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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
Website
Guest Editor
Professor of Oncologic Sciences, Mitchell Cancer Institute| 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. Gerd Wagner
Website
Guest Editor
Professor of Medicinal Chemistry & Chemical Biology, Queen’s University Belfast | School of Pharmacy, Medical Biology Centre, 97 Lisburn Road | Belfast BT9 7BL, UK
Interests: medicinal chemistry; chemical biology; carbohydrate and nucleotide chemistry; enzyme inhibitors; antimicrobial resistance; bioassays; glycobiology; drug discovery
Special Issues and Collections 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

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

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

Published Papers (7 papers)

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Research

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Open AccessArticle
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
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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Open AccessArticle
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
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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Open AccessReview
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
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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Open AccessReview
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
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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Open AccessReview
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
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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Open AccessReview
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
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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Open AccessReview
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
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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