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Special Issue "From Cell Signalling to Anticancer Drug Discovery: A Theme Issue in Honor of Professor Barry Potter"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (15 October 2020).

Special Issue Editors

Prof. Dr. Marie Migaud
E-Mail Website
Guest Editor
Department of Pharmacology, University of South Alabama, 1660 Springhill Ave., Mobile, AL 36604, USA
Interests: chemical biology; carbohydrate and nucleotide chemistry; organo-phosphorus chemistry; adenine-dinucleotide derived cofactors; enzyme inhibitors; vitamin B3 (niacin) metabolism and isotopic tracers
Prof. Dr. Gerd Wagner
E-Mail Website
Guest Editor
School of Pharmacy, Queen’s University Belfast, Belfast, UK
Interests: medicinal chemistry; chemical biology; carbohydrate and nucleotide chemistry; enzyme inhibitors; antimicrobial resistance; bioassays; glycobiology; drug discovery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Innovative drug discovery is often underpinned by breakthroughs in academic research. However, few successful academic researchers go on to also become successful drug discoverers. Professor Barry Potter is an outstanding example of this rare breed.

During a research career spanning over 40 years, Professor Potter has made numerous important contributions to both fundamental and translational research in medicinal chemistry, chemical biology and drug discovery. His laboratory has developed an arsenal of chemical tools that have enabled new and fundamental insights into the role of second messengers such as inositol phosphates, cyclic adenosine 5'-diphosphate ribose (cADPR), adenosine 5'-diphosphate ribose (ADPR) and nicotinic acid adenine-5'-diphosphate-2'-phosphate (NAADP) for calcium signalling.

He has also successfully used chemistry to study the key role of steroid biosynthetic enzymes in hormone-dependent cancers. This research has not only led to the identification of novel drug targets and therapeutic concepts in anti-cancer drug discovery but has also laid the foundation for the successful translation of basic science into clinical drug candidates. To date, “first-in class” agents from the Potter laboratory have been evaluated in 19 Phase I and II human clinical trials, including the steroid sulfatase inhibitor Irosustat.

Professor Potter has received numerous awards for his work, including the Medal for Chemical Biology and the Malcolm Campbell Medal from the Royal Society of Chemistry (RSC), the GlaxoSmithKline International Achievement Award, and the European Life Sciences Award. He has also held the RSC-BMCS Medicinal Chemistry Lectureship, and he is a recipient of the Tu Youyou Award in Medicinal & Natural Product Chemistry.

This Special Issue of Molecules is dedicated to Professor Potter on the occasion of his retirement. It brings together topical research across the different research areas on which Professor Potter has left an indelible mark, including synthetic nucleotide and inositol phosphate chemistry, calcium signalling, aromatase and steroid sulfatase inhibitor development, and anti-cancer drug discovery. It will serve, we hope, as an inspiration for both basic science and drug discovery.

Prof. Marie Migaud
Prof. Gerd Wagner
Guest Editors

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Keywords

  • inositol phosphate
  • cADPR
  • NAADP
  • calcium signaling
  • steroid sulfatase inhibitor
  • aromatase inhibitor
  • chemical tools
  • anti-cancer drug discovery
  • academic drug discovery

Published Papers (13 papers)

