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1.
Biochem Biophys Res Commun ; 548: 217-221, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33647799

RESUMO

Up to date alcohols have been scarcely investigated as carbonic anhydrase (CA) inhibitors. To get more insights into the CA inhibition properties of this class of molecules, in this paper, by means of inhibition assays and X-ray crystallographic studies we report a detailed characterization of the CA inhibition properties and the binding mode to human CA II of benzyl alcohol. Results show that, although possessing a very simple scaffold, this molecule acts as a micromolar CA II inhibitor, which anchors to the enzyme active site by means of an H-bond interaction with the zinc bound solvent molecule. Taken together our results clearly indicate primary alcohols as a class of CA inhibitors that deserve to be more investigated.

2.
J Enzyme Inhib Med Chem ; 36(1): 719-726, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33648390

RESUMO

Carbonic anhydrases (CAs, EC 4.2.1.1) activators were shown to be involved in memory enhancement and learning in animal models of cognition. Here we investigated the CA activating effects of a large series of histamine based compounds, including histamine receptors (H1R - H4R) agonists, antagonists and other derivatives of this autacoid. CA activators may be thus useful for improving cognition as well as in diverse therapeutic areas (phobias, obsessive-compulsive disorder, generalised anxiety, post-traumatic stress disorders), for which activation of this enzyme was recently shown to be involved.

3.
Bioorg Med Chem Lett ; : 127877, 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33640442

RESUMO

With an aim to develop novel potential anti-cancer agents we have designed a series of novel 4,7-disubstituted coumarin hybrids synthesis and evaluated for their inhibitory activity against the human carbonic anhydrase isoforms namely CA I, CA II, CA IX and CA XII. The results of CA inhibition clearly showed that the novel 4, 7-disubstituted coumarin hybrids (7a-i & 8a-j) exhibited selective inhibition towards tumor associated isoforms, CA IX and CA XII without inhibiting CA I and CA II isoforms. Among all the compound 8b showed a significant inhibition against hCA IX with a Ki of 0.58 µM whereas, the compound 7c showed a significant inhibition against hCA XII with a Ki of 0.36 µM respectively. All other compounds have shown a good inhibition against hCA IX and hCA XII over hCA I and hCA II within the range of 0.46 to 9.35 µM. Therefore, compound 8b and 7c would be the potential leads for developing selective cytotoxic agents targeting hCA IX and XII.

4.
Bioorg Chem ; 108: 104647, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33530019

RESUMO

The primary sulfonamide group is one of the most efficient zinc binding group (ZBG) for designing carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. In the present study primary sulfonamide linked with indolylchalcone were designed. The newly synthesized molecules (5a-r) were examined against four human (h) CA isoforms (hCA I, hCA II, hCA IX and hCA XIII). These sulfonamides showed good inhibition activity against isoforms hCA I, hCA II and hCA XIII. Compound 5i (2.3 nM), 5m (2.4 nM), 5o (3.6 nM) and 5q (7.0 nM) were more potent than standard drug AAZ (12.1 nM) against isoform hCA II, respectively. Most of the other compounds in the present series inhibited hCA XIII and hCA IX in the range of 50 nM - 100 nM.

5.
Bioorg Med Chem Lett ; 37: 127856, 2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33609663

RESUMO

A new series of benzenesulphonamide linked-1,3,4-oxadiazole hybrids (6a-s) has been synthesized and tested for their carbonic anhydrase inhibition against human (h) carbonic anhydrase (CA) isoforms hCA I, II, IX, and XIII. Fluorescence properties of some of the synthesized molecules were studied. Most of the molecules exhibited significant inhibitory power, comparable or better than the standard drug acetazolamide (AAZ) on hCA XIII. Out of 19 tested molecules, compound 6e (75.8 nM) was 3 times more potent than AAZ (250.0 nM) against hCA I, whereas compound 6e (15.4 nM), 6g (16.2 nM), 6h (16.4 nM) and 6i (17.0 nM) were found to be more potent than AAZ (17.0 nM) against isoform hCA XIII. It is anticipated that these compounds could be taken as the potential leads for the development of selective hCA XIII isoform inhibitors with improved potency.

6.
J Enzyme Inhib Med Chem ; 36(1): 561-580, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33615947

RESUMO

Inorganic anions inhibit the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) generally by coordinating to the active site metal ion. Cyanate was reported as a non-coordinating CA inhibitor but those erroneous results were subsequently corrected by another group. We review the anion CA inhibitors (CAIs) in the more general context of drug design studies and the discovery of a large number of inhibitor classes and inhibition mechanisms, including zinc binders (sulphonamides and isosteres, dithiocabamates and isosteres, thiols, selenols, benzoxaboroles, ninhydrins, etc.); inhibitors anchoring to the zinc-coordinated water molecule (phenols, polyamines, sulfocoumarins, thioxocoumarins, catechols); CAIs occluding the entrance to the active site (coumarins and derivatives, lacosamide), as well as compounds that bind outside the active site. All these new chemotypes integrated with a general procedure for obtaining isoform-selective compounds (the tail approach) has resulted, through the guidance of rigorous X-ray crystallography experiments, in the development of highly selective CAIs for all human CA isoforms with many pharmacological applications.

