Synthesis of 7-Deaza-cyclic Adenosine-5′-diphosphate-carbocyclic-ribose and Its 7-Bromo Derivative as Intracellular Ca²⁺-Mobilizing Agents

Abstract

Cyclic ADP-carbocyclic-ribose (cADPcR, 3) is a biologically and chemically stable equivalent of cyclic ADP-ribose (cADPR, 1), a Ca(2+)-mobilizing second messenger. We became interested in the biological activity of the 7-deaza analogues of cADPcR, i.e., 7-deaza-cADPcR (7) and its 7-bromo derivative, i.e., 7-deaza-7-Br-cADPcR (8), because 7-deazaadenosine is an efficient bioisostere of adenosine. The synthesis of 7 and 8 required us to construct the key N1-carbocyclic-ribosyl-7-deazaadenosine structure. Therefore, we developed a general method for preparing N1-substituted 7-deazaadenosines by condensing a 2,3-disubstituted pyrrole nucleoside with amines. Using this method, we prepared the N1-carbocyclic ribosyl 7-deazaadenosine derivative 10a, from which we then synthesized the target 7-deaza-cADPcR (7) via an Ag(+)-promoted intramolecular condensation to construct the 18-membered pyrophosphate ring structure. The corresponding 7-bromo derivative 8, which was the first analogue of cADPR with a substitution at the 7-position, was similarly synthesized. Biological evaluation for Ca(2+)-mobilizing activity in the sea urchin egg homogenate system indicated that 7-deaza-cADPcR (7) and 7-deaza-7-Br-cADPcR (8) acted as a full agonist and a partial agonist, respectively.

Synthesis of 8-(1,2,3-triazol-1-yl)-7-deazapurine nucleosides by azide–alkyne click reactions and direct C H bond functionalization

“…Synthetic transformations, biological activities and physicochemical properties of 7-deazapurine derivatives (mainly tubercidin, toyocamycin, and sangivamycin antibiotics) have been extensively studied 1–9 and are subject of the excellent reviews. 10–12 In recent years 7-deazapurine nucleosides have been explored as substrates for 1,4-regioselective copper-catalyzed azide/alkyne cycloaddition (CuAAC), which resulted in developing fluorogenic DNA probes.…”

Cyclic ADP-Carbocyclic-Ribose and -4-Thioribose, as Stable Mimics of Cyclic ADP-Ribose, a Ca²⁺-Mobilizing Second Messenger

“…The chemical synthetic method is now generally employed for synthesizing these types of biologically important cyclic nucleotides particularly those chemically modified in the N-1-linked ribose moiety, which are not expected to be accessible by an enzymatic route. [55][56][57][58][59][60][61][62][63][64][65][66] …”

Safety issues of compounds acting on adenosinergic signalling

“…Evidence also supports the indirect pathway of bronchi contraction by stimulating mastocytes and nerves to release leukotrienes, histamine and other mediators . Effective intracellular Ca 2+ ‐mobilizing compounds are 7‐deazaadenosine derivatives of cyclic ADP‐ribose and its congeners . They act as second messengers, similar as cAMP …”

“…[109] Effective intracellular Ca 2+ -mobilizing compounds are 7-deazaadenosine derivatives of cyclic ADP-ribose and its congeners. [110] They act as second messengers, similar as cAMP. [110] Other mechanisms of toxicity…”