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Research

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Article
Novel Substrates for Kinases Involved in the Biosynthesis of Inositol Pyrophosphates and Their Enhancement of ATPase Activity of a Kinase
Molecules 2021, 26(12), 3601; https://doi.org/10.3390/molecules26123601 - 11 Jun 2021
Cited by 1 | Viewed by 1480
Abstract
IP6K and PPIP5K are two kinases involved in the synthesis of inositol pyrophosphates. Synthetic analogs or mimics are necessary to understand the substrate specificity of these enzymes and to find molecules that can alter inositol pyrophosphate synthesis. In this context, we synthesized four [...] Read more.
IP6K and PPIP5K are two kinases involved in the synthesis of inositol pyrophosphates. Synthetic analogs or mimics are necessary to understand the substrate specificity of these enzymes and to find molecules that can alter inositol pyrophosphate synthesis. In this context, we synthesized four scyllo-inositol polyphosphates—scyllo-IP5, scyllo-IP6, scyllo-IP7 and Bz-scyllo-IP5—from myo-inositol and studied their activity as substrates for mouse IP6K1 and the catalytic domain of VIP1, the budding yeast variant of PPIP5K. We incubated these scyllo-inositol polyphosphates with these kinases and ATP as the phosphate donor. We tracked enzyme activity by measuring the amount of radiolabeled scyllo-inositol pyrophosphate product formed and the amount of ATP consumed. All scyllo-inositol polyphosphates are substrates for both the kinases but they are weaker than the corresponding myo-inositol phosphate. Our study reveals the importance of axial-hydroxyl/phosphate for IP6K1 substrate recognition. We found that all these derivatives enhance the ATPase activity of VIP1. We found very weak ligand-induced ATPase activity for IP6K1. Benzoyl-scyllo-IP5 was the most potent ligand to induce IP6K1 ATPase activity despite being a weak substrate. This compound could have potential as a competitive inhibitor. Full article
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Article
Characterization of Signalling Pathways That Link Apoptosis and Autophagy to Cell Death Induced by Estrone Analogues Which Reversibly Depolymerize Microtubules
Molecules 2021, 26(3), 706; https://doi.org/10.3390/molecules26030706 - 29 Jan 2021
Cited by 2 | Viewed by 836
Abstract
The search for novel anti-cancer compounds which can circumvent chemotherapeutic drug resistance and limit systemic toxicity remains a priority. 2-Ethyl-3-O-sulphamoyl-estra-1,3,5(10)15-tetraene-3-ol-17one (ESE-15-one) and 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10)16-tetraene (ESE-16) are sulphamoylated 2-methoxyestradiol (2-ME) analogues designed by our research team. Although their cytotoxicity has been [...] Read more.
The search for novel anti-cancer compounds which can circumvent chemotherapeutic drug resistance and limit systemic toxicity remains a priority. 2-Ethyl-3-O-sulphamoyl-estra-1,3,5(10)15-tetraene-3-ol-17one (ESE-15-one) and 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10)16-tetraene (ESE-16) are sulphamoylated 2-methoxyestradiol (2-ME) analogues designed by our research team. Although their cytotoxicity has been demonstrated in vitro, the temporal and mechanistic responses of the initiated intracellular events are yet to be determined. In order to do so, assays investigating the compounds’ effects on microtubules, cell cycle progression, signalling cascades, autophagy and apoptosis were conducted using HeLa cervical- and MDA-MB-231 metastatic breast cancer cells. Both compounds reversibly disrupted microtubule dynamics as an early event by binding to the microtubule colchicine site, which blocked progression through the cell cycle at the G1/S- and G2/M transitions. This was supported by increased pRB