Identification of Potent and Selective Human Carbonic Anhydrase VII (hCA VII) Inhibitors

Gitto, Rosaria; Agnello, Stefano; Ferro, Stefania; Vullo, Daniela; Supuran, Claudiu T.; Chimirri, Alba

doi:10.1002/cmdc.201000044

Cited by 26 publications

(22 citation statements)

References 24 publications

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“…In fact, the most developed research area on CA VII has been linked to drug development, which has led to the discoveries of several potent activators and inhibitors for this isozyme [16,17]. The expression of CA VII protein was first studied in the brain tissue [18].…”

Section: Introductionmentioning

confidence: 99%

Carbonic anhydrase VII–a potential prognostic marker in gliomas

Bootorabi¹,

Haapasalo²,

Smith³

et al. 2011

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Carbonic anhydrase VII (CA VII) is a cytosolic enzyme expressed in several organs, including the human brain, but it has not been investigated earlier in any tumors. We designed the present study to evaluate CA VII expression in a cohort of human diffuse astrocytomas, mixed oligoastrocytomas and oligodendrogliomas. CA VII immunostaining was correlated to clinicopathologic findings, survival data, and expression of other molecular factors, including Ki-67, p53 protein and epidermal growth factor receptor. CA VII-positive staining was observed in 94% of astrocytomas and 85% of oligodendrogliomas. In the tumor specimens, strong positive areas were often located in close proximity to necrosis. The CA VII immunoreactivity showed positive correlation with tumor malignancy grades of astrocytomas (p = 0.02, chi-square test). In all tumor categories, CA VII-positive staining was often seen in the endothelial cells of neovessels in addition to the tumor cells. CA VII intensity showed no significant association with p53 nor did it correlate with the amplification of epidermal growth factor receptor (analyzed only in astrocytomas) or cell proliferation. Our present results show that CA VII may act as a useful biomarker in histopathologic diagnostics of gliomas. The high expression of CA VII in the tumor cells and endothelium suggests important roles for the enzyme in tumor metabolism. The results also led us to conclude that CA VII might serve as a marker of poor prognosis in diffuse astrocytomas.

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Section: Introductionmentioning

confidence: 99%

Carbonic anhydrase VII–a potential prognostic marker in gliomas

Bootorabi¹,

Haapasalo²,

Smith³

et al. 2011

Health

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“…The AAZ (1), TMP (2) and classical CA inhibitors (CAIs) contain a sulfamide, sulfonamide or sulfamate moiety able to coordinate the metal within the catalytic binding site thus blocking the CA enzymatic activity. [24][25][26][27][28][29][30][31][32][33][34][35][36][37] X-ray crystallographic data confirmed that hCA isoform selectivity is generally controlled by the remaining molecular frame. [36,[38][39][40][41][42][43][44] So the high selectivity towards several isoforms is conditioned by profitable interactions between the hydrophobic/hydrophilic residues on the CA cleft and suitable functional groups of the most selective hCAIs.…”

Section: Introductionmentioning

confidence: 70%