Next Article in Journal
Antiphytoviral Activity of Sesquiterpene-Rich Essential Oils from Four Croatian Teucrium Species
Previous Article in Journal
Enzymatic Kinetic Resolution of tert-Butyl 2-(1-Hydroxyethyl)phenylcarbamate, A Key Intermediate to Chiral Organoselenanes and Organotelluranes
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 16
Issue 9
10.3390/molecules16098110
molecules-logo
Submit to this Journal Review for this Journal Edit a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Solid-Phase Synthesis of a New Diphosphate 5-Aminoimidazole-4-carboxamide Riboside (AICAR) Derivative and Studies toward Cyclic AICAR Diphosphate Ribose

by 1,
Giorgia Oliviero
1,2,*, 1, 1, 3, 1, 1 and 1,2
1
Dipartimento di Chimica delle Sostanze Naturali, Università degli Studi di Napoli Federico II, Via D. Montesano, 49, 80131, Napoli, Italy
2
Facoltà di Scienze Biotecnologiche, Università degli Studi di Napoli Federico II, Via D. Montesano, 49, 80131, Napoli, Italy
3
Dipartimento di Chimica Organica e Biochimica, Università degli Studi di Napoli Federico II, Via Cynthia, 4, 80126, Napoli, Italy
*
Author to whom correspondence should be addressed.
Molecules 2011, 16(9), 8110-8118; https://doi.org/10.3390/molecules16098110
Received: 1 August 2011 / Revised: 9 September 2011 / Accepted: 13 September 2011 / Published: 21 September 2011
Browse Figures
Versions Notes

Abstract

:
The solid-phase synthesis of the first example of a new diphosphate AICAR derivative is reported. The new substance is characterized by the presence of a 5'-phosphate group while a second phosphate moiety is installed on a 5-hydroxypentyl chain attached to the 4-N-position of AICAR. Cyclization of the diphosphate derivative by pyrophosphate bond formation allowed for the formation of a novel AICAR-based cyclic ADP-ribose (cADPR) mimic.

Graphical Abstract

1. Introduction

Modified nucleosides and nucleotides are among the most studied biomolecules due to their numerous biological and pharmacological applications. Apart from being the genomic building blocks, nucleosides interact with roughly one-third of the protein classes in the human genome, including polymerases, kinases, reductases, motor proteins, membrane receptors, and structural proteins, all targets of biological importance.
Many nucleoside analogues are currently used as antiviral [1,2], antineoplastic [3,4,5,6] and antifungal [7,8,9] agents. Numerous nucleoside derivatives interact with enzymes such as CD38 [10] or 5'-AMP-activated protein kinase (AMPK), playing a key role in the signal transduction or regulation of energy metabolism. In particular, 5-aminoimidazole-4-carboxamide riboside (AICAR, Figure 1) activates the AMPK pathway in skeletal muscle, adipocytes and hepatocytes [11,12,13]. The adipocytes and adipose tissue-derived macrophages release a variety of pro-inflammatory cytokines and chemokines including tumor necrosis factor alpha (TNF alpha), interleukin-6 and interleukin-8, the production of which is enhanced in the obese state [11,12,13]. Moreover, recent studies indicate that stimulation of the AMPK system by AICAR in type 2 diabetic patients reduces plasma glucose and NEFA (non-esterified fatty acids) [14]. Furthermore, AICAR has been indicated as a promising prodrug, which induces benefits in patients suffering from autism, cerebral palsy, insomnia, schizophrenia, and other neuropsychiatric symptoms generally associated to chronic low levels of adenosine [15].
Molecules 16 08110 g001 550
Figure 1. Structures of AICAR and cADPR.
Figure 1. Structures of AICAR and cADPR.
Molecules 16 08110 g001
However, AICAR has a short half-life in the cell [16], it does not efficiently cross the blood–brain barrier and is poorly adsorbed from the gastrointestinal tract. Consequently, the production of new AICAR derivatives is an appealing objective in the field of medicinal chemistry. In recent years, the syntheses of a number of AICAR derivatives, such as the 2-aryl-, 4-N-benzyl-, 4-substituted-, 5-substituted-, 5-hydroxyl- (bredinin), triazolyl-riboside- (ribavirin), and 2′,3′-secoriboside derivatives, have been reported in the literature [17]. AICAR is phosphorylated in the cell at the 5′-position to produce AICAR 5′-monophosphate (ZMP) which in turn is expected to possess higher activity than AICAR in AMPK activation. On these grounds we decided to synthesise a new type of AICAR derivative embodying two phosphate groups using a solid-phase strategy recently developed in our laboratories to prepare ZMP [18] and some 4-N-alkyl AICA-ribotides [17].
Furthermore, the presence of two fully deprotected phosphate groups allowed us to prepare an unprecedented mimic of cyclic ADP-ribose (cADPR, Figure 1) in which 5-aminoimidazole-4-carboxamide was constructed instead of the adenine moiety and the northern ribose was replaced by a hydroxypentyl chain. The cADPR analogue was obtained by the cyclization of the corresponding linear precursor once detached from its respective solid support.

