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

[Display omitted] Replacing one of the morpholine groups of the phosphatidylinositol 3-kinase (PI3K) inhibitor ZSTK474 with a variety of sulfonamide-linked solubilizing substituents produced a new class of active and potent PI3Kα inhibitors, with several derivatives demonstrating high PI3Kα enzyme p...

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Veröffentlicht in:	Bioorganic & medicinal chemistry 2019-04, Vol.27 (8), p.1529-1545
Hauptverfasser:	Giddens, Anna C., Gamage, Swarna A., Kendall, Jackie D., Lee, Woo-Jeong, Baguley, Bruce C., Buchanan, Christina M., Jamieson, Stephen M.F., Dickson, James M.J., Shepherd, Peter R., Denny, William A., Rewcastle, Gordon W.
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Antineoplastic Agents - chemical synthesis Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Cell Line, Tumor Cell Proliferation - drug effects Drug Evaluation, Preclinical Female Humans Inhibitory Concentration 50 Mice Neoplasms - drug therapy p110α Phosphatidylinositol 3-kinase Phosphatidylinositol 3-Kinases - chemistry Phosphatidylinositol 3-Kinases - metabolism Phosphoinositide-3 Kinase Inhibitors - chemical synthesis Phosphoinositide-3 Kinase Inhibitors - pharmacology Phosphoinositide-3 Kinase Inhibitors - therapeutic use PI3K Protein Subunits - antagonists & inhibitors Protein Subunits - metabolism SN32976 Structure-Activity Relationship Sulfonamides - chemistry Sulfonamides - pharmacology Sulfonamides - therapeutic use Transplantation, Heterologous Triazines - chemistry ZSTK474
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Zusammenfassung:	[Display omitted] Replacing one of the morpholine groups of the phosphatidylinositol 3-kinase (PI3K) inhibitor ZSTK474 with a variety of sulfonamide-linked solubilizing substituents produced a new class of active and potent PI3Kα inhibitors, with several derivatives demonstrating high PI3Kα enzyme potency and good cellular potency in two human derived cell lines. The overall results suggest a preference for linear and somewhat flexible solubilizing functions. From this series, compound 16, also known as SN32976, was selected for advanced preclinical evaluation.
ISSN:	0968-0896 1464-3391
DOI:	10.1016/j.bmc.2019.02.050