatidylinositol 3-kinase inhibitors: Solubilized 4-substituted benzimidazole analogs of 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474)

Gordon W Rewcastle; Swarna A Gamage; Jack U Flanagan; Jackie D Kendall; William A Denny; Bruce C Baguley; Christina M Buchanan; Mindy Chao; Philip Kestell; Sharada Kolekar; Woo-Jeong Lee; Claire L Lill; Alisha Malik; Ripudaman Singh; Stephen M F Jamieson; Peter R Shepherd

doi:10.1016/j.ejmech.2013.03.038

Synthesis and biological evaluation of novel phosphatidylinositol 3-kinase inhibitors: Solubilized 4-substituted benzimidazole analogs of 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474)

Eur J Med Chem. 2013 Jun:64:137-47. doi: 10.1016/j.ejmech.2013.03.038. Epub 2013 Apr 6.

Authors

Gordon W Rewcastle¹, Swarna A Gamage, Jack U Flanagan, Jackie D Kendall, William A Denny, Bruce C Baguley, Christina M Buchanan, Mindy Chao, Philip Kestell, Sharada Kolekar, Woo-Jeong Lee, Claire L Lill, Alisha Malik, Ripudaman Singh, Stephen M F Jamieson, Peter R Shepherd

Affiliation

¹ Auckland Cancer Society Research Centre, School of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. g.rewcastle@auckland.ac.nz

PMID: 23644197
DOI: 10.1016/j.ejmech.2013.03.038

Abstract

A range of 4-substituted derivatives of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474) were prepared in a search for more soluble analogs. 4-Aminoalkoxy substituents provided the most potent derivatives, with the 4-O(CH2)3NMe2 analog (compound 14) being identified as displaying the best overall activity in combination with good aqueous solubility (25 mg/mL for the hydrochloride salt). This compound was tested in a U87MG xenograft model, but displayed less potency than ZSTK474 as a result of an unfavorable pharmacokinetic profile.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Female
HCT116 Cells
Homeodomain Proteins / metabolism
Humans
Male
Mice
Mice, Inbred C57BL
Models, Molecular
Molecular Structure
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Signal Transduction / drug effects
Solubility
Structure-Activity Relationship
Triazines / chemical synthesis
Triazines / chemistry
Triazines / pharmacology*

Substances

Antineoplastic Agents
Homeodomain Proteins
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
Triazines
ZSTK474
RAG-1 protein