2. Results and Discussion

In a previous study we described the solid-phase synthesis of a number of 4-N-alkyl derivatives of ZMP through the pyrimidine ring degradation of suitable 5'-phosphate inosine precursors [18]. As a further extension of this strategy, we report here the synthesis of the new diphosphate AICAR derivative 6 (Scheme 1) carrying phosphate groups at both the 5'-position and on a 5-hydroxypentyl chain bonded to the 4-N-position of AICAR.
Molecules 16 08110 g002 550
Scheme 1. Preparation of compounds 4 and 6-8.
Scheme 1. Preparation of compounds 4 and 6-8.
Molecules 16 08110 g002
The proposed solid-phase procedure can be easily extended to the preparation of further analogues of the same class simply by modulating the 4-N-alkyl chain length. In addition, we also report preliminary studies toward the intramolecular cyclization of the diphosphate 6 by pyrophosphate bond formation, leading to 8. The synthesised cyclic diphosphate AICAR analogue 8 can be seen as a new mimic of cADPR, an endogenous metabolite that regulates the Ca2+-mobilization via ryanodine receptors (RyR) in various cell types [19,20,21,22,23,24,25,26]. It could also represent a useful molecule for studying the structure-activity relationships of cADPR analogues and exploring the cADPR/RyR Ca2+ signalling system.
Our synthetic procedure uses solid support 2 (0.7 mmol/g) (Scheme 1) carrying the N-1-(5-hydroxypentyl)inosine bound to a polystyrene resin through a 2',3'-benzylidene linker. Support 2 was prepared according to a procedure previously developed in our laboratories [18,29,30,31] and then converted into the bis-protected diphosphate support 3a by treatment with bis-(2-cyanoethyl)-N,N'-diisopropylphosphoramidite [(iPr)2NP(OCE)2] in the presence of tetrazole, followed by oxidation with t-butyl hydroperoxide (t-BuOOH).
The successive treatment of support 3a with ethanolic NaOH failed to give the desired AICAR diphosphate derivative 5a through the expected degradation of the pyrimidine ring. We hypothesize that the basic treatment [18] produces the fast loss of the cyanoethyl protecting groups and the negative charges generated on the phosphates prevent the nucleophilic attack of the hydroxyl ion to the electron-deficient C-2 purine carbon, the first step in the six-membered ring degradation [17,30]. This reduced reactivity of C-2 when flanked by a 5'-phosphate confirmes our previous results obtained during the synthesis of ZMP starting from AICAR [18]. Therefore, we used the commercially available bis-trimethylsilylethoxy-N,N'-diisopropylphosphoramidite [31] [(iPr)2NP(OTMSEt)2], in which the base-stable TMSEt groups can be removed by fluoride ions or trifluoroacetic acid treatment, for the synthesis of the compounds 4 and 6. According to this strategy, reaction of 2 with [(iPr)2NP(OTMSEt)2] in THF, in the presence of tetrazole afforded support 3b in high yields after the usual phosphite oxidation with t-BuOOH. The reaction yields of the bis-phosphorylation steps, leading to 3a or 3b, were evaluated analyzing the inosine diphosphate derivative 4 released from a weighted amount of the resins 3a and 3b.
In particular, for 3b the acid treatment assured the complete deprotection of both phosphates as well as the release of the nucleotidic material from the resin. In the case of 3a ammonia treatment was needed to remove all of the 2-cyanoethyl phosphate protecting groups before the acid treatment. In both cases the bis-phosphorylation yields were in the 90–92% range (from 2). Spectral data for 4 (from 3b) were in full agreement with those previously reported [29]. Support 3b was successively treated with ethanolic NaOH to give the AICAR diphosphate support 5b. Acid treatment of 5b with 2% trifluoroacetic acid (TFA) in DCM eventually provided the diphosphate AICAR derivative 6 with 69% yield (from 2), the structure of which was confirmed by spectroscopic data (see Experimental). 31P-NMR data (δP singlets at 1.85 and 1.71) confirmed the presence of two phosphomonoester functions in 6. Next, the intramolecular cyclization of 6 by pyrophosphate bond formation was addressed. To this end, the diphosphate derivative 6 was converted in 80% yield into 2',3'-isopropylidene derivative 7, by reaction with dimethoxypropane (DMP) in the presence of catalytic amounts of p-toluenesulfonic acid (p-TsOH) in DMF. Subsequently, we focused on the cyclization step. In the first attempts, 1-ethyl-3-(3-(dimethylamino)propyl) carbodiimide hydrochloride (EDC) [32] and 1,3-dicyclohexylcarbodiimide (DCC) [33,34,35], which have been successfully used in previous instances for the pyrophosphate bond formation, were employed. Disappointingly, in our case both these reagents only gave a complex mixture of products (HPLC profiles) among which no cyclization product could be detected by NMR and mass spectral analyses. We eventually succeeded in obtaining the desired cyclic compound 8 (20% yield) by using 1,1'-carbonyldiimidazole (CDI) (5.0 equiv. in DMF) [36]. Compound 8 was purified by HPLC on a reverse-phase C-18 column and its structure was confirmed by NMR and HRESI-MS data.

