Limits...
Synthetic tools for studying the chemical biology of InsP8.

Riley AM, Wang H, Shears SB, L Potter BV - Chem. Commun. (Camb.) (2015)

Bottom Line: To synthesise stabilised mimics of InsP8, the most phosphorylated inositol phosphate signalling molecule in Nature, we replaced its two diphosphate (PP) groups with either phosphonoacetate (PA) or methylenebisphosphonate (PCP) groups.Utility of the PA and PCP analogues was verified by structural and biochemical analyses of their interactions with enzymes of InsP8 metabolism.

View Article: PubMed Central - PubMed

Affiliation: Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK.

ABSTRACT
To synthesise stabilised mimics of InsP8, the most phosphorylated inositol phosphate signalling molecule in Nature, we replaced its two diphosphate (PP) groups with either phosphonoacetate (PA) or methylenebisphosphonate (PCP) groups. Utility of the PA and PCP analogues was verified by structural and biochemical analyses of their interactions with enzymes of InsP8 metabolism.

Show MeSH

Related in: MedlinePlus

Synthesis of 1 and 2. Reagents and conditions: (a) EDAC, 4, CH2Cl2; (b) H2, Pd(OH)2/C, MeOH, H2O; (c) i. (BnO)2PNPri2, 5-phenyl-1H-tetrazole, CH2Cl2; ii. mCPBA, CH2Cl2; (d) i. TMSBr, CH2Cl2; ii. MeOH, TEAB; (e) (EtO)2P(O)CH2P(O)(OEt)Cl, DIPEA, CH2Cl2; (f) H2, Pd(OH)2/C, MeOH, THF, H2O, AcOH. TEAB, aqueous triethylammonium bicarbonate; Bn, benzyl. Yields are shown in respect of each step. Stereogenic phosphorus atoms are indicated by an asterisk.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4643724&req=5

sch1: Synthesis of 1 and 2. Reagents and conditions: (a) EDAC, 4, CH2Cl2; (b) H2, Pd(OH)2/C, MeOH, H2O; (c) i. (BnO)2PNPri2, 5-phenyl-1H-tetrazole, CH2Cl2; ii. mCPBA, CH2Cl2; (d) i. TMSBr, CH2Cl2; ii. MeOH, TEAB; (e) (EtO)2P(O)CH2P(O)(OEt)Cl, DIPEA, CH2Cl2; (f) H2, Pd(OH)2/C, MeOH, THF, H2O, AcOH. TEAB, aqueous triethylammonium bicarbonate; Bn, benzyl. Yields are shown in respect of each step. Stereogenic phosphorus atoms are indicated by an asterisk.

Mentions: The syntheses of 1 and 2 (Scheme 1) begins with diol (–)-3, obtained by regioselective reduction of 2,4,6-tri-O-benzyl myo-inositol orthobenzoate,19 followed by optical resolution of racemic 3via the formation of diastereoisomeric monocamphanate esters20 (see ESI† for details).‡


Synthetic tools for studying the chemical biology of InsP8.

Riley AM, Wang H, Shears SB, L Potter BV - Chem. Commun. (Camb.) (2015)

Synthesis of 1 and 2. Reagents and conditions: (a) EDAC, 4, CH2Cl2; (b) H2, Pd(OH)2/C, MeOH, H2O; (c) i. (BnO)2PNPri2, 5-phenyl-1H-tetrazole, CH2Cl2; ii. mCPBA, CH2Cl2; (d) i. TMSBr, CH2Cl2; ii. MeOH, TEAB; (e) (EtO)2P(O)CH2P(O)(OEt)Cl, DIPEA, CH2Cl2; (f) H2, Pd(OH)2/C, MeOH, THF, H2O, AcOH. TEAB, aqueous triethylammonium bicarbonate; Bn, benzyl. Yields are shown in respect of each step. Stereogenic phosphorus atoms are indicated by an asterisk.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4643724&req=5

sch1: Synthesis of 1 and 2. Reagents and conditions: (a) EDAC, 4, CH2Cl2; (b) H2, Pd(OH)2/C, MeOH, H2O; (c) i. (BnO)2PNPri2, 5-phenyl-1H-tetrazole, CH2Cl2; ii. mCPBA, CH2Cl2; (d) i. TMSBr, CH2Cl2; ii. MeOH, TEAB; (e) (EtO)2P(O)CH2P(O)(OEt)Cl, DIPEA, CH2Cl2; (f) H2, Pd(OH)2/C, MeOH, THF, H2O, AcOH. TEAB, aqueous triethylammonium bicarbonate; Bn, benzyl. Yields are shown in respect of each step. Stereogenic phosphorus atoms are indicated by an asterisk.
Mentions: The syntheses of 1 and 2 (Scheme 1) begins with diol (–)-3, obtained by regioselective reduction of 2,4,6-tri-O-benzyl myo-inositol orthobenzoate,19 followed by optical resolution of racemic 3via the formation of diastereoisomeric monocamphanate esters20 (see ESI† for details).‡

Bottom Line: To synthesise stabilised mimics of InsP8, the most phosphorylated inositol phosphate signalling molecule in Nature, we replaced its two diphosphate (PP) groups with either phosphonoacetate (PA) or methylenebisphosphonate (PCP) groups.Utility of the PA and PCP analogues was verified by structural and biochemical analyses of their interactions with enzymes of InsP8 metabolism.

View Article: PubMed Central - PubMed

Affiliation: Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK.

ABSTRACT
To synthesise stabilised mimics of InsP8, the most phosphorylated inositol phosphate signalling molecule in Nature, we replaced its two diphosphate (PP) groups with either phosphonoacetate (PA) or methylenebisphosphonate (PCP) groups. Utility of the PA and PCP analogues was verified by structural and biochemical analyses of their interactions with enzymes of InsP8 metabolism.

Show MeSH
Related in: MedlinePlus