Synthesis of dimeric analogs of adenophostin A that potently evoke Ca²⁺release through IP₃receptors

Abstract

Syntheses and Ca2+ release potentials of four dimeric analogs of adenophostin A (AdA) through activation of type 1 IP3R are reported. These analogs are full agonists of IP3R and are equipotent to AdA, the most potent agonist of IP3R.

d-chiro-Inositol Ribophostin: A Highly Potent Agonist of d-myo-Inositol 1,4,5-Trisphosphate Receptors: Synthesis and Biological Activities

“…This is supported by mutagenesis data. 12 The N6 position can be modified with little effect on activity 21 and, while substantial modifications to the adenine base are tolerated, 16,17,41 a bicyclic ring system is preferred. The two sugar hydroxymethyl groups are not important for potent activity, and ribose 2′-phosphate, while not critical, mimics the 1-phosphate of Ins(1,4,5)P 3 .…”

“…3-O-Benzyl Diastereoisomer (15). (17). A mixture of the 2-O-benzyl derivative (16, 184 mg, 0.234 mmol) and DDQ (188 mg, 0.825 mmol) was stirred in dichloromethane (9.5 mL) and water (0.5 mL) for 1 h after which a salmoncolored precipitate was observed.…”

“…10-fold more potent than Ins­(1,4,5)­P 3 in evoking Ca 2+ release through each of the three mammalian Ins­(1,4,5)­P 3 R subtypes (Ins­(1,4,5)­P 3 R1–3) . Their structure has inspired much synthetic work by us − and others − and provided numerous ligands with modifications at the phosphate groups, nucleobase motif, and at both sugars. ,, However, the bisphosphorylated glucose moiety that is thought to mimic the key Ins­(1,4,5)­P 3 pharmacophore has never been replaced by a cyclitol bisphosphate structure until very recently . Here, the glucose motif of adenophostin A was replaced with d - chiro -inositol and thus the pyranose–furanose disaccharide linkage was replaced with a sec–sec ether to give d - chiro -inositol adenophostin 4 , which is nearly 2-fold more potent than adenophostin A …”

Inositol Adenophostin: Convergent Synthesis of a Potent Agonist of d-myo-Inositol 1,4,5-Trisphosphate Receptors

“…PMB Removal Model Reaction: DL-1,4-Di-O-Benzyl-2,3-Oisopropylidene-myo-inositol (33). To a solution of 45 (60 mg, 0.115 mmol) in anhydrous DCM (5 mL) was added a solution of TFA (0.5 mL) in anhydrous DCM (0.5 mL).…”

“…Dimer analogues (Figure 4, compound 20) are broadly equipotent to AdA. 33 SAR and modeling studies suggest the potential for enhanced binding of the adenine ring with Arg504 in the IBC through a cation−π interaction (Figure 2b). 15,34 Studies with a mutated IP 3 R1 with Arg504 replaced by glutamine revealed reduced activity for both IP 3 and AdA; however, the detrimental effect is more marked for AdA than for IP 3 (353fold vs 13-fold 17 ).…”