7.
Eur J Med Chem ; 214: 113260, 2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33581552

RESUMO

A series of d-proline peptidomimetics were evaluated as dual inhibitors of both human carbonic anhydrases (hCAs) and human gelatinases (MMP2 and MMP9), as these enzymes are both involved in the carcinogenesis and tumor invasion processes. The synthesis and enzyme inhibition kinetics of d-proline derivatives containing a biphenyl sulfonamido moiety revealed an interesting inhibition profile of compound XIV towards MMP9 and CAII. The SAR analysis and docking studies revealed a stringent requirement of a trans geometry for the two arylsulfonyl moieties, which are both necessary for inhibition of MMP9 and CAII. As MMP9 and CAII enzymes are both overexpressed in gastrointestinal stromal tumor cells, this molecule may represent an interesting chemical probe for a multitargeting approach on gastric and colorectal cancer.

8.
Nat Prod Res ; : 1-7, 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33533668

RESUMO

Malassezia spp. are lipophilic fungi that are part of the normal flora of the human skin and are the etiological agents of dandruff and seborrheic dermatitis. ß-Carbonic Anhydrases (CAs; EC 4.2.1.1) expressed from the pathogenic fungi are an alternative/complementary drug target. Previous work by our groups demonstrated that flavonoids and depsides can effectively inhibit Malassezia globosa ß-CA (MgCA). In continuation of this study herein we report the inhibitory activity of a variety of phenols from Origanum dictamnus L. and Thymus vulgaris L. against ß-MgCA, among them I4-II7-di-carvacrol, a new natural product. Structure elucidation of the compounds was performed by 1 D, 2 D NMR and spectrometric analyses. Xanthomicrol and rosmarinic acid were active in the (sub)micromolar range (KIS 0.6 and 2.2 µM, respectively vs 40.0 µM of the standard inhibitor acetazolamide). Finally, the compounds were not cytotoxic, but showed in vitro no activity against Malassezia furfur.

9.
J Enzyme Inhib Med Chem ; 36(1): 685-692, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33602041

RESUMO

A small library of coumarin and their psoralen analogues EMAC10157a-b-d-g and EMAC10160a-b-d-g has been designed and synthesised to investigate the effect of structural modifications on their inhibition ability and selectivity profile towards carbonic anhydrase isoforms I, II, IX, and XII. None of the new compounds exhibited activity towards hCA I and II isozymes. Conversely, both coumarin and psoralen derivatives were active against tumour associated isoforms IX and XII in the low micromolar or nanomolar range of concentration. These data further corroborate our previous findings on analogous derivatives, confirming that both coumarins and psoralens are interesting scaffolds for the design of isozyme selective hCA inhibitors.

10.
Bioorg Chem ; 107: 104618, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33485104

RESUMO

A library of iodoquinazolinones endowed with benzenesulfonamide moiety was designed and synthesized as human carbonic anhydrase (hCA) inhibitors. Compounds 4-17 showed generally poor activity against the cytosolic hCA I and hCA II isoforms. Contrarily they were more potent and showed a variable spectrum of selectivity against the tumor-specific isoforms hCA IX and hCA XII. The 4-iodophenyl derivative 12 and the 4-pyridinyl derivative 15 were the most active and selective in this series against hCA IX and hCA XII isoforms with KI of 18 and 9 nM, respectively. Compounds 12 and 15 were further screened for their cytotoxicity against MCF-7, HepG-2 and HCT-116 cancer cell lines besides WI38 and MCF-10A normal cell lines to determine their selectivity towards cancer cells. Compound 12 was selective towards HepG-2 and HCT-116 cell lines but less selective towards MCF-7. While compound 15 showed higher selectivity towards HepG-2 than HCT-116 and MCF-7 cell lines. The ability of compounds 12 and 15 to sensitize the cells against gamma irradiation's effect proved their potential radiosensitizing activity. Molecular docking analysis was carried out to discover the possible binding mode of the compounds within the active site of isoform hCA IX and XII. Compounds 12 and 15 revealed the probable fundamental interactions explaining the good activity and selectivity towards the tumor-specific isoforms.

