Giuseppina De Simone

• Chemistry
• Research Director at Italian National Research Council

In this study, four depsides were isolated from Origanum dictamnus L. and Satureja pilosa Velen. medicinal plants and their structures were assessed by means of one‐dimensional (1D)‐ and two‐dimensional (2D)‐nuclear magnetic resonance, high resolution mass spectrometry, and electronic circular dichroism analyses. The compound 1 , herein reported fo...

The human carbonic anhydrase IX (CA IX) is a hypoxia-induced transmembrane protein belonging to the α-CA enzyme family. It has a crucial role in pH regulation in hypoxic cells and acts by buffering intracellular acidosis induced by hypoxia. Indeed, it is frequently expressed in cancer cells, where it contributes to tumor progression. CA IX is also...

In this study, we investigated the development of dual-targeted ligands that bind to both μ-opioid receptor (MOR) and carbonic anhydrase (CA) enzymes, using fentanyl structure as a template. We synthesized and evaluated 21 novel compounds with dual-targeted affinity identifying the lead candidate compound 8, showing selective affinity for MOR and p...

Benzoxaborole is currently a scaffold of great relevance in medicinal chemistry. In 2016, it was reported to be a new and valuable chemotype for designing carbonic anhydrase (CA) inhibitors. Herein, using an in silico design, we report the synthesis and characterization of substituted 6-(1H-1,2,3-triazol-1-yl)benzoxaboroles. 6-Azidobenzoxaborole wa...

Simple Summary Carbonic anhydrases are a family of enzymes that catalyze an essential physiological reaction for living organisms: the reversible conversion of CO2 to bicarbonate ion. In humans, these enzymes impact many physiological and pathological processes including respiration, pH and CO2 homeostasis, electrolyte secretion, gluconeogenesis, u...

Conventional chemotherapy represents the main systemic treatment used for triple-negative breast cancer (TNBC) patients, although many of them develop drug resistance. The hypoxic TME is the crucial driver in the onset of insensitivity to chemotherapy. In this research, we elucidated the role played by bone marrow-derived mesenchymal stem cells (BM...

Background Hypoxic tumor microenvironment (TME) contributes to the onset of many aspects of the cancer biology associated to the resistance to conventional therapies. Hypoxia is a common characteristic and negative prognostic factor in the head and neck squamous carcinomas (HNSCC) and is correlated with aggressive and invasive phenotype as well as...

Carbonic anhydrases (CAs) are ubiquitous enzymes that catalyze the reversible carbon dioxide hydration reaction. Among the eight different CA classes existing in nature, the α-class is the largest one being present in animals, bacteria, protozoa, fungi, and photosynthetic organisms. Although many studies have been reported on these enzymes, few fun...

Melioidosis is a severe disease caused by the highly pathogenic gram-negative bacterium Burkholderia pseudomallei. Several studies have highlighted the broad resistance of this pathogen to many antibiotics and pointed out the pivotal importance of improving the pharmacological arsenal against it. Since γ-carbonic anhydrases (γ-CAs) have been recent...

The head and neck squamous carcinomas (HNSSCs) are the sixth most common cancer worldwide. Given the heterogeneous nature of HNSCC, this carcinoma results in higher resistance to chemoradiotherapy. Recent evidence highlight the importance of the hypoxic microenvironment in contributing to cisplatin resistance. Therefore, the aim of this study was t...

Human carbonic anhydrases IX (hCA IX) and XII (hCA XII) are two proteins associated with tumor formation and development. These enzymes have been largely investigated both from a biochemical and a functional point of view. However, limited data are currently available on the characterization of their post-translational modifications (PTMs) and the...

Intrinsically Disordered Proteins (IDPs) lack stable tertiary and secondary structures and are extensively distributed across eukaryotic cells, playing critical roles in cell signaling and regulation. [...]

The Chromatin Assembly Factor 1 is a heterotrimeric complex responsible for the nucleosome assembly during DNA replication and DNA repair. In humans, the largest subunit P150 is the major actor of this process. It has been recently considered as a tumor-associated protein due to its overexpression in many malignancies. Structural and functional stu...

Trichomonas vaginalis is a unicellular parasite responsible for trichomoniasis, which is one of the world’s leading sexually transmitted infections (STIs). The diagnosis and effective treatment of trichomoniasis has become an extremely important goal for global health, due to the increasing experimental evidences showing the relationship between tr...