and p27Kip1 phosphorylation. Induction of apoptosis with time-dependent signalling involving the p-JNK, Erk1/2 and Akt/mTOR pathways and loss of mitochondrial membrane potential was demonstrated. Inhibition of autophagy attenuated the apoptotic response. In conclusion, the 2-ME analogues induced a time-dependent cross-talk between cell cycle checkpoints, apoptotic signalling and autophagic processes, with an increased reactive oxygen species formation and perturbated microtubule functioning appearing to connect the processes. Subtle differences in the responses were observed between the two compounds and the different cell lines. Full article
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Communication
Thiocoumarin Caged Nucleotides: Synthetic Access and Their Photophysical Properties
Molecules 2020, 25(22), 5325; https://doi.org/10.3390/molecules25225325 - 15 Nov 2020
Viewed by 1359
Abstract
Photocages have been successfully applied in cellular signaling studies for the controlled release of metabolites with high spatio-temporal resolution. Commonly, coumarin photocages are activated by UV light and the quantum yields of uncaging are relatively low, which can limit their applications in vivo. [...] Read more.
Photocages have been successfully applied in cellular signaling studies for the controlled release of metabolites with high spatio-temporal resolution. Commonly, coumarin photocages are activated by UV light and the quantum yields of uncaging are relatively low, which can limit their applications in vivo. Here, syntheses, the determination of the photophysical properties, and quantum chemical calculations of 7-diethylamino-4-hydroxymethyl-thiocoumarin (thio-DEACM) and caged adenine nucleotides are reported and compared to the widely used 7-diethylamino-4-hydroxymethyl-coumarin (DEACM) caging group. In this comparison, thio-DEACM stands out as a phosphate cage with improved photophysical properties, such as red-shifted absorption and significantly faster photolysis kinetics. Full article
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Article
Novel Pathway of Adenosine Generation in the Lungs from NAD+: Relevance to Allergic Airway Disease
Molecules 2020, 25(21), 4966; https://doi.org/10.3390/molecules25214966 - 27 Oct 2020
Cited by 2 | Viewed by 714
Abstract
Adenosine and uric acid (UA) play a pivotal role in lung diseases such as asthma and chronic obstructive pulmonary disease (COPD). In the present experiments, we measured adenosine synthesis from nicotinamide adenine dinucleotide (NAD+) in membranes prepared from wild type (WT) [...] Read more.
Adenosine and uric acid (UA) play a pivotal role in lung diseases such as asthma and chronic obstructive pulmonary disease (COPD). In the present experiments, we measured adenosine synthesis from nicotinamide adenine dinucleotide (NAD+) in membranes prepared from wild type (WT) and CD38 knockout (CD38KO) mouse lungs, from cultured airway smooth muscle and epithelial cells, and in bronchoalveolar lavage fluid after airway challenge with epidemiologically relevant allergens. Adenosine was determined using an enzymatically coupled assay that produces ATP and is detected by luminescence. Uric acid was determined by ELISA. Exposure of cultured airway epithelial cells to Alternaria alternata extract caused significant nucleotide (NAD+ and ATP) release in the culture media. The addition of NAD+ to membranes prepared from WT mice resulted in faster generation of adenosine compared to membranes from CD38KO mice. Formation of adenosine from NAD+ affected UA and ATP concentrations, its main downstream molecules. Furthermore, NAD+ and adenosine concentrations in the bronchoalveolar lavage fluid decreased significantly following airway challenge with house-dust mite extract in WT but not in CD38KO mice. Thus, NAD+ is a significant source of adenosine and UA in the airways in mouse models of allergic airway disease, and the capacity for their generation from NAD+ is augmented by CD38, a major NADase with high affinity for NAD+. This novel non-canonical NAD+-adenosine-UA pathway that is triggered by allergens has not been previously described in the airways. Full article
