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Metalloenzyme Inhibitors and Activators

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

Deadline for manuscript submissions: closed (28 February 2018) | Viewed by 45236

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Prof. Dr. Claudiu T. Supuran

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Neurofarba Department, Section of Farmaceutical and Neutraceutical Sciences, University of Florence, Sesto Fiorentino, 50019 Florence, Italy
Interests: drug design; metalloenzymes; carbonic anhydrases; anticancer agents; antiinfectives; sulfonamides; coumarins
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Special Issue Information

Dear Colleagues,

Enzymes have long been considered as important drug targets for the treatment of major human diseases, as several thousands of such proteins are encoded in the human genome, and they play key roles in virtually every physiological/pathological process. Currently, at least 70 human enzymes and 20 bacterial, viral, fungal or parasite enzymes are targets of approved drugs, e.g., up to 40% of the current known drug targets. Enzymes containing metals (metalloenzymes) are of increasing interest and importance, as the genetic and phsysiologic consequences of metalloprotein regulation became better understood processes. All major six enzyme classes established by the International Union of Biochemistry, i.e., oxidoreductases, transferases, hydrolases, lyases, isomerases and ligases have important members among the metalloenzymes known to date. Over the last years, important achievements have been done regarding their characterization, with crucial inhibition/activation studies which led to the identifications of compounds with potential pharmacologic and biotechnologic applications. The present Special Issue of Molecules welcomes contributions dealing with all aspects of metalloenzymes research, including drug design, inhibitors, activators, structure–function relationship, etc.

Prof. Dr. Claudiu T. Supuran
Guest Editor

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Keywords

metalloenzyme
enzyme inhibitor
enzyme activator
structure-function relationship
drug design
metal-binding function

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Published Papers (7 papers)

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Research

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17 pages, 3945 KiB

Open AccessArticle

Novel 6- and 7-Substituted Coumarins with Inhibitory Action against Lipoxygenase and Tumor-Associated Carbonic Anhydrase IX

by Aikaterini Peperidou, Silvia Bua, Murat Bozdag, Dimitra Hadjipavlou-Litina and Claudiu T. Supuran

Molecules 2018, 23(1), 153; https://doi.org/10.3390/molecules23010153 - 12 Jan 2018

Cited by 30 | Viewed by 4664

Abstract

A series of carboxamide derivatives of 6- and 7-substituted coumarins have been prepared by an original procedure starting from the corresponding 6- or 7-hydroxycoumarins which were alkylated with ethyl iodoacetate, and the obtained ester was converted to the corresponding carboxylic acids which were thereafter reacted with a series of aromatic/aliphatic/heterocyclic amines leading to the desired amides. The new derivatives were investigated as inhibitors of two enzymes, human carbonic anhydrases (hCAs) and soy bean lipoxygenase (LOX). Compounds 4a and 4b were potent LOX inhibitors, whereas many effective hCA IX inhibitors (K_Is in the range of 30.2–30.5 nM) were detected in this study. Two compounds, 4b and 5b, showed the phenomenon of dual inhibition. Furthermore, these coumarins did not significantly inhibit the widespread cytosolic isoforms hCA I and II, whereas they were weak hCA IV inhibitors, making them hCA IX-selective inhibitors. As hCA IX and LOX are validated antitumor targets, these results are promising for the investigation of novel drug targets involved in tumorigenesis. Full article

(This article belongs to the Special Issue Metalloenzyme Inhibitors and Activators)

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Open AccessFeature PaperArticle

Activation Profile Analysis of CruCA4, an α-Carbonic Anhydrase Involved in Skeleton Formation of the Mediterranean Red Coral, Corallium rubrum

by Sonia Del Prete, Daniela Vullo, Didier Zoccola, Sylvie Tambutté, Claudiu T. Supuran and Clemente Capasso

Molecules 2018, 23(1), 66; https://doi.org/10.3390/molecules23010066 - 28 Dec 2017