We report a series of compounds 1–17 derived from the antiepileptic drug Sulthiame (SLT) from which both the benzenesulfonamide and the sultam moiety were retained. All compounds were tested in vitro for their inhibition activity against the human (h) Carbonic Anhydrase (CA; EC 4.2.1.1) I, II, VII, IX and XII isoforms. Among the series, derivatives...

CDCA1 is a very peculiar member of the Carbonic Anhydrase (CA) family. It has been the first enzyme to show an efficient utilization of Cd(II) ions in Nature and a unique adaptation capability to live on the surface ocean. Indeed, in this environment, which is extremely depleted in essential metal ions, CDCA1 can utilize Zn(II) or Cd(II) as catalyt...

To tackle the challenge of isoform selectivity, we explored the entrance of the cavity for selected druggable human Carbonic Anhydrases (hCAs). Based on X-ray crystallographic studies on the 4-(4-(2-chlorobenzoyl)piperazine-1-carbonyl)benzenesulfonamide in complex with the brain expressed hCA VII (PDB code: 7NC4), a series of 4-(4(hetero)aroylpiper...

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 hu...

hCA IX is a multi-domain protein belonging to the family of hCAs which are ubiquitous zinc enzymes that catalyze the reversible hydration of CO2 to HCO3⁻ and H⁺. hCA IX is a tumor-associated enzyme with a limited distribution in normal tissues, but over-expressed in many tumors, and is a promising drug target. Although many studies concerning the C...

It has been clearly established that some proteins or protein regions are devoid of any stable secondary and/or tertiary structure under physiological conditions, but still possess fundamental biological functions [...]

2-(4-Benzhydrylpiperazin-1-yl)-N-(4-sulfamoylphenyl)acetamide is an effective human carbonic anhydrase (hCA) inhibitor designed through the tail approach using the acetamide moiety as linker and the benzhydrylpiperazine group as tail. Here we report the crystal structures of this compound in complex both with the ubiquitous hCA II and the brain-ass...

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 β-class, TvaCA1 and TvaCA2. Here we report the first sulphonamide inhibition study of TvaCA1, with a series of simple aromatic/heterocyclic prim...

The protozoan pathogen Trichomonas vaginalis encodes two carbonic anhydrases (CAs, EC 4.2.1.1) belonging to the β-class. One of these enzymes, T. vaginalis carbonic anhydrase 1 (TvaCA1), was recently cloned and characterized by our group, and its X-ray crystal structure reported. No inhibitors of this enzyme were reported up until now. Here we inve...

Cell plasticity is the ability that cells have to modify their phenotype, adapting to the environment. Cancer progression is under the strict control of the the tumor microenvironment that strongly determines its success by regulating the behavioral changes of tumor cells. The cross-talk between cancer and stromal cells and the interactions with th...

Catechols adopt a peculiar binding mode to the CA active site which involves both the zinc bound water molecule and the “deep water”.

The tumor microenvironment is crucial for the growth of cancer cells, triggering particular biochemical and physiological changes, which frequently influence the outcome of anticancer therapies. The biochemical rationale behind many of these phenomena resides in the activation of transcription factors such as hypoxia-inducible factor 1 and 2 (HIF-1...

p>Triple negative breast cancer (TNBC) is a heterogeneous disease, and even though it occurs in only 15-20% of all patients with breast cancer, it is characterized by an extremely high rate of mortality due to metastatic and drug-resistance recurrent disease. Chemotherapy is the primary established systemic treatment for TNBC patients in both the e...

2-Mercaptobenzoxazole represents an interesting lead compound alternative to the classical sulfonamides for the development of selective carbonic anhydrase inhibitors.

Human carbonic anhydrase (CA; EC 4.2.1.1) isoforms II and VII are implicated in neuronal excitation, seizures and neuropathic pain (NP). Their selective inhibition over off-target CAs is expected to produce an anti-NP action devoid of side effects due to promiscuous CA modulation. Here a drug-design strategy based on the observation of (dis)similar...

