Synthesis and biological activity of metabolically stabilized cyclopentyl trisphosphate analogues of D-myo-Ins(1,4,5)P3.
We describe the synthesis of four novel metabolically stabilized analogues of Ins(1,4,5)P(3) based on the known cyclopentane pentaol tris(phosphate) 2: tris(phosphorothioate) 3, tris(methylenephosphate) 4, tris(sulfonamide) 5, and tris(sulfate) 6. Of these analogues, only the tris(phosphorothioate) 3 and parent tris(phosphate) 2 bound to the type I InsP(3)R construct. In addition, both the tris(phosphorothioate) 3 and parent tris(phosphate) 2 elicited calcium release in MDA MB-435 breast cancer cells. The Ins(1,4,5)P(3) agonist activities of these two compounds can be rationalized on the basis of computational docking of the ligands to the binding domain of the type I InsP(3)R.
Zhang
Liuyin
L
Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, UT 84108-1257, USA.
Huang
Wei
W
Tanimura
Akihiko
A
Morita
Takao
T
Harihar
Sitaram
S
Dewald
Daryll B
DB
Prestwich
Glenn D
GD
D018360:Crystallography, X-Ray; D015544:Inositol 1,4,5-Trisphosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D009943:Organophosphorus Compounds; D015544:Inositol 1,4,5-Trisphosphate