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Contribution of phosphates and adenine to the potency of adenophostins at the IP₃ receptor: synthesis of all possible bisphosphates of adenophostin A.

Sureshan KM, Riley AM, Thomas MP, Tovey SC, Taylor CW, Potter BV - J. Med. Chem. (2012)

Bottom Line: Compound 6 is the most potent bisphosphate yet discovered with activity at IP(3)R.Thus, adenosine has a direct role independent of the 2'-phosphate group in contributing toward the potency of adenophostins, the vicinal bisphosphate motif is not essential for activity at the IP(3)R, as always thought, and it is possible to design potent agonists with just two of the three phosphates.A model with a possible adenine-R504 interaction supports the activity of 5 and 6 and also allows a reappraisal of the unexpected activity previously reported for the AdA regioisomer 2″-phospho-3″-dephospho-AdA 40.

View Article: PubMed Central - PubMed

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

ABSTRACT
Although adenophostin A (AdA), the most potent agonist of d-myo-inositol 1,4,5-trisphosphate receptors (IP(3)R), is thought to mimic IP(3), the relative roles of the different phosphate groups and the adenosine motif have not been established. We synthesized all three possible bisphosphate analogues of AdA and glucose 3,4-bisphosphate (7, AdA lacking the 2'-AMP). 2'-Dephospho-AdA (6) was prepared via a novel regioselective dephosphorylation strategy. Assessment of the abilities of these bisphosphates to stimulate intracellular Ca(2+) release using recombinant rat type 1 IP(3)R (IP(3)R1) revealed that 6, a mimic of Ins(4,5)P(2), is only 4-fold less potent than IP(3), while 7 is some 400-fold weaker and even 3″-dephospho-AdA (5) is measurably active, despite missing one of the vicinal bisphosphate groups normally thought to be crucial for IP(3)-like activity. Compound 6 is the most potent bisphosphate yet discovered with activity at IP(3)R. Thus, adenosine has a direct role independent of the 2'-phosphate group in contributing toward the potency of adenophostins, the vicinal bisphosphate motif is not essential for activity at the IP(3)R, as always thought, and it is possible to design potent agonists with just two of the three phosphates. A model with a possible adenine-R504 interaction supports the activity of 5 and 6 and also allows a reappraisal of the unexpected activity previously reported for the AdA regioisomer 2″-phospho-3″-dephospho-AdA 40.

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Synthesis of 4″-Dephospho-adenophostin A (4)Reagents and conditions:(a)BnBr, NaH, DMF, 0 °C–room temperature, 2 h. (b) 80% aqueousHOAc, reflux, 1 h. (c) Bu2SnO, BnBr, Bu4NBr,MeCN, 3 Å molecular sieves, reflux, 24 h. (d) Bu4NHSO4, BnBr, DCM: 5% aqueous NaOH (1:1), room temperature. (e)Ac2O, pyr, room temperature, 12 h. (f) Compound 16, NIS, TMSOTf, dioxane:toluene (3:1 v/v), 3 Å molecular sieves,room temperature, 30 min. (g) 90% TFA, room temperature, 15 min. (h)Ac2O, pyr, room temperature, 3 h. (i) 6-Chloropurine, BSA,TMSOTf, MeCN, 70 °C, overnight. (j) NH3, EtOH, 70°C, 5 days. (k) (1) (BnO)2PN(iPr)2, ImOTf,DCM, room temperature, 30 min; (2) mCPBA, −78 °C–roomtemperature, 1 h. (l) Cyclohexene, Pd(OH)2, MeOH, H2O, 80 °C, overnight.
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sch1: Synthesis of 4″-Dephospho-adenophostin A (4)Reagents and conditions:(a)BnBr, NaH, DMF, 0 °C–room temperature, 2 h. (b) 80% aqueousHOAc, reflux, 1 h. (c) Bu2SnO, BnBr, Bu4NBr,MeCN, 3 Å molecular sieves, reflux, 24 h. (d) Bu4NHSO4, BnBr, DCM: 5% aqueous NaOH (1:1), room temperature. (e)Ac2O, pyr, room temperature, 12 h. (f) Compound 16, NIS, TMSOTf, dioxane:toluene (3:1 v/v), 3 Å molecular sieves,room temperature, 30 min. (g) 90% TFA, room temperature, 15 min. (h)Ac2O, pyr, room temperature, 3 h. (i) 6-Chloropurine, BSA,TMSOTf, MeCN, 70 °C, overnight. (j) NH3, EtOH, 70°C, 5 days. (k) (1) (BnO)2PN(iPr)2, ImOTf,DCM, room temperature, 30 min; (2) mCPBA, −78 °C–roomtemperature, 1 h. (l) Cyclohexene, Pd(OH)2, MeOH, H2O, 80 °C, overnight.