3. Experimental

3.1. General

4-Methoxytrityl chloride resin (MMTCl, 1% divinylbenzene, 200–400 mesh, 1.3 mmol/g loading) was purchased from CBL (Greece). All reagents were obtained from commercial sources (Sigma-Aldrich, Germany) and were used without further purification. The reactions on solid phase were performed using glass columns (10 mm diameter, 100 mm length) with fused-in sintered glass-disc PO (bore of plug 2.5 mm), which were shaken in an orbital shaker, or in round-bottomed flasks, when reactions required high temperatures. 1H-NMR spectra were recorded on a Varian Mercury Plus 400 MHz in D2O solvent. 31P-NMR were recorded on a Varian Unity Inova 500 MHz instrument in D2O solvent using 85% H3PO4 as an external standard (0 ppm). Chemical shifts are reported in parts per million (δ) relative to the residual solvent signals: D2O 4.80 for 1H-NMR. The abbreviations s, bs, d, dd and m stand for singlet, broad singlet, doublet, doublet of doublets and multiplet, respectively. High performance liquid chromatography (HPLC) analyses and purifications were carried out on a Jasco UP-2075 Plus pump equipped with a Jasco UV-2075 Plus UV detector using a 4.8 × 150 mm C-18 reverse-phase column (particle size 5 µm) eluted with a linear gradient of CH3CN in 0.1 M triethylammonium bicarbonate (TEAB) buffer, pH = 7.0 (from 0 to 100% in 120 min, flow 1.4 mL/min). UV spectra were recorded on a Jasco V-530 UV spectrophotometer. High Resolution MS spectra were recorded on a Bruker APEX II FT-ICR (9.4 T) mass spectrometer using electrospray ionization (ESI) in negative mode. Analytical TLC analyses were performed using F254 silica gel plates (0.2 mm, Merck). TLC spots were detected under UV light (254 nm).