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Article
Sulphamoylated Estradiol Analogue Induces Reactive Oxygen Species Generation to Exert Its Antiproliferative Activity in Breast Cancer Cell Lines
Molecules 2020, 25(18), 4337; https://doi.org/10.3390/molecules25184337 - 22 Sep 2020
Cited by 3 | Viewed by 716
Abstract
2-Methoxyestradiol (2ME), a 17β-estradiol metabolite, exerts anticancer properties in vitro and in vivo. To address 2ME’s low bioavailability, research led to the in silico design of sulphamoylated 2ME analogues. However, the role of oxidative stress induced in the activity exerted by sulphamoylated compounds [...] Read more.
2-Methoxyestradiol (2ME), a 17β-estradiol metabolite, exerts anticancer properties in vitro and in vivo. To address 2ME’s low bioavailability, research led to the in silico design of sulphamoylated 2ME analogues. However, the role of oxidative stress induced in the activity exerted by sulphamoylated compounds remains elusive. In the current study, the influence of 2-Ethyl-17-oxoestra-1,3,5(10)-trien-3-yl sulphamate (ESE-one) on reactive oxygen species (ROS) induction and its effect on cell proliferation, as well as morphology, were assessed in breast tumorigenic cells (MCF-7 and MDA-MB-231). Fluorescent microscopy showed that sulphamoylated estradiol analogues induced hydrogen peroxide and superoxide anion, correlating with decreased cell growth demonstrated by spectrophotometry data. ESE-one exposure resulted in antiproliferation which was repressed by tiron (superoxide inhibitor), trolox (peroxyl inhibitor) and N,N′-dimethylthiourea (DMTU) (hydrogen peroxide inhibitor). Morphological studies demonstrated that tiron, trolox and DMTU significantly decreased the number of rounded cells and shrunken cells in MCF-7 and MDA-MB-231 cells induced by ESE-one. This in vitro study suggests that ESE-one induces growth inhibition and cell rounding by production of superoxide anion, peroxyl radical and hydrogen peroxide. Identification of these biological changes in cancer cells caused by sulphamoylated compounds hugely contributes towards improvement of anticancer strategies and the ROS-dependent cell death pathways in tumorigenic breast cells. Full article
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Article
Conformational Restriction of Histamine with a Rigid Bicyclo[3.1.0]hexane Scaffold Provided Selective H3 Receptor Ligands
Molecules 2020, 25(16), 3562; https://doi.org/10.3390/molecules25163562 - 05 Aug 2020
Cited by 2 | Viewed by 973
Abstract
We designed and synthesized conformationally rigid histamine analogues with a bicyclo[3.1.0]hexane scaffold. All the compounds were selectively bound to the H3 receptor subtype over the H4 receptor subtype. Notably, compound 7 showed potent binding affinity and over 100-fold selectivity for the [...] Read more.
We designed and synthesized conformationally rigid histamine analogues with a bicyclo[3.1.0]hexane scaffold. All the compounds were selectively bound to the H3 receptor subtype over the H4 receptor subtype. Notably, compound 7 showed potent binding affinity and over 100-fold selectivity for the H3 receptors (Ki = 5.6 nM for H3 and 602 nM for H4). These results suggest that the conformationally rigid bicyclo[3.1.0]hexane structure can be a useful scaffold for developing potent ligands selective for the target biomolecules. Full article
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Review