11.
J Enzyme Inhib Med Chem ; 36(1): 372-376, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33390061

RESUMO

Burkholderia territorii, a Gram-negative bacterium, encodes for the ι-class carbonic anhydrase (CA, EC 4.2.1.1) BteCAι, which was recently characterised. It acts as a good catalyst for the hydration of CO2 to bicarbonate and protons, with a kcat value of 3.0 × 105 s-1 and kcat/KM value of 3.9 × 107 M-1 s-1. No inhibition data on this new class of enzymes are available to date. We report here an anion and small molecules inhibition study of BteCAι, which we prove to be a zinc(II)- and not manganese(II)-containing enzyme, as reported for diatom ι-CAs. The best inhibitors were sulphamic acid, stannate, phenylarsonic acid, phenylboronic acid and sulfamide (KI values of 6.2-94 µM), whereas diethyldithiocarbamate, tellurate, selenate, bicarbonate and cyanate were submillimolar inhibitors (KI values of 0.71-0.94 mM). The halides (except iodide), thiocyanate, nitrite, nitrate, carbonate, bisulphite, sulphate, hydrogensulfide, peroxydisulfate, selenocyanate, fluorosulfonate and trithiocarbonate showed KI values in the range of 3.1-9.3 mM.

12.
Int J Mol Sci ; 22(2)2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33430028

RESUMO

Carbonic anhydrases (CAs) are essential metalloenzymes in nature, catalyzing the carbon dioxide reversible hydration into bicarbonate and proton. In humans, breathing and many other critical physiological processes depend on this enzymatic activity. The CA superfamily function and inhibition in pathogenic bacteria has recently been the object of significant advances, being demonstrated to affect microbial survival/virulence. Targeting bacterial CAs may thus be a valid alternative to expand the pharmacological arsenal against the emergence of widespread antibiotic resistance. Here, we report an extensive study on the inhibition profile of the recently discovered ι-CA class present in some bacteria, including Burkholderia territorii, namely BteCAι, using substituted benzene-sulfonamides and clinically licensed sulfonamide-, sulfamate- and sulfamide-type drugs. The BteCAι inhibition profile showed: (i) several benzene-sulfonamides with an inhibition constant lower than 100 nM; (ii) a different behavior with respect to other α, ß and γ-CAs; (iii) clinically used drugs having a micromolar affinity. This prototype study contributes to the initial recognition of compounds which efficiently and selectively inhibit a bacterial member of the ι-CA class, for which such a selective inhibition with respect to other protein isoforms present in the host is highly desired and may contribute to the development of novel antimicrobials.

13.
Nat Rev Drug Discov ; 2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33510482

RESUMO

Natural products and their structural analogues have historically made a major contribution to pharmacotherapy, especially for cancer and infectious diseases. Nevertheless, natural products also present challenges for drug discovery, such as technical barriers to screening, isolation, characterization and optimization, which contributed to a decline in their pursuit by the pharmaceutical industry from the 1990s onwards. In recent years, several technological and scientific developments - including improved analytical tools, genome mining and engineering strategies, and microbial culturing advances - are addressing such challenges and opening up new opportunities. Consequently, interest in natural products as drug leads is being revitalized, particularly for tackling antimicrobial resistance. Here, we summarize recent technological developments that are enabling natural product-based drug discovery, highlight selected applications and discuss key opportunities.

14.
Int J Mol Sci ; 22(3)2021 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-33498779

RESUMO

Hypoxic tumors overexpress membrane-bound isozymes of carbonic anhydrase (CA) CA IX and CA XII, which play key roles in tumor pH homeostasis under hypoxia. Selective inhibition of these CA isozymes has the potential to generate pH imbalances that can lead to tumor cell death. Since these isozymes are dimeric, we designed a series of bifunctional PEGylated CA inhibitors (CAIs) through the attachment of our preoptimized CAI warhead 1,3,4-thiadiazole-2-sulfonamide to polyethylene glycol (PEG) backbones with lengths ranging from 1 KDa to 20 KDa via a succinyl linker. A detailed structure-thermal properties and structure-biological activity relationship study was conducted via differential scanning calorimetry (DSC) and via viability testing in 2D and 3D (tumor spheroids) cancer cell models, either CA IX positive (HT-29 colon cancer, MDA-MB 231 breast cancer, and SKOV-3 ovarian cancer) or CA IX negative (NCI-H23 lung cancer). We identified PEGylated CAIs DTP1K 28, DTP2K 23, and DTP3.4K 29, bearing short and medium PEG backbones, as the most efficient conjugates under both normoxic and hypoxic conditions, and in the tumor spheroid models. PEGylated CAIs did not affect the cell viability of CA IX-negative NCI-H23 tumor spheroids, thus confirming a CA IX-mediated cell killing for these potential anticancer agents.