3.2. Preparation of Solid Supports 3b

Solid support 2 (0.10 g, 0.070 mmol), swollen in dry THF, was treated with (iPr)2NP(OTMSEt)2 (0.3 g, 0.8 mmol) and tetrazole (0.09 g, 1.3 mmol) in dry THF/DCM (9:1, 2.5 mL) and shaken for 15 h at room temperature. Then the resin was filtered and the solid support was washed with THF (3 × 5 mL), THF/MeOH (1:1, 3 × 5 mL) and MeOH (3 × 5 mL) and finally dried under vacuum. The resin was treated with t-BuOOH (5.5 M in decane, 0.4 mL, 2.4 mmol) in THF (2.5 mL) for 2.5 h at room temperature and then washed with THF (3 × 5 mL), THF/MeOH (1:1, 3 × 5 mL), MeOH (3 × 5 mL) and finally dried under vacuum to give 3b (136 mg). The bis-phosphorylation yield was calculated by detaching the nucleotidic material from a weighted amount of resin 3b with 2% TFA in DCM for 20 min at room temperature (H2O washings collected) and analyzing the crude material by HPLC. From 20 mg of resin 3b, 6.9 mg of 4 (92% yield from 2) as bis-triethylammonium salt were obtained.

3.3. Preparation of Solid Support 5b

Resin 3b (0.10 g, 0.047 mmol) was suspended in a 5 M solution of NaOH in EtOH (2 mL) for 5 h at reflux. The resin was cooled, filtered and washed with EtOH (3 × 5 mL), EtOH/H2O (1:1, 3 × 5 mL), EtOH (3 × 5 mL) and then dried under reduced pressure, affording 5b (99 mg). The reaction yield was calculated by detaching the nucleotidic material from a weighted amount of resin 5b with 2% TFA in DCM for 20 min at room temperature (H2O washings collected) and analyzing the crude by HPLC. From 20 mg of resin 5b, 4.9 mg of 6 (69% yield from 2) as bis-triethylammonium salt were obtained.
5-Amino-1-(β-D-ribofuranosyl)imidazole-4-[N-(5-O-phosphorylpentyl)]carboxamide5'-phosphate (6): White foam, bis-triethylammonium salt; 1H-NMR (400 MHz, D2O, assignments by HH-COSY) δH 7.58 (s, 1H, 4-H), 5.68 (d, J = 6.8 Hz, 1H, 1'-H), 4.66–4.61 (m, 1H, 2'-H), 4.45–4.41 (m, 1H, 3'-H), 4.36–4.31 (m, 1H, 4'-H), 4.13–4.08 (m, 2H, 5'-Ha,b), 3.93–3.85 (m, 2H, CH2O), 3.36 (t, J = 6.9 Hz, 2H, CH2N), 3.21 (q, J = 7.3 Hz, 12H, 6 × CH2, triethylammonium), 1.74-1.59 (two overlapped multiplets, 4H, 2 × CH2), 1.51-1.41 (m, 2H, CH2), 1.29 (t, J = 7.3 Hz, 18H, 6 × CH3, triethylammonium); 31P-NMR (202 MHz, D2O) δP 1.85, 1.71 (two singlets); HRESI-MS m/z 503.0956 ([M-H]−, requires 503.0950); UV (H2O) λmax 266 nm.

