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Mar Drugs
2018 Mar 10;163:. doi: 10.3390/md16030089.
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Synthesis and Biological Evaluation of a New Structural Simplified Analogue of cADPR, a Calcium-Mobilizing Secondary Messenger Firstly Isolated from Sea Urchin Eggs.
D'Errico S
,
Borbone N
,
Catalanotti B
,
Secondo A
,
Petrozziello T
,
Piccialli I
,
Pannaccione A
,
Costantino V
,
Mayol L
,
Piccialli G
,
Oliviero G
.
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Herein, we reported on the synthesis of cpIPP, which is a new structurally-reduced analogue of cyclic ADP-ribose (cADPR), a potent Ca2+-releasing secondary messenger that was firstly isolated from sea urchin eggs extracts. To obtain cpIPP the "northern" ribose of cADPR was replaced by a pentyl chain and the pyrophosphate moiety by a phophono-phosphate anhydride. The effect of the presence of the new phosphono-phosphate bridge on the intracellular Ca2+ release induced by cpIPP was assessed in PC12 neuronal cells in comparison with the effect of the pyrophosphate bridge of the structurally related cyclic N1-butylinosine diphosphate analogue (cbIDP), which was previously synthesized in our laboratories, and with that of the linear precursor of cpIPP, which, unexpectedly, revealed to be the only one provided with Ca2+ release properties.
Figure 1. Some representative cyclic ADP-ribose (cADPR) analogues.
Scheme 1. Reagents and conditions. (i) ref. [37]; (ii) NaH, HPO(OtBu)2, DMF, 0 °C, 16 h; (iii) TBAF, THF, r.t., 2 h; (iv) mesyl chloride (MsCl), TEA, CH2Cl2, 0 °C, 1 h; (v) KI, DMF, 70 °C, 5 h.
Scheme 2. Reagents and conditions. (i) 19, K2CO3, DMF, r.t., 16 h; (ii) TBAF, THF, r.t., 1 h; (iii) (a) (tBuO)2PN(iPr)2, 1-H-tetrazole, THF, r.t., 4 h, (b) tBuOOH, THF, r.t., 1 h; (iv) 5% TFA in CH2Cl2, 0 °C, 5 h; (v) 50% TFA in H2O, r.t., 4 h; (vi) EDC, DMF, r.t., 72 h.; (vii) 60% HCO2H in H2O, r.t., 16 h.
Figure 3. Side (left) and top (right) view of the lowest energy conformers of cbIDP (10, grey), cpIDP (11, pink) and cpIPP (13, green) superimposed on the hypoxanthine ring. Non-polar hydrogens were omitted for sake of clarity. Oxygens were reported in red, nitrogens in blue, phosphates in magenta, hydrogens in white.
Figure 4. Definition of the geometrical descriptors. d1: distance between O6 purine atom and P atom of the southern phosphate; d2: distance between N3 purine atom and P atom of the southern phosphate; d3: distance between N3 purine atom and P atom of the northern phosphate/phosphonate.
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