15.
J Enzyme Inhib Med Chem ; 36(1): 394-401, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33430654

RESUMO

In this paper, the efficiency of the carbonic anhydrase (CA) enzyme in accelerating the hydration of CO2 is evaluated using a measurement system which consists of a vessel in which a gaseous flow of mixtures of nitrogen and CO2 is bubbled into water or water solutions containing a known quantity of CA enzyme. The pH value of the solution and the CO2 concentration at the measurement system gas exhaust are continuously monitored. The measured CO2 level allows for assessing the quantity of CO2, which, subtracted from the gaseous phase, is dissolved into the liquid phase and/or hydrated to bicarbonate. The measurement procedure consists of inducing a transient and observing and modelling the different kinetics involved in the steady-state recovery with and without CA. The main contribution of this work is exploiting dynamical system theory and chemical kinetics modelling for interpreting measurement results for characterising the activity of CA enzymes. The data for model fitting are obtained from a standard bioreactor, in principle equal to standard two-phase bioreactors described in the literature, in which two different techniques can be used to move the process itself away from the steady-state, inducing transients.

16.
J Enzyme Inhib Med Chem ; 36(1): 469-479, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33472446

RESUMO

The binding mode of aromatic sulphonamides and clinically licenced drugs to the three carbonic anhydrase (CA, EC 4.2.1.1) isoforms from the human pathogen V. cholerae was here thouroghly characterised by a joint docking and molecular dynamics in silico protocol. In fact, VchCA, VchCAß, and VchCAγ are crucial in the pathogen life cycle and growth and represent innovative targets to fight V. cholerae proliferation overcoming the spreading chemoresistance to the available drugs. A set of 40 sulphonamides/sulfamates VchCAs inhibitors was studied using the proteins homology built 3 D models unveiling the key and stable interactions responsible for a potent CA inhibition. This study has the aim to offer insights and guidelines for the future rational design of potent and selective inhibitors targeting CA isoforms from V. cholerae or other human pathogens.

17.
J Enzyme Inhib Med Chem ; 36(1): 329-334, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33356653

RESUMO

Sulphonamides and their isosteres are classical inhibitors of the carbonic anhydrase (CAs, EC 4.2.1.1) metalloenzymes. The protozoan pathogen Trichomonas vaginalis encodes two such enzymes belonging to the ß-class, TvaCA1 and TvaCA2. Here we report the first sulphonamide inhibition study of TvaCA1, with a series of simple aromatic/heterocyclic primary sulphonamides as well as with clinically approved/investigational drugs for a range of pathologies (diuretics, antiglaucoma, antiepileptic, antiobesity, and antitumor drugs). TvaCA1 was effectively inhibited by acetazolamide and ethoxzolamide, with KIs of 391 and 283 nM, respectively, whereas many other simple or clinically used sulphonamides were micromolar inhibitors or did not efficiently inhibit the enzyme. Finding more effective TvaCA1 inhibitors may constitute an innovative approach for fighting trichomoniasis, a sexually transmitted infection, caused by T. vaginalis.

18.
J Enzyme Inhib Med Chem ; 36(1): 48-57, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33103482

RESUMO

The synthesis and carbonic anhydrase (CA; EC 4.2.1.1) activating effects of a series of oxime ether-based amino alcohols towards four human (h) CA isoforms expressed in human brain, hCA I, II, IV and VII, are described. Most investigated amino alcohol derivatives induced a consistent activation of the tested CAs, with KAs spanning from a low micromolar to a medium nanomolar range. Specifically, hCA II and VII, putative main CA targets when central nervous system (CNS) diseases are concerned, were most efficiently activated by these oxime ether derivatives. Furthermore, a multitude of selective hCA VII activators were identified. As hCA VII is one of the key isoforms involved in brain metabolism and other brain functions, the identified potent and selective hCA VII activators may be considered of interest for investigations of various therapeutic applications or as lead compounds in search of even more potent and selective CA activators.

20.
Eur J Med Chem ; : 113046, 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33303236

RESUMO

The tumour-associated, cell membrane-bound isoforms IX and XII of human carbonic anhydrase (CA, EC 4.2.1.1) are overexpressed in cancer cells contributing to the hypoxic tumour pH/metabolism regulating machinery and as thus, can serve as markers of malignant neoplastic tissue. Inhibitors of CAs can be employed both for the treatment of hypoxic tumours and in the design of radiotracers for positron emission tomography and imaging of such cancers. The present review provides a comprehensive summary of the progress achieved to-date in the field of developing PET-tracers based on monoclonal antibodies, biomolecules, and small-molecule ligands of CA IX and XII.

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