Synthesis, biological evaluation and molecular modelling of sulfonohydrazides as selective PI3K p110alpha inhibitors.
A series of 2-methyl-5-nitrobenzenesulfonohydrazides were prepared and evaluated as inhibitors of PI3K. An isoquinoline derivative shows good selectivity for the p110alpha isoform over p110beta and p110delta, and also demonstrates good in vitro activity in a cell proliferation assay. Molecular modelling provides a rationalisation for the observed SAR.
Kendall
Jackie D
JD
Auckland Cancer Society Research Centre, School of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1020, New Zealand.
Rewcastle
Gordon W
GW
Frederick
Raphael
R
Mawson
Claire
C
Denny
William A
WA
Marshall
Elaine S
ES
Baguley
Bruce C
BC
Chaussade
Claire
C
Jackson
Shaun P
SP
Shepherd
Peter R
PR
D000595:Amino Acid Sequence; D000730:Androstadienes / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004341:Drug Evaluation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006834:Hydrazines / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009025:Morpholines / Q000494:pharmacology; D009578:Nitrobenzenes / Q000737:chemistry* / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D000077191:Wortmannin
C526494:2-methyl-5-nitrobenzenesulfonohydrazide; D000730:Androstadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D006834:Hydrazines; D009025:Morpholines; D009578:Nitrobenzenes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D000077191:Wortmannin