We report the synthesis and biochemical evaluation of a series of substituted 4-(4-aroylpiperazine-1-carbonyl)benzenesulfonamides (5a-s) developed as inhibitors of druggable carbonic anhydrase (CA) isoforms, as tools for the identification of new therapeutics. X-ray crystallography confirmed that this class of benzenesulfonamides binds CAs through...

We report the biochemical and structural characterisation of a beta-carbonic anhydrase (β-CA) from Trichomonas vaginalis, a unicellular parasite responsible for one of the world’s leading sexually transmitted infections, trichomoniasis. CAs are ubiquitous metalloenzymes belonging to eight evolutionarily divergent groups (α, β, γ, δ, ζ, η, θ, and ι)...

Human carbonic anhydrases (CAs) have become a well-recognized target for the design of inhibitors and activators with biomedical applications. Accordingly, an enormous amount of literature is available on their biochemical, functional and structural aspects. Nevertheless post-translational modifications (PTMs) occurring on these enzymes and their f...

6A10 is a CA XII inhibitory monoclonal antibody, which was demonstrated to reduce the growth of cancer cells in vitro and in a xenograft model of lung cancer. It was also shown to enhance chemosensitivity of multiresistent cancer cell lines, and to significantly reduce the number of lung metastases in combination with doxorubicin in mice carrying h...

Carbonic anhydrases (CAs) are ubiquitous metallo-enzymes that catalyse the reversible hydration of carbon dioxide to bicarbonate and proton. In humans there are 15 isoforms among which only 12 are catalytically active. Since active human (h) CAs show different efficiency, the understanding of the molecular determinants affecting it is a matter of d...

Recent studies identified the benzoxaborole moiety as a new zinc-binding group able to interact with carbonic anhydrase (CA) active site. Here, we report a structural analysis of benzoxaboroles containing urea/thiourea groups, showing that these molecules are very versatile since they can bind the enzyme assuming different binding conformations and...

Introduction: Based on the initial studies of J. Folkman in 1970s, which led to the proposal of the antiangiogenic therapy, many drugs targeting VEGF or its receptors have been developed with some of them approved for cancer treatment. However, these molecules so far have shown only a limited effect on survival benefits in patients. Thus, new appro...

Guided by the crystal structure of 4-(3,4-dihydroquinolin-1(2H)-ylcarbonyl)benzenesulfonamide 3 in complex with hCA II (PDB code 4Z0Q), a novel series of cycloalkylamino-1-carbonylbenzenesulfonamides was designed and synthesized. Thus, we replaced the quinoline ring with an azepine/piperidine/piperazine nucleus and introduced further modifications...

Human carbonic anhydrase IX (hCA IX) is a tumour-associated enzyme present in a limited number of normal tissues, but overexpressed in several malignant human tumours. It is a transmembrane protein, where the extracellular region consists of a greatly investigated catalytic CA domain and a much less investigated proteoglycan-like (PG) domain. Consi...

N-unsubstituted carbamates have scarcely been investigated so far as Carbonic Anhydrase inhibitors (CAIs). By means of kinetic and structural studies, in this paper we demonstrate that such molecules can effectively...

Under oxidative stress conditions, several constitutive cellular defense systems are activated, which involve both enzymatic systems and molecules with antioxidant properties such as glutathione and vitamins. In addition, proteins containing reactive sulfhydryl groups may eventually undergo reversible redox modifications whose products act as prote...

Although important progress has been achieved in understanding the catalytic mechanism of Carbonic Anhydrases, a detailed picture of all factors influencing the catalytic efficiency of the various human isoforms is still missing. In this paper we report a detailed structural study and theoretical pKa calculations on a hCA VII variant. The obtained...

Human carbonic anhydrase (CA) IX is a tumor‐associated protein, since it is scarcely present in normal tissues, but highly overexpressed in a large number of solid tumors, where it actively contributes to survival and metastatic spread of tumor cells. Due to these features, the characterization of its biochemical, structural, and functional feature...

Protozoans belonging to Plasmodium, Leishmania and Trypanosoma genera provoke widespread parasitic diseases with few treatment options and many of the clinically used drugs experiencing an extensive drug resistance phenomenon. In the last several years, the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) was cloned and characterized in the genome...

Pyridinium containing sulfonamides have been largely investigated as carbonic anhydrase inhibitors (CAIs), showing interesting selectivity features. Nevertheless, only few structural studies are so far available on adducts that these compounds form with diverse CA isoforms. In this paper, we report the structural characterization of the adduct that...