Cited by 5 | Viewed by 3908

Abstract

CruCA4, a coral α-carbonic anhydrase (CA, EC 4.2.1.1) involved in the biomineralization process of the Mediterranean red coral, Corallium rubrum, was investigated for its activation with a panel of amino acids and amines. Most compounds showed considerable activating properties, with a rather well defined structure–activity relationship. The most effective CruCA4 activators were d-His, 4-H₂N-l-Phe, Histamine, Dopamine, Serotonin, 1-(2-Aminoethyl)-piperazine, and l-Adrenaline, with activation constants in the range of 8–98 nM. Other amines and amino acids, such as d-DOPA, l-Tyr, 2-Pyridyl-methylamine, 2-(2-Aminoethyl) pyridine and 4-(2-Aminoethyl)-morpholine, were submicromolar CruCA4 activators, with K_A ranging between 0.15 and 0.93 µM. Since it has been shown that CA activators may facilitate the initial phases of in-bone mineralization, our study may be relevant for finding modulators of enzyme activity, which can enhance the formation of the red coral skeleton. Full article

(This article belongs to the Special Issue Metalloenzyme Inhibitors and Activators)

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3093 KiB

Open AccessArticle

Five- and Six-Membered Nitrogen-Containing Compounds as Selective Carbonic Anhydrase Activators

by Adriano Mollica, Giorgia Macedonio, Azzurra Stefanucci, Simone Carradori, Atilla Akdemir, Andrea Angeli and Claudiu T. Supuran

Molecules 2017, 22(12), 2178; https://doi.org/10.3390/molecules22122178 - 9 Dec 2017

Cited by 17 | Viewed by 5010

Abstract

It has been proven that specific isoforms of human carbonic anhydrase (hCA) are able to fine-tune physiological pathways connected to signal processing, and that decreased CAs expression negatively influences cognition, leading to mental retardation, Alzheimer’s disease, and aging-related cognitive dysfunctions. For this reason, a small library of natural and synthetic nitrogen containing cyclic derivatives was assayed as activators of four human isoforms of carbonic anhydrase (hCA I, II, IV and VII). Most of the compounds activated hCA I, IV and VII in the micromolar range, with K_As ranging between 3.46 and 80.5 μM, whereas they were not active towards hCA II (K_As > 100 μM). Two natural compounds, namely l-(+)-ergothioneine (1) and melatonin (2), displayed K_As towards hCA VII in the nanomolar range after evaluation by a CO₂ hydration method in vitro, showing a rather efficient and selective activation profile with respect to histamine, used as a reference compound. Corroborated with the above in vitro findings, a molecular modelling in silico approach has been performed to correlate these biological data, and to elucidate the binding interaction of these activators within the enzyme active site. Full article

(This article belongs to the Special Issue Metalloenzyme Inhibitors and Activators)

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3258 KiB

Open AccessArticle

Development of a Non-Hydroxamate Dual Matrix Metalloproteinase (MMP)-7/-13 Inhibitor

by Thomas Fischer and Rainer Riedl

Molecules 2017, 22(9), 1548; https://doi.org/10.3390/molecules22091548 - 14 Sep 2017

Cited by 9 | Viewed by 7919

Abstract

Matrix metalloproteinase 7 (MMP-7) is a member of the MMP superfamily and is able to degrade extracellular matrix proteins such as casein, gelatin, fibronectin and proteoglycan. MMP-7 is a validated target for the development of small molecule drugs against cancer. MMP-13 is within the enzyme class the most efficient contributor to type II collagen degeneration and is a validated target in arthritis and cancer. We have developed the dual MMP-7/-13 inhibitor ZHAWOC6941 with IC₅₀-values of 2.2 μM (MMP-7) and 1.2 μM (MMP-13) that is selective over a broad range of MMP isoforms. It spares MMP-1, -2, -3, -8, -9, -12 and -14, making it a valuable modulator for targeted polypharmacology approaches. Full article

(This article belongs to the Special Issue Metalloenzyme Inhibitors and Activators)

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1593 KiB

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Anti-Melanogenic Effects of Flavonoid Glycosides from Limonium tetragonum (Thunb.) Bullock via Inhibition of Tyrosinase and Tyrosinase-Related Proteins

by Seul-Gi Lee, Fatih Karadeniz, Youngwan Seo and Chang-Suk Kong

Molecules 2017, 22(9), 1480; https://doi.org/10.3390/molecules22091480 - 5 Sep 2017