3.4. Synthesis of Compound 7

6 (10 mg, 0.014 mmol) was dissolved in DMF (1.0 mL). p-TsOH (catalytic amounts) and DMP (0.017 mL, 0.14 mmol) were added and the mixture was shaken at r.t. for 2 h (TLC monitoring isopropanol/NH4OH(aq)/H2O, 6:3:1). The solvents were evaporated under reduced pressure and the crude was dissolved in 1.0 mL of TEAB 0.1 M (pH = 7.0) solution and then purified by HPLC (see 2.1, General). The fractions containing the title compound were collected and evaporated under reduced pressure. The target compound was dissolved in H2O (3 × 2.0 mL) and was lyophilized three times affording 8.4 mg of pure 7 (80% yield).
5-Amino-1-(β-D-ribofuranosyl)imidazole-4-[N-(5-O-phosphorylpentyl)]carboxamide-2',3'-O-iso-propylidene 5'-phosphate (7): White foam, bis-triethylammonium salt; 1H-NMR (400 MHz, D2O, assignments by HH-COSY experiment) δH 7.60 (s, 1H, 4-H), 5.94 (d, J = 6.8 Hz, 1H, 1'-H), 5.28–5.23 (m, 1H, 2'-H), 5.13–5.09 (m, 1H, 3'-H), 4.65–4.61 (m, 1H, 4'-H), 4.07–4.01 (m, 2H, 5'-Ha,b), 3.89–3.82 (m, 2H, CH2O), 3.32 (t, J = 6.9 Hz, 2H, CH2N), 3.16 (q, J = 7.3 Hz, 12H, 6 × CH2, triethylammonium), 1.68–1.55 (complex signal, 7H, 2 × CH2, CH3), 1.46–1.37 (complex signal, 5H, CH2 and CH3), 1.24 (t, J = 7.3 Hz, 18H, 6 × CH3, triethylammonium); 31P-NMR (202 MHz, D2O) δP 1.78, 1.67 (two singlets); HRESI-MS m/z 553.1114 ([M-H]−, requires 553.1106); UV (H2O) λmax 266 nm.

3.5. Pyrophosphate Bond Formation: Synthesis of Compound 8

Compound 7 (5.0 mg, 0.0067 mmol) was dissolved in DMF (15 mL) and CDI (5.2 mg, 0.033 mmol) was added in one portion. The mixture was shaken at room temperature for 48 h. The solvent was removed under reduced pressure and the crude was dissolved in 1.0 mL of TEAB 0.1 M (pH = 7.0) solution and then purified by HPLC (see General). The fractions containing the title compound were collected and evaporated under reduced pressure. The target compound was dissolved in H2O (3 × 2.0 mL) and was lyophilized three times affording 0.84 mg of 8 (20% yield).
4-N-pentyl-cyclic AICAR-2',3'-O-isopropylidene diphosphate (8): Amorphous solid, triethylammonium salt; 1H-NMR (400 MHz, D2O, assignments by HH-COSY experiment) δH 7.45 (s, 1H, 4-H), 6.05 (bs, 1H, 1'-H), 5.68–5.62 (m, 1H, 2'-H), 5.43–5.39 (m, 1H, 3'-H), 4.61–4.58 (m, 1H, 4'-H), 3.70–3.65 (m, 2H, 5'-Ha,b), 3.85–3.79 (m, 2H, CH2O), 3.40 (m, 2H, CH2N), 3.16 (q, J = 7.4 Hz, 6H, 3 × CH2, triethylammonium), 1.65–1.58 (complex signal, 7H, 2 × CH2, CH3), 1.45–1.35 (complex signal, 5H, CH2 and CH3), 1.24 (t, J = 7.4 Hz, 9H, 3 × CH3, triethylammonium); 31P-NMR (202 MHz, D2O) δP −9.5, −10.4; HRESI-MS m/z 525.1162 ([M-H]−, requires 525.1157); UV (H2O) λmax 265 nm.

4. Conclusions

In the present study we have carried out the solid-phase synthesis of a new type of AICAR diphosphate derivative as well as its cyclization to a new AICAR-based mimic of cADPR. Work is in progress to extend our methodology to the synthesis of other analogues of both 6 and 8 by modulating the 4-N-alkyl chain length. Biological assays on the synthesised substances are in progress as well.

Acknowledgments

This work was supported by a PRIN grant 2009 from the Italian Ministero dell’Università e della Ricerca [2009J54YAP]. We would like to thank Luisa Cuorvo for her valuable technical assistance.
  • Sample Availability: Samples of the compounds 4, 6, 7, 8 are available from the authors.

