Novel Sulfamide-Containing Compounds as Selective Carbonic Anhydrase I Inhibitors

Berrino, Emanuela; Bua, Silvia; Mori, Mattia; Botta, Maurizio; Murthy, Vallabhaneni S.; Vijayakumar, V.; Tamboli, Yasinalli; Bartolucci, Gianluca; Mugelli, Alessandro; Cerbai, Elisabetta; Supuran, Claudiu T.; Carta, Fabrizio

doi:10.3390/molecules22071049

Cited by 27 publications

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“…The next three papers in the special issue [ 37 , 38 , 39 ] deal with targeting carbonic anhydrases (CAs) from various organisms [ 1 , 2 , 8 , 9 , 10 , 11 , 12 ]. Indeed, these metalloenzymes are potently inhibited by various classes of sulfonamides, many of which show pharmacologic applications as antiglaucoma [ 8 , 10 ], antiobesity [ 13 ], antitumor [ 8 , 9 , 11 , 18 ], or diuretic [ 15 ] drugs.…”

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confidence: 99%

“…In the paper by Berrino et al [ 39 ] a new series of benzenesulfamide derivatives (-NH-SO 2 NH 2 ) which incorporate a 1-benzhydrylpiperazine tail, connected to the sulfonamide scaffolf by means of β-alanyl or nipecotyl spacers was reported and investigated for the inhibition of CAs of human (h) origin, such as hCA I, II, IV and IX. Some of these isoforms are established drug targets, but many sulfonamide or sulfamide inhibitors show little selectivity when inhibiting them.…”

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confidence: 99%

“…Some of these isoforms are established drug targets, but many sulfonamide or sulfamide inhibitors show little selectivity when inhibiting them. Some of the new sulfamides reported in this paper did show some selective inhibitory profile, mainly against hCA I, which has been rationalized by using computational methods [ 39 ].…”

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Special Issue: Sulfonamides

Supuran

2017

Molecules

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The sulfonamides and their structurally related derivatives, such as the sulfamates and sulfamides, possess the general formula A-SO2NHR, in which the functional group is either directly bound to an aromatic, heterocyclic, aliphatic, or sugar scaffold (of type A), or appended to such a scaffold via a heteroatom, most frequently oxygen or nitrogen (leading thus to sulfamates and sulfamides, respectively) [...]

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Special Issue: Sulfonamides

Supuran

2017

Molecules

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“…An Applied Photophysics stopped-flow instrument was used for assaying the CA catalyzed CO 2 hydration activity ( Khalifah, 1971 ). The method was exactly as described previously ( Berrino et al, 2017 ) except that the inhibitor dilutions were done up to 0.5 nM.…”

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confidence: 99%

Identification and characterization of a novel zebrafish (Danio rerio) pentraxin–carbonic anhydrase

Patrikainen

Tolvanen

Aspatwar

et al. 2017

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BackgroundCarbonic anhydrases (CAs) are ubiquitous, essential enzymes which catalyze the conversion of carbon dioxide and water to bicarbonate and H+ ions. Vertebrate genomes generally contain gene loci for 15–21 different CA isoforms, three of which are enzymatically inactive. CA VI is the only secretory protein of the enzymatically active isoforms. We discovered that non-mammalian CA VI contains a C-terminal pentraxin (PTX) domain, a novel combination for both CAs and PTXs.MethodsWe isolated and sequenced zebrafish (Danio rerio) CA VI cDNA, complete with the sequence coding for the PTX domain, and produced the recombinant CA VI–PTX protein. Enzymatic activity and kinetic parameters were measured with a stopped-flow instrument. Mass spectrometry, analytical gel filtration and dynamic light scattering were used for biophysical characterization. Sequence analyses and Bayesian phylogenetics were used in generating hypotheses of protein structure and CA VI gene evolution. A CA VI–PTX antiserum was produced, and the expression of CA VI protein was studied by immunohistochemistry. A knock-down zebrafish model was constructed, and larvae were observed up to five days post-fertilization (dpf). The expression of ca6 mRNA was quantitated by qRT-PCR in different developmental times in morphant and wild-type larvae and in different adult fish tissues. Finally, the swimming behavior of the morphant fish was compared to that of wild-type fish.ResultsThe recombinant enzyme has a very high carbonate dehydratase activity. Sequencing confirms a 530-residue protein identical to one of the predicted proteins in the Ensembl database (ensembl.org). The protein is pentameric in solution, as studied by gel filtration and light scattering, presumably joined by the PTX domains. Mass spectrometry confirms the predicted signal peptide cleavage and disulfides, and N-glycosylation in two of the four observed glycosylation motifs. Molecular modeling of the pentamer is consistent with the modifications observed in mass spectrometry. Phylogenetics and sequence analyses provide a consistent hypothesis of the evolutionary history of domains associated with CA VI in mammals and non-mammals. Briefly, the evidence suggests that ancestral CA VI was a transmembrane protein, the exon coding for the cytoplasmic domain was replaced by one coding for PTX domain, and finally, in the therian lineage, the PTX-coding exon was lost. We knocked down CA VI expression in zebrafish embryos with antisense morpholino oligonucleotides, resulting in phenotype features of decreased buoyancy and swim bladder deflation in 4 dpf larvae.DiscussionThese findings provide novel insights into the evolution, structure, and function of this unique CA form.

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“…To further explore the molecular determinants responsible for potent and selective inhibition of hCAs by carboxylic acids, here we used the tail approach to design a number of derivatives of the previous CAI hit GV2-20. Indeed, this is a versatile tool to design and optimize hit and lead CAIs possibly improving potency and selectivity [ 49 , 50 ]. Our previous results showed that the symmetric 3,5-dinitrobenzoic acid moiety of GV2-20 binds preferentially the catalytic site, thus becoming the head of the molecular scaffold; accordingly, the tail moiety is expected to bind the external and highly variable region of hCAs [ 51 ] and enhance selectivity inhibition.…”

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Potent and Selective Carboxylic Acid Inhibitors of Tumor-Associated Carbonic Anhydrases IX and XII

et al. 2017

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Selective inhibition of tumor-associated carbonic anhydrase (CA; EC 4.2.1.1) isoforms IX and XII is a crucial prerequisite to develop successful anticancer therapeutics. Herein, we confirmed the efficacy of the 3-nitrobenzoic acid substructure in the design of potent and selective carboxylic acid derivatives as CAs inhibitors. Compound 10 emerged as the most potent inhibitor of the tumor-associated hCA IX and XII (Ki = 16 and 82.1 nM, respectively) with a significant selectivity with respect to the wide spread hCA II. Other 3-nitrobenzoic acid derivatives showed a peculiar CA inhibition profile with a notable potency towards hCA IX.

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Novel Sulfamide-Containing Compounds as Selective Carbonic Anhydrase I Inhibitors

Cited by 27 publications

References 32 publications

Special Issue: Sulfonamides

Special Issue: Sulfonamides

Identification and characterization of a novel zebrafish (Danio rerio) pentraxin–carbonic anhydrase

Potent and Selective Carboxylic Acid Inhibitors of Tumor-Associated Carbonic Anhydrases IX and XII

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