Contribution of phosphates and adenine to the potency of adenophostins at the IP₃ receptor: synthesis of all possible bisphosphates of adenophostin A.

Sureshan KM, Riley AM, Thomas MP, Tovey SC, Taylor CW, Potter BV - J. Med. Chem. (2012)

Synthesis of 4″-Dephospho-adenophostin A (4)Reagents and conditions:(a)BnBr, NaH, DMF, 0 °C–room temperature, 2 h. (b) 80% aqueousHOAc, reflux, 1 h. (c) Bu2SnO, BnBr, Bu4NBr,MeCN, 3 Å molecular sieves, reflux, 24 h. (d) Bu4NHSO4, BnBr, DCM: 5% aqueous NaOH (1:1), room temperature. (e)Ac2O, pyr, room temperature, 12 h. (f) Compound 16, NIS, TMSOTf, dioxane:toluene (3:1 v/v), 3 Å molecular sieves,room temperature, 30 min. (g) 90% TFA, room temperature, 15 min. (h)Ac2O, pyr, room temperature, 3 h. (i) 6-Chloropurine, BSA,TMSOTf, MeCN, 70 °C, overnight. (j) NH3, EtOH, 70°C, 5 days. (k) (1) (BnO)2PN(iPr)2, ImOTf,DCM, room temperature, 30 min; (2) mCPBA, −78 °C–roomtemperature, 1 h. (l) Cyclohexene, Pd(OH)2, MeOH, H2O, 80 °C, overnight.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3285137&req=5

sch1: Synthesis of 4″-Dephospho-adenophostin A (4)Reagents and conditions:(a)BnBr, NaH, DMF, 0 °C–room temperature, 2 h. (b) 80% aqueousHOAc, reflux, 1 h. (c) Bu2SnO, BnBr, Bu4NBr,MeCN, 3 Å molecular sieves, reflux, 24 h. (d) Bu4NHSO4, BnBr, DCM: 5% aqueous NaOH (1:1), room temperature. (e)Ac2O, pyr, room temperature, 12 h. (f) Compound 16, NIS, TMSOTf, dioxane:toluene (3:1 v/v), 3 Å molecular sieves,room temperature, 30 min. (g) 90% TFA, room temperature, 15 min. (h)Ac2O, pyr, room temperature, 3 h. (i) 6-Chloropurine, BSA,TMSOTf, MeCN, 70 °C, overnight. (j) NH3, EtOH, 70°C, 5 days. (k) (1) (BnO)2PN(iPr)2, ImOTf,DCM, room temperature, 30 min; (2) mCPBA, −78 °C–roomtemperature, 1 h. (l) Cyclohexene, Pd(OH)2, MeOH, H2O, 80 °C, overnight.
Bottom Line: Compound 6 is the most potent bisphosphate yet discovered with activity at IP(3)R.Thus, adenosine has a direct role independent of the 2'-phosphate group in contributing toward the potency of adenophostins, the vicinal bisphosphate motif is not essential for activity at the IP(3)R, as always thought, and it is possible to design potent agonists with just two of the three phosphates.A model with a possible adenine-R504 interaction supports the activity of 5 and 6 and also allows a reappraisal of the unexpected activity previously reported for the AdA regioisomer 2″-phospho-3″-dephospho-AdA 40.

View Article: PubMed Central - PubMed

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

ABSTRACT
Although adenophostin A (AdA), the most potent agonist of d-myo-inositol 1,4,5-trisphosphate receptors (IP(3)R), is thought to mimic IP(3), the relative roles of the different phosphate groups and the adenosine motif have not been established. We synthesized all three possible bisphosphate analogues of AdA and glucose 3,4-bisphosphate (7, AdA lacking the 2'-AMP). 2'-Dephospho-AdA (6) was prepared via a novel regioselective dephosphorylation strategy. Assessment of the abilities of these bisphosphates to stimulate intracellular Ca(2+) release using recombinant rat type 1 IP(3)R (IP(3)R1) revealed that 6, a mimic of Ins(4,5)P(2), is only 4-fold less potent than IP(3), while 7 is some 400-fold weaker and even 3″-dephospho-AdA (5) is measurably active, despite missing one of the vicinal bisphosphate groups normally thought to be crucial for IP(3)-like activity. Compound 6 is the most potent bisphosphate yet discovered with activity at IP(3)R. Thus, adenosine has a direct role independent of the 2'-phosphate group in contributing toward the potency of adenophostins, the vicinal bisphosphate motif is not essential for activity at the IP(3)R, as always thought, and it is possible to design potent agonists with just two of the three phosphates. A model with a possible adenine-R504 interaction supports the activity of 5 and 6 and also allows a reappraisal of the unexpected activity previously reported for the AdA regioisomer 2″-phospho-3″-dephospho-AdA 40.

Show MeSH
Related in: MedlinePlus