References

  1. Antiviral Nucleosides: Chiral Synthesis and Chemotherapy; Chu, C.K. (Ed.) Elsevier: Amsterdam, The Netherlands, 2003.
  2. Simons, C.; Wu, Q.; Htar, T.T. Recent Advances in Antiviral Nucleoside and Nucleotide Therapeutics. Curr. Top. Med. Chem. 2005, 5, 1191–1203. [Google Scholar] [CrossRef]
  3. Lagoja, I.M. Pyrimidine as constituent of natural biologically active compounds. Chem. Biodivers. 2005, 2, 1–50. [Google Scholar] [CrossRef]
  4. Kimura, K.; Bugg, T.D.H. Recent advances in antimicrobial nucleoside antibiotics targeting cell wall biosynthesis. Nat. Prod. Rep. 2003, 20, 252–273. [Google Scholar] [CrossRef]
  5. Rachakonda, S.; Cartee, L. Challenges in antimicrobial drug discovery and the potential of nucleoside antibiotics. Curr. Med. Chem. 2004, 11, 775–793. [Google Scholar] [CrossRef]
  6. Knapp, S. Synthesis of Complex Nucleoside Antibiotics. Chem. Rev. 1995, 95, 1859–1876. [Google Scholar] [CrossRef]
  7. Miura, S.; Izuta, S. DNA polymerases as targets of anticancer nucleosides. Curr. Drug Targets 2004, 5, 191–195. [Google Scholar] [CrossRef]
  8. Parker, W.B.; Secrist, J.A.; Waud, W.R. Purine nucleoside antimetabolites in development for the treatment of cancer. Curr. Opin. Investig. Drugs 2004, 5, 592–596. [Google Scholar]
  9. Szafraniec, S.I.; Stachnick, K.J.; Skierski, J.S. New nucleoside analogs in the treatment of hematological disorders. Acta Pol. Pharm. 2004, 61, 223–232. [Google Scholar]
  10. Kitanaka, A.; Ohta, Y.; Mihara, K.; Imataki, O.; Ohnishi, H.; Tanaka, T.; Taminato, T.; Kubota, Y. Expression of CD38 with intracellular enzymatic activity: A possible explanation for the insulin release induced by intracellular cADPR. Mol. Cell. Biochem. 2011, 352, 293–299. [Google Scholar] [CrossRef]
  11. Rutter, G.A.; Silva Xavier, G.; Lecler, I. Roles of 5'-AMP-activated protein kinase (AMPK) in mammalian glucose homoeostasis. Biochem. J. 2003, 375, 1–16. [Google Scholar] [CrossRef]
  12. Lihn, A.S.; Pedersen, S.B.; Lund, S.; Richelsen, B. The anti-diabetic AMPK activator AICAR reduces IL-6 and IL-8 in human adipose tissue and skeletal muscle cells. Mol. Cell. Endocrinol. 2008, 292, 36–41. [Google Scholar] [CrossRef]
  13. Lang, C.C.; Wong, A.K.F.; Howie, J.; Petrie, J.R. AMP-activated protein kinase pathway: A potential therapeutic target in cardiometabolic disease. Clin. Sci. 2009, 116, 607–620. [Google Scholar] [CrossRef]
  14. Boon, H.; Bosselaar, M.; Praet, S.F.E.; Blaak, E.E.; Saris, W.H.M.; Wagenmakers, A.J.M.; Mcgee, S.L.; Tack, C.J.; Smits, P.; Hargreaves, M.; van Loon, L.J.C. Intravenous AICAR administration reduces hepatic glucose output and inhibits whole body lipolysis in type 2 diabetic patients. Diabetologia 2008, 51, 1893–1900. [Google Scholar] [CrossRef]
  15. Lara, D.R.; Dall’Igna, O.P.; Ghisolfi, E.S.; Brunstein, M.G. Involvement of adenosine in the neurobiology of schizophrenia and its therapeutic implications. Prog. Neuro-psychopharmacol. Biol. Psychiatry 2006, 30, 617–629. [Google Scholar] [CrossRef]
  16. Karagounis, L.G.; Hawley, J.A. The 5' adenosine monophosphate-activated protein kinase: Regulating the ebb and flow of cellular energetics. Int. J. Biochem. Cell. Biol. 2009, 41, 2360–2363. [Google Scholar] [CrossRef]
  17. Piccialli, G.; Oliviero, G.; Amato, J.; Borbone, N.; D’Errico, S.; Bucci, E.; Piccialli, V.; Mayol, L. Synthesis of 4-N-alkyl and ribose-modified AICAR analogues on solid support. Tetrahedron 2008, 64, 6475–6481, and references cited in. [Google Scholar]
  18. Piccialli, G.; Oliviero, G.; D’Errico, S.; Borbone, N.; Amato, J.; Piccialli, V.; Mayol, L. Facile Solid-Phase Synthesis of AICAR 5'-Monophosphate (ZMP) and Its 4-N-Alkyl Derivatives. Eur. J. Org. Chem. 2010, 1517–1524. [Google Scholar]
  19. Potter, B.V.L.; Walseth, T.F. Medicinal chemistry and pharmacology of cyclic ADP-ribose. Curr. Mol. Med. 2004, 4, 303–311. [Google Scholar] [CrossRef]
  20. Wagner, G.K.; Guse, A.H.; Potter, B.V.L. Rapid synthetic route toward structurally modified derivatives of cyclic adenosine 5'-diphosphate ribose. J. Org. Chem. 2005, 70, 4810–4819. [Google Scholar] [CrossRef]