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Review
Steroid Sulphatase and Its Inhibitors: Past, Present, and Future
Molecules 2021, 26(10), 2852; https://doi.org/10.3390/molecules26102852 - 11 May 2021
Cited by 2 | Viewed by 786
Abstract
Steroid sulphatase (STS), involved in the hydrolysis of steroid sulphates, plays an important role in the formation of both active oestrogens and androgens. Since these steroids significantly impact the proliferation of both oestrogen- and androgen-dependent cancers, many research groups over the past 30 [...] Read more.
Steroid sulphatase (STS), involved in the hydrolysis of steroid sulphates, plays an important role in the formation of both active oestrogens and androgens. Since these steroids significantly impact the proliferation of both oestrogen- and androgen-dependent cancers, many research groups over the past 30 years have designed and developed STS inhibitors. One of the main contributors to this field has been Prof. Barry Potter, previously at the University of Bath and now at the University of Oxford. Upon Prof. Potter’s imminent retirement, this review takes a look back at the work on STS inhibitors and their contribution to our understanding of sulphate biology and as potential therapeutic agents in hormone-dependent disease. A number of potent STS inhibitors have now been developed, one of which, Irosustat (STX64, 667Coumate, BN83495), remains the only one to have completed phase I/II clinical trials against numerous indications (breast, prostate, endometrial). These studies have provided new insights into the origins of androgens and oestrogens in women and men. In addition to the therapeutic role of STS inhibition in breast and prostate cancer, there is now good evidence to suggest they may also provide benefits in patients with colorectal and ovarian cancer, and in treating endometriosis. To explore the potential of STS inhibitors further, a number of second- and third-generation inhibitors have been developed, together with single molecules that possess aromatase–STS inhibitory properties. The further development of potent STS inhibitors will allow their potential therapeutic value to be explored in a variety of hormone-dependent cancers and possibly other non-oncological conditions. Full article
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Review
Reconsidering Aromatase for Breast Cancer Treatment: New Roles for an Old Target
Molecules 2020, 25(22), 5351; https://doi.org/10.3390/molecules25225351 - 16 Nov 2020
Cited by 7 | Viewed by 892
Abstract
The current therapeutic approach for the treatment of hormone dependent breast cancer includes interference with estrogen receptors via either selective modulators or estrogens deprivation, by preventing their biosynthesis with aromatase inhibitors. Severe side effects and acquired resistance are drawbacks of both drug classes, [...] Read more.
The current therapeutic approach for the treatment of hormone dependent breast cancer includes interference with estrogen receptors via either selective modulators or estrogens deprivation, by preventing their biosynthesis with aromatase inhibitors. Severe side effects and acquired resistance are drawbacks of both drug classes, and the efforts to overcome these issues still allow for research in this field to be animated. This review reports on recent findings that have opened new avenues for reconsidering the role of aromatase enzymes (and estrogen receptors) leading to the possibility of looking at well-known targets in a new perspective. Full article
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Review
The Circular Life of Human CD38: From Basic Science to Clinics and Back
Molecules 2020, 25(20), 4844; https://doi.org/10.3390/molecules25204844 - 21 Oct 2020
Cited by 6 | Viewed by 1019
Abstract
Monoclonal antibodies (mAbs) were initially considered as a possible “magic bullet” for in vivo elimination of tumor cells. mAbs represented the first step: however, as they were murine in nature (the earliest experience on the field), they were considered unfit for human applications. [...] Read more.
Monoclonal antibodies (mAbs) were initially considered as a possible “magic bullet” for in vivo elimination of tumor cells. mAbs represented the first step: however, as they were murine in nature (the earliest experience on the field), they were considered unfit for human applications. This prompted the development of techniques for cloning the variable regions of conventional murine antibodies, genetically mounted on human IgG. The last step in this years-long process was the design for the preparation of fully human reagents. The choice of the target molecule was also problematic, since cancer-specific targets are quite limited in number. To overcome this obstacle in the planning phases of antibody-mediated therapy, attention was focused on a set of normal molecules, whose quantitative distribution may balance a tissue-dependent generalized expression. The results and clinical success obtained with anti-CD20 mAbs revived interest in this type of strategy. Using multiple myeloma (MM) as a tumor model was challenging first of all because the plasma cells and their neoplastic counterpart eluded the efforts of the Workshop on Differentiation Antigens to find a target molecule exclusively expressed by these cells. For this reason, attention was turned to surface molecules which fulfill the requisites of being reasonably good targets, even if not specifically restricted to tumor cells. In 2009, we proposed CD38 as a MM target in virtue of its expression: it is absent on early hematological progenitors, has variable but generalized limited expression by normal cells, but is extremely high in plasma cells and in myeloma. Further, regulation of its expression appeared to be dependent on a variety of factors, including exposure to all-trans retinoic acid (ATRA), a potent and highly specific inducer of CD38 expression in human promyelocytic leukemia cells that are now approved for in vivo use. This review discusses the history of human CD38, from its initial characterization to its targeting in antibody-mediated therapy of human myeloma. Full article