Cited by 38 | Viewed by 5945

Abstract

Overproduction and stimulation of tyrosinase result in increased melanogenesis of which several skin disorders such as freckles, spots, and hyperpigmentation appear as complications. Limonium tetragonum is a halophyte well-known for its antioxidative properties. This study investigated the anti-melanogenic effects of solvent-partitioned L. tetragonum extracts (LTEs) and its bioactive constituents, two isolated flavonoid glycosides. Current study followed a set of experiments on B16-F10 mouse melanoma cell model with a focus on tyrosinase activity and production. The anti-melanogenic capacity of LTEs was confirmed by their tyrosinase inhibitory effects, prevention of DOPA oxidation, and suppression of melanin production. The inhibition of tyrosinase and DOPA oxidation by LTEs was suggested to be related with the downregulation of microphthalmia-associated transcription factor, tyrosinase, tyrosinase-related protein-1, and tyrosinase-related protein-2, verified with mRNA and protein expression levels. Among all tested LTEs, 85% aq. MeOH and n-BuOH were found to be the most active fractions which later yielded the two known compounds, myricetin 3-galactoside and quercetin 3-O-β-galactopyronaside. The anti-melanogenic potential of the compounds were confirmed by their tyrosinase inhibitory effects. These results suggested that L. tetragonum may serve as a potential source of bioactive substances with effective anti-melanogenesis properties. Full article

(This article belongs to the Special Issue Metalloenzyme Inhibitors and Activators)

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Review

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14 pages, 2291 KiB

Open AccessReview

Carbonic Anhydrase Inhibitors as Novel Drugs against Mycobacterial β-Carbonic Anhydrases: An Update on In Vitro and In Vivo Studies

by Ashok Aspatwar, Jean-Yves Winum, Fabrizio Carta, Claudiu T. Supuran, Milka Hammaren, Mataleena Parikka and Seppo Parkkila

Molecules 2018, 23(11), 2911; https://doi.org/10.3390/molecules23112911 - 8 Nov 2018

Cited by 25 | Viewed by 4663

Abstract

Mycobacteria cause a variety of diseases, such as tuberculosis, leprosy, and opportunistic diseases in immunocompromised people. The treatment of these diseases is problematic, necessitating the development of novel treatment strategies. Recently, β-carbonic anhydrases (β-CAs) have emerged as potential drug targets in mycobacteria. The genomes of mycobacteria encode for three β-CAs that have been cloned and characterized from Mycobacterium tuberculosis (Mtb) and the crystal structures of two of the enzymes have been determined. Different classes of inhibitor molecules against Mtb β-CAs have subsequently been designed and have been shown to inhibit these mycobacterial enzymes in vitro. The inhibition of these centrally important mycobacterial enzymes leads to reduced growth of mycobacteria, lower virulence, and impaired biofilm formation. Thus, the inhibition of β-CAs could be a novel approach for developing drugs against the severe diseases caused by pathogenic mycobacteria. In the present article, we review the data related to in vitro and in vivo inhibition studies in the field. Full article

(This article belongs to the Special Issue Metalloenzyme Inhibitors and Activators)

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22 pages, 5922 KiB

Open AccessReview

Cancer Drug Development of Carbonic Anhydrase Inhibitors beyond the Active Site

by Srishti Singh, Carrie L. Lomelino, Mam Y. Mboge, Susan C. Frost and Robert McKenna

Molecules 2018, 23(5), 1045; https://doi.org/10.3390/molecules23051045 - 30 Apr 2018

Cited by 104 | Viewed by 11164

Abstract

Carbonic anhydrases (CAs) catalyze the reversible hydration of carbon dioxide to produce bicarbonate and a proton. Multiple CA isoforms are implicated in a range of diseases, including cancer. In solid tumors, continuously dividing cells create hypoxic conditions that eventually lead to an acidic microenvironment. Hypoxic tumor cells have different mechanisms in place to regulate and adjust the surrounding microenvironment for survival. These mechanisms include expression of CA isoform IX (CA IX) and XII (CA XII). These enzymes help maintain a physiological intracellular pH while simultaneously contributing to an acidic extracellular pH, leading to tumor cell survival. Expression of CA IX and CA XII has also been shown to promote tumor cell invasion and metastasis. This review discusses the characteristics of CA IX and CA XII, their mechanism of action, and validates their prospective use as anticancer targets. We discuss the current status of small inhibitors that target these isoforms, both classical and non-classical, and their future design in order to obtain isoform-specificity for CA IX and CA XII. Biologics, such as monoclonal antibodies, monoclonal-radionuclide conjugated chimeric antibodies, and antibody-small molecule conjugates are also discussed. Full article

(This article belongs to the Special Issue Metalloenzyme Inhibitors and Activators)

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