  21. Xu, J.; Yang, Z.; Dammermann, W.; Zhang, L.; Guse, A.H.; Zhang, L. Synthesis and agonist activity of cyclic ADP-ribose analogues with substitution of the northern ribose by ether or alkane chains. J. Med. Chem. 2006, 49, 5501–5512. [Google Scholar] [CrossRef]
  22. Kudoh, T.; Murayama, T.; Matsuda, A.; Shuto, S. Substitution at the 8-position of 3''-deoxy-cyclic ADP-carbocyclic-ribose, a highly potent Ca2+-mobilizing agent, provides partial agonists. Bioorg. Med. Chem. 2007, 15, 3032–3040. [Google Scholar]
  23. Zhang, L.R.; Wu, H.M.; Yang, Z.J.; Zhang, L.H. Concise synthesis of novel acyclic analogues of cADPR with an ether chain as the northern moiety. New J. Chem. 2010, 34, 956–966. [Google Scholar]
  24. Huang, X.; Min, D.; Liu, J.; Zhang, K.; Yang, Z.; Zhang, L.; Zhang, L. Concise syntheses of trifluoromethylated cyclic and acyclic analogues of cADPR. Molecules 2010, 15, 8689–8701. [Google Scholar]
  25. Dong, M.; Kirchberger, T.; Huang, X.; Yang, Z.J.; Zhang, L.R.; Guse, A.H.; Zhang, L.H. Trifluoromethylated cyclic-ADP-ribose mimic: Synthesis of 8-trifluoromethyl-N(1)-[(5''-O-phosphorylethoxy)methyl]-5'-O-phosphorylinosine-5',5''-cyclic pyrophosphate (8-CF(3)-cIDPRE) and its calcium release activity in T cells. Org. Biomol. Chem. 2010, 8, 4705–4715. [Google Scholar] [CrossRef]
  26. Moreau, C.; Ashamu, G.A.; Bailey, V.C.; Galione, A.; Guse, A.H.; Potter, B.V.L. Synthesis of cyclic adenosine 5'-diphosphate ribose analogues: A C2'endo/syn "southern" ribose conformation underlies activity at the sea urchin cADPR receptor. Org. Biomol. Chem. 2011, 9, 278–290. [Google Scholar] [CrossRef]
  27. Catalanotti, B.; De Napoli, L.; Galeone, A.; Mayol, L.; Oliviero, G.; Piccialli, G.; Varra, M. Syntheses of [1-N-15]-2'-deoxyinosine, [4-N-15]-2'-deoxyAICAR, and [1-N-15]-2'-deoxyguanosine. Eur. J. Org. Chem. 1999, 2235–2239. [Google Scholar]
  28. Piccialli, G.; Oliviero, G.; Amato, J.; Borbone, N.; D’Errico, S.; Mayol, L. Synthesis of N-1 and ribose modified inosine analogues on solid support. Tetrahedron Lett. 2007, 48, 397–400. [Google Scholar] [CrossRef]
  29. Piccialli, G.; Oliviero, G.; D’Errico, S.; Borbone, N.; Amato, J.; Piccialli, V.; Varra, M.; Mayol, L. A solid-phase approach to the synthesis of N-1-alkyl analogues of cyclic inosine-diphosphate-ribose (cIDPR). Tetrahedron 2010, 66, 1931–1936. [Google Scholar] [CrossRef]
  30. Kohyama, N.; Yamamoto, Y. A facile synthesis of AICAR from inosine. Synthesis 2003, 17, 2639–2642. [Google Scholar] [CrossRef]
  31. Ross, K.C.; Rathbone, D.L.; Thomson, W.; Freeman, S. Use of bis[2-(trialkylsilyl)ethyl]N,N-dialkylphosphoramidites for the synthesis of phosphate monoesters. J. Chem. Soc. Perkin Trans. 1995, 4, 421–426. [Google Scholar]
  32. Galeone, A.; Mayol, L.; Oliviero, G.; Piccialli, G.; Varra, M. Synthesis of a new N-1-pentyl analogue of cyclic inosine diphosphate ribose (cIDPR) as a stable potential mimic of cyclic ADP ribose (cADPR). Eur. J. Org. Chem. 2002, 4234–4238. [Google Scholar]
  33. Blackburn, M. Nucleic Acids in Chemistry and Biology; Blackburn, M., Gait, M.J., Loakes, D., Williams, D.M., Eds.; RSC Publishing: Cambridge, UK, 2006. [Google Scholar]
  34. Fukuoka, M.; Shuto, S.; Minakawa, N.; Ueno, Y.; Matsuda, A. An Efficient Synthesis of Cyclic IDP- and Cyclic 8-Bromo-IDP-Carbocyclic-Riboses Using a Modified Hata Condensation Method to Form an Intramolecular Pyrophosphate Linkage as a Key Step. An Entry to a General Method for the Chemical Synthesis of Cyclic ADP-Ribose Analogues. J. Org. Chem. 2000, 65, 5238–5248. [Google Scholar] [CrossRef]
  35. Fortt, S.M.; Potter, B.V.L. An approach to a carbocyclic analogue of cyclic adenosine 5′-diphosphate ribose. The synthesis and bisphosphorylation of N1-[(1S, 3R)-3-(Hydroxymethyl)cyclopent-1-yl]inosine. Tetrahedron Lett. 1997, 38, 5371–5374. [Google Scholar] [CrossRef]
  36. Maeda, M.; Patel, A.D.; Hampton, A. Formation of ribonucleotide 2',3'-cyclic carbonates during conversion of ribonucleoside S-phosphates to diphosphates and triphosphates by the phosphorimidazolidate procedure. Nucleic Acids Res. 1977, 4, 2843–2853. [Google Scholar] [CrossRef]