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Review
Roles of NAD+ and Its Metabolites Regulated Calcium Channels in Cancer
Molecules 2020, 25(20), 4826; https://doi.org/10.3390/molecules25204826 - 20 Oct 2020
Cited by 2 | Viewed by 1034
Abstract
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, [...] Read more.
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. Full article
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Review
On a Magical Mystery Tour with 8-Bromo-Cyclic ADP-Ribose: From All-or-None Block to Nanojunctions and the Cell-Wide Web
Molecules 2020, 25(20), 4768; https://doi.org/10.3390/molecules25204768 - 16 Oct 2020
Cited by 1 | Viewed by 1325
Abstract
A plethora of cellular functions are controlled by calcium signals, that are greatly coordinated by calcium release from intracellular stores, the principal component of which is the sarco/endooplasmic reticulum (S/ER). In 1997 it was generally accepted that activation of various G protein-coupled receptors [...] Read more.
A plethora of cellular functions are controlled by calcium signals, that are greatly coordinated by calcium release from intracellular stores, the principal component of which is the sarco/endooplasmic reticulum (S/ER). In 1997 it was generally accepted that activation of various G protein-coupled receptors facilitated inositol-1,4,5-trisphosphate (IP3) production, activation of IP3 receptors and thus calcium release from S/ER. Adding to this, it was evident that S/ER resident ryanodine receptors (RyRs) could support two opposing cellular functions by delivering either highly localised calcium signals, such as calcium sparks, or by carrying propagating, global calcium waves. Coincidentally, it was reported that RyRs in mammalian cardiac myocytes might be regulated by a novel calcium mobilising messenger, cyclic adenosine diphosphate-ribose (cADPR), that had recently been discovered by HC Lee in sea urchin eggs. A reputedly selective and competitive cADPR antagonist, 8-bromo-cADPR, had been developed and was made available to us. We used 8-bromo-cADPR to further explore our observation that S/ER calcium release via RyRs could mediate two opposing functions, namely pulmonary artery dilation and constriction, in a manner seemingly independent of IP3Rs or calcium influx pathways. Importantly, the work of others had shown that, unlike skeletal and cardiac muscles, smooth muscles might express all three RyR subtypes. If this were the case in our experimental system and cADPR played a role, then 8-bromo-cADPR would surely block one of the opposing RyR-dependent functions identified, or the other, but certainly not both. The latter seemingly implausible scenario was confirmed. How could this be, do cells hold multiple, segregated SR stores that incorporate different RyR subtypes in receipt of spatially segregated signals carried by cADPR? The pharmacological profile of 8-bromo-cADPR action supported not only this, but also indicated that intracellular calcium signals were delivered across intracellular junctions formed by the S/ER. Not just one, at least two. This article retraces the steps along this journey, from the curious pharmacological profile of 8-bromo-cADPR to the discovery of the cell-wide web, a diverse network of cytoplasmic nanocourses demarcated by S/ER nanojunctions, which direct site-specific calcium flux and may thus coordinate the full panoply of cellular processes. Full article
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Review
Metabolism and Functions of Inositol Pyrophosphates: Insights Gained from the Application of Synthetic Analogues
Molecules 2020, 25(19), 4515; https://doi.org/10.3390/molecules25194515 - 02 Oct 2020
Cited by 2 | Viewed by 869
Abstract
Inositol pyrophosphates (PP-InsPs) comprise an important group of intracellular, diffusible cellular signals that a wide range of biological processes throughout the yeast, plant, and animal kingdoms. It has been difficult to gain a molecular-level mechanistic understanding of the actions of these molecules, due [...] Read more.
Inositol pyrophosphates (PP-InsPs) comprise an important group of intracellular, diffusible cellular signals that a wide range of biological processes throughout the yeast, plant, and animal kingdoms. It has been difficult to gain a molecular-level mechanistic understanding of the actions of these molecules, due to their highly phosphorylated nature, their low levels, and their rapid metabolic turnover. More recently, these obstacles to success are being surmounted by the chemical synthesis of a number of insightful PP-InsP analogs. This review will describe these analogs and will indicate the important chemical and biological information gained by using them. Full article
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Review
25 Years of Collaboration with A Genius: Deciphering Adenine Nucleotide Ca2+ Mobilizing Second Messengers Together with Professor Barry Potter
Molecules 2020, 25(18), 4220; https://doi.org/10.3390/molecules25184220 - 15 Sep 2020
Viewed by 722
Abstract
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 [...] Read more.
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. Full article
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