Synthesis of phosphonoacetate analogues of the second messenger adenosine 5′-diphosphate ribose (ADPR)

Baszczyňski, Ondřej; Watt, Joanna M.; Rozewitz, Monika D.; Fliegert, Ralf; Guse, Andreas H.; Potter, Barry V. L.

doi:10.1039/c9ra09284f

Cited by 6 publications

(4 citation statements)

References 32 publications

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“…However, for many other inhibitors, the binding site and mechanism of inhibition are not well understood. ND [96,110] 3"-deoxy-ADPR (Removal of hydroxyl group from terminal ribose) ND [96,110] 1"-β-O-Me-2",3"-O-iPr-ADPR (Masking all hydroxyl groups on the terminal ribose) ND [96,110] α -1"-O-methyl-ADPR ND [96,111] THF-ADP ND [96,111] methyl-ADP ND [96,111] Adenosine monophosphate (AMP) 70 [112] 8-Br-cyclic ADPR (a cyclic ADPR analogue) 100 [112] Peptide inhibitor N-Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Gly-Ser-Arg-Glu-Pro-Gly-Glu-Met-Leu-Pro-Arg-Lys-Leu-Lys-Arg-Val-Leu-Arg-Gln-Glu-Phe-Trp-Val-OH (tat-M2NX) 0.40 Designed to correspond to the C-terminal NUDT9-H domain [96,103,113] Molecules identified by high throughput screening Scalaradial 0.21 Inhibits TRPM7 channels [96,114] Ethyl (3-[4-(trifluoromethyl) Mechanism does not appear to involve direct block of the channel or a reduction in ROS [119] * Classification is based in that of Zhang et al (2020) [96]. ADPR represents ADP-ribose.…”

Section: Trpm2 Channels Are Potential Pharmacological Targets For the Prevention Of Liver Injury Induced By Reactive Oxygen Speciesmentioning

confidence: 99%

TRPM2 Non-Selective Cation Channels in Liver Injury Mediated by Reactive Oxygen Species

2021

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TRPM2 channels admit Ca2+ and Na+ across the plasma membrane and release Ca2+ and Zn2+ from lysosomes. Channel activation is initiated by reactive oxygen species (ROS), leading to a subsequent increase in ADP-ribose and the binding of ADP-ribose to an allosteric site in the cytosolic NUDT9 homology domain. In many animal cell types, Ca2+ entry via TRPM2 channels mediates ROS-initiated cell injury and death. The aim of this review is to summarise the current knowledge of the roles of TRPM2 and Ca2+ in the initiation and progression of chronic liver diseases and acute liver injury. Studies to date provide evidence that TRPM2-mediated Ca2+ entry contributes to drug-induced liver toxicity, ischemia–reperfusion injury, and the progression of non-alcoholic fatty liver disease to cirrhosis, fibrosis, and hepatocellular carcinoma. Of particular current interest are the steps involved in the activation of TRPM2 in hepatocytes following an increase in ROS, the downstream pathways activated by the resultant increase in intracellular Ca2+, and the chronology of these events. An apparent contradiction exists between these roles of TRPM2 and the role identified for ROS-activated TRPM2 in heart muscle and in some other cell types in promoting Ca2+-activated mitochondrial ATP synthesis and cell survival. Inhibition of TRPM2 by curcumin and other “natural” compounds offers an attractive strategy for inhibiting ROS-induced liver cell injury. In conclusion, while it has been established that ROS-initiated activation of TRPM2 contributes to both acute and chronic liver injury, considerable further research is needed to elucidate the mechanisms involved, and the conditions under which pharmacological inhibition of TRPM2 can be an effective clinical strategy to reduce ROS-initiated liver injury.

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Section: Trpm2 Channels Are Potential Pharmacological Targets For the Prevention Of Liver Injury Induced By Reactive Oxygen Speciesmentioning

confidence: 99%

TRPM2 Non-Selective Cation Channels in Liver Injury Mediated by Reactive Oxygen Species

2021

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“…has made brilliant contributions to the identification of these NAD + metabolites as these ion channels activators/regulators, which have been cited above. More importantly, based on the fact that these ion channels have been regarded as new cancer therapeutic targets, Professor Potter has designed and synthesized a series of ligands/inhibitors of these calcium channels [ 72 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 ], which certainly play critical roles in the development of anti-cancer drugs targeting these ion channels. In addition, some potassium and sodium channels can also be activated by NAD + and its metabolites, and there are also some calcium channels whose activity can be indirectly affected by NAD + and its metabolites.…”

Section: Conclusion and Expectationmentioning

confidence: 99%

Roles of NAD+ and Its Metabolites Regulated Calcium Channels in Cancer

Cai

Liang

et al. 2020

Molecules

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Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor for redox enzymes, but also moonlights as a regulator for ion channels, the same as its metabolites. Ca2+ homeostasis is dysregulated in cancer cells and affects processes such as tumorigenesis, angiogenesis, autophagy, progression, and metastasis. Herein, we summarize the regulation of the most common calcium channels (TRPM2, TPCs, RyRs, and TRPML1) by NAD+ and its metabolites, with a particular focus on their roles in cancers. Although the mechanisms of NAD+ metabolites in these pathological processes are yet to be clearly elucidated, these ion channels are emerging as potential candidates of alternative targets for anticancer therapy.

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“…Further studies on the structure–activity relationship of ADPR followed, showing a critical role for OH-groups at C1”, C2” and C3” at the terminal ribose for agonist properties of ADPR [ 36 ] and demonstrating again that replacement of the pyrophosphate bridge, here replacement by a phosphonoacetate linker, resulted in the loss of any biological or pharmacological activity [ 37 ].…”

Section: Adenosine Diphospho-ribose (Adpr) and 2′-deoxy-adpr (2dadmentioning

confidence: 99%

25 Years of Collaboration with A Genius: Deciphering Adenine Nucleotide Ca2+ Mobilizing Second Messengers Together with Professor Barry Potter

Guse

2020

Molecules

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Ca2+-mobilizing adenine nucleotide second messengers cyclic adenosine diphosphoribose, (cADPR), nicotinic acid adenine dinucleotide phosphate (NAADP), adenosine diphosphoribose (ADPR), and 2′deoxy-ADPR were discovered since the late 1980s. They either release Ca2+ from endogenous Ca2+ stores, e.g., endoplasmic reticulum or acidic organelles, or evoke Ca2+ entry by directly activating a Ca2+ channel in the plasma membrane. For 25 years, Professor Barry Potter has been one of the major medicinal chemists in this topical area, designing and contributing numerous analogues to develop structure–activity relationships (SAR) as a basis for tool development in biochemistry and cell biology and for lead development in proof-of-concept studies in disease models. With this review, I wish to acknowledge our 25-year-long collaboration on Ca2+-mobilizing adenine nucleotide second messengers as a major part of Professor Potter’s scientific lifetime achievements on the occasion of his retirement in 2020.

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Synthesis of phosphonoacetate analogues of the second messenger adenosine 5′-diphosphate ribose (ADPR)

Abstract: Pyrophosphate replacement using phosphonoacetate isosteres – tools to study biological targets of ADPR.

Cited by 6 publications

References 32 publications

TRPM2 Non-Selective Cation Channels in Liver Injury Mediated by Reactive Oxygen Species

TRPM2 Non-Selective Cation Channels in Liver Injury Mediated by Reactive Oxygen Species

Roles of NAD+ and Its Metabolites Regulated Calcium Channels in Cancer

25 Years of Collaboration with A Genius: Deciphering Adenine Nucleotide Ca2+ Mobilizing Second Messengers Together with Professor Barry Potter

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