Sulphamate and sulphamide derivatives have been largely investigated as carbonic anhydrase inhibitors (CAIs) by means of different experimental techniques. However, the structural determinants responsible for their different binding mode to the enzyme active site were not clearly defined so far. In this paper, we report the X-ray crystal structure...

On the basis of X-ray crystallographic studies of the complex of hCA II with 4-(3,4-dihydro-1H-isoquinoline-2-carbonyl)benzenesulfonamide (3) (PDB code 4Z1J), a novel series of 4-(1-aryl-3,4-dihydro-1H-isoquinolin-2-carbonyl)benzenesulfonamides (23-33) was designed. Specifically, our idea was to improve the selectivity toward druggable isoforms thr...

Human Carbonic Anhydrase (hCA) IX is a membrane-associated member of the CA enzyme family, involved in solid tumor acidification. This enzyme is a marker of tumor hypoxia and a prognostic factor for several human cancers. In a recent paper we showed that CA IX interacts with cullin-associated NEDD8-dissociated protein 1 (CAND1), a nuclear protein i...

Carbonic anhydrases (CAs) III and VII are two cytosolic isoforms of the α-CA family which catalyze the physiological reaction of carbon dioxide hydration to bicarbonate and proton. Despite these two enzymes share a 49% sequence identity and present a very similar three-dimensional structure, they show profound differences when comparing the specifi...

In this paper we report the synthesis of a series of benzoxaborole derivatives, their inhibition properties against some carbonic anhydrases (CAs), recognized as important drug targets, and the characterization of the binding mode of these molecules to the CA active site. Our data provide the first experimental evidence that benzoxaboroles can be e...

The antimalarial drugs are of fundamental importance in the control of malaria, especially for the lack of efficient treatments and acquired resistance to the existing drugs. For this reason, there is a continuous work in identifying novel, less toxic and effective chemotherapies as well as new therapeutic targets against the causative agents of ma...

Herein we report an in vitro kinetic evaluation against the most relevant human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms (I, II, IX and XII) of a small series of lactate dehydrogenase (LDH, EC 1.1.1.27) inhibitors. All compounds contain a primary sulfonamide zinc-binding group (ZBG) substituted with the 2-thio-6-oxo-1,6-dihydropyrimidine scaff...

JNJ-26990990 ((benzo[b]thien-3-yl)methyl)sulfamide, a sulfamide derivative structurally related to the antiepileptic drug zonisamide, was reported to be devoid of carbonic anhydrase (CA, EC 4.2.1.1) inhibitory properties. Here we report that JNJ-26990990 and its S,S-dioxide analog significantly inhibit six human (h) isoforms, hCA I, II, VII, IX, XI...

Bacterial infections constitute an always growing health problem worldwide. The resistance to antibiotics of an increasing number of bacterial pathogens necessitates a permanent search for new molecules with different mechanisms of action. Histidine biosynthesis is an ancient pathway found in bacteria, archaebacteria, fungi and plants but absent in...

Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes that catalyze the carbon dioxide hydration to bicarbonate and protons, with five genetically distinct classes known to date, the α-, β-, γ-, δ-, and ζ-CAs. These enzymes are involved in a multitude of physiologic processes in organisms all over the phylogenetic tree. Their biochemical feature...

Carbonic anhydrases (CAs) are metalloenzymes present in both prokaryotes and eukaryotes, which play important physiological roles in all life kingdoms. In phytoplankton, CAs are essential for the acquisition of inorganic carbon for photosynthesis, being involved in the carbon-concentrating mechanism (CCM). Recently, CDCA1, a new CA from the marine...

A total of 15 different isoforms of α-carbonic anhydrases have been so far described in humans. These enzymes differ with respect to catalytic properties, cellular localization, and tissue distribution and are involved in a large number of physiological processes. Since abnormal levels and/or activities of these enzymes have been often associated w...

Inhibition of CA II has pharmacological applications in the field of antiglaucoma and diuretic agents, for the treatment of altitude sickness, for some anticonvulsants, and probably against some cancer types. Sulfonamides and their isosteres (sulfamates/sulfamides) constitute the main class of inhibitors targeting CA II. Recently the dithiocarbamat...