Share and Cite

MDPI and ACS Style

D’Errico, S.; Oliviero, G.; Borbone, N.; Amato, J.; Piccialli, V.; Varra, M.; Mayol, L.; Piccialli, G. Solid-Phase Synthesis of a New Diphosphate 5-Aminoimidazole-4-carboxamide Riboside (AICAR) Derivative and Studies toward Cyclic AICAR Diphosphate Ribose. Molecules 2011, 16, 8110-8118. https://doi.org/10.3390/molecules16098110

AMA Style

D’Errico S, Oliviero G, Borbone N, Amato J, Piccialli V, Varra M, Mayol L, Piccialli G. Solid-Phase Synthesis of a New Diphosphate 5-Aminoimidazole-4-carboxamide Riboside (AICAR) Derivative and Studies toward Cyclic AICAR Diphosphate Ribose. Molecules. 2011; 16(9):8110-8118. https://doi.org/10.3390/molecules16098110

Chicago/Turabian Style

D’Errico, Stefano, Giorgia Oliviero, Nicola Borbone, Jussara Amato, Vincenzo Piccialli, Michela Varra, Luciano Mayol, and Gennaro Piccialli. 2011. "Solid-Phase Synthesis of a New Diphosphate 5-Aminoimidazole-4-carboxamide Riboside (AICAR) Derivative and Studies toward Cyclic AICAR Diphosphate Ribose" Molecules 16, no. 9: 8110-8118. https://doi.org/10.3390/molecules16098110

Article Metrics

Back to TopTop