Carboxylates are the least investigated class of inhibitors of carbonic anhydrases (CAs). Here we explain the versatility of binding of these molecules to CAs by examining a new adduct of CA II with N-carboxymethyl-saccharin.

New 1,1'-biphenylsulfonamides were synthesized and evaluated as inhibitors of the ubiquitous human carbonic anhydrase isoforms I, II, IX, XII and XIV using acetazolamide (AAZ) as reference compound. The sulfonamides 1-21 inhibited all the isoforms with Ki values in the nanomolar range of concentra-tion, and were superior to AAZ against all of them....

Carbonic anhydrases are ubiquitous metallo-enzymes which catalyze the reversible hydration of carbon dioxide in bicarbonate ions and protons. Recent years have seen an increasing interest in the utilization of these enzymes in CO2 capture and storage processes. However, since this use is greatly limited by the harsh conditions required in these pro...

Hydroxylamine-O-sulfonamide, a molecule incorporating two zinc-binding groups (ZBGs), has been investigated as carbonic anhydrase inhibitor (CAI) by means of kinetic, crystallographic and Raman spectroscopy studies, highlighting interesting results on its mechanism of action. These data can be exploited to design new effective and selective CAIs

The Carbon Concentration Mechanism (CCM) allows phytoplakton species to accumulate the dissolved inorganic carbon (DIC) necessary for an efficient photosynthesis even under carbon dioxide limitation. In this mechanism of primary importance for diatoms, a key role is played by carbonic anhydrase (CA) enzymes which catalyze the reversible hydration o...

Two thermostable α-carbonic anhydrases (α-CAs) isolated from thermophilic Sulfurihydrogenibium spp., namely SspCA (from S. yellowstonensis) and SazCA (from S. azorense), were shown in a previous work to possess interesting complementary properties. SspCA was shown to have an exceptional thermal stability, whereas SazCA demonstrated to be the most a...

In this Letter we reinvestigate the sequence analysis and report a homology model of the carbonic anhydrase (CA, EC 4.2.1.1) from the protozoan parasite Plasmodium falciparum, recently reported by us to belong to a new genetic family, the η-CA class. Our findings show that the metal ion coordination pattern of this CA is unique among all five other...

6-Sulfamoyl-saccharin was investigated as an inhibitor of 11 α-carbonic anhydrase (CA, EC 4.2.1.1) isoforms of human (h) origin, hCA I-XIV, and X-ray crystallographic data were obtained for its adduct with hCA II, the physiologically dominant isoform. This compound possesses two potential zinc-binding groups, the primary sulfamoyl one and the secon...

Human carbonic anhydrase VII (hCA VII) is a cytosolic isoform belonging to the α-CA family that shows high carbon dioxide hydration activity. Recently, S-glutathionylation of two cysteine residues (i.e., Cys183 and Cys217) of this protein was observed, suggesting that hCA VII could act as an oxygen radical scavenger, in addition to its well-establi...

Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous metalloenzymes, present throughout most living organisms and encoded by five evolutionarily unrelated gene families. The Carbonic Anhydrases as Biocatalysts: From Theory to Medical and Industrial Applications presents information on the growing interest in the study of this enzyme family and thei...

A structural study of the adduct which 2-benzylsulfinylbenzoic acid forms with human carbonic anhydrase II is reported, showing a binding mode completely different from any other class of carbonic anhydrase inhibitors investigated so far: this carboxylate binds in a pocket situated out of the enzyme active site.

A new series of compounds containing a sulfamide moiety as zinc-binding group (ZBG) has been synthesized and tested for determining inhibitory properties against four human carbonic anhydrase (hCA) isoforms, namely, CAs I, II, IX, and XII. The X-ray structure of the cytosolic dominant isoform hCA II in complex with the best inhibitor of the series...

The potential of carbonic anhydrase (CA) family as target for the drug design of inhibitors with various medicinal chemistry applications has been recognized from long time, whereas the industrial interest in using these enzymes as biocatalysts for carbon dioxide sequestration and biofuel production is only recently emerging. However, an efficient...

Carbonic Anhydrase isoform XIV (CA XIV) is the last member of the human (h) CA family discovered so far, being localized in brain, kidneys, colon, small intestine, urinary bladder, liver and spinal cord. It has recently been described as a possible drug target for treatment of epilepsy, some retinopathies as well as some skin tumors. hCA XIV is a m...

Carbonic anhydrases (CAs) are metalloenzymes and exist as five distinct families, the a-, b-, g-, d- and z-CAs, in all organisms from the tree of life.

Protein disulfide oxidoreductases (PDOs) are proteins involved in disulfide bond formation playing a crucial role in adaptation to extreme environment. This paper reports the functional and structural characterization of Sso1120, a PDO from the hyperthermophilic archaeon Sulfolobus solfataricus. The protein was expressed in Escherichia coli and pur...

l-histidinol dehydrogenase from Brucella suis (BsHDH) is an enzyme involved in the histidine biosynthesis pathway which is absent in mammals, thus representing a very interesting target for the development of anti-Brucella agents. In this paper we report the crystallographic structure of a mutated form of BsHDH both in its unbound form and in compl...

A series of nitroimidazoles incorporating sulfonamide/sulfamide/sulfamate moieties were designed and synthesized as radio/chemosensitizing agent targeting the tumor-associated carbonic anhydrase (CA) isoforms IX and XII. Most of the new compounds were nanomolar inhibitors of these isoforms. Crystallographic studies on the complex of hCA II with the...

Abstract C3 and C4 plant carbonic anhydrases (CAs) are zinc-enzymes that catalyze the reversible hydration of CO2. They are sub-divided in three classes: α, β and γ, being distributed between both photosynthetic subtypes. The C4 dicotyledon species Flaveria bidentis (L.) "Kuntze" contains a small gene family encoding three distinct β-CAs, named Fbi...

Abstract Human carbonic anhydrase VII (hCA VII) is a cytosolic enzyme with high carbon dioxide hydration activity. Recently, S-glutathionylation of two cysteine residues from the enzyme was revealed, suggesting a new role as oxygen radical scavenger. We analyzed the effect of native and tetramutated hCA VII (all cysteines mutated into serines) in a...

SspCA, a novel ‘extremo-α-carbonic anhydrase’ isolated from the thermophilic bacterium Sulfurihydrogenibium yellow­stonense YO3AOP1, is an efficient catalyst for the hydration of CO2 and presents exceptional thermostability. Indeed, SspCA retains a high catalytic activity even after being heated to 343–373 K for several hours. Here, the crystallogr...

Introduction: Human carbonic anhydrases (EC 4.2.1.1) IX (hCA IX) and XII (hCA XII) are two tumor-associated proteins, being overexpressed in many tumors and involved in critical processes associated with cancer progression and response to therapy. Both are multi-domain proteins consisting of an extracellular catalytic domain (CA), a transmembrane...

Introduction: Carbonic anhydrases (CAs, EC 4.2.1.1) exist as five genetically distinct families (α, β, γ, δ and ζ) in organisms all over the phylogenetic tree. Due to the ubiquity of such enzymes, the selective inhibition and polypharmacology of inhibitors is an important aspect of all drug design campaigns. There are several classes of CA inhibit...

Fructosamines, also known as Amadori products, are formed by the condensation of glucose with the amino group of amino acids or proteins. These compounds are precursors of advanced glycation end products (AGEs) that can be formed either endogenously during aging and diabetes, and exogenously in heat-processed food. The negative effects of dietary A...

Several β-carbonic anhydrases (CAs, EC 4.2.1.1) are present in all land plants examined thus far. Here we report the first detailed biochemical characterization of one such isoform, FbiCA 1, from the C plant Flaveria bidentis, which was cloned, purified and characterized as recombinant protein. FbiCA 1 has an interesting CO hydrase catalytic activi...

Carbonic anhydrase IX (CA IX) is a transmembrane protein affecting pH regulation, cell migration/invasion and survival in hypoxic tumors. Although the pathways related to CA IX have begun to emerge, molecular partners mediating its functions remain largely unknown. Here we characterize the CA IX interactome in hypoxic HEK-293 cells. Most of the ide...

Hydroxamates (R-CONHOH) have been scarcely investigated as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors (CAIs). An inhibition/structural study of PhCONHOH is reported against all human isoforms. Comparing aliphatic (R = Me and CF(3)) and aromatic (R = Ph) hydroxamates as CAIs, we prove that CONHOH is a versatile zinc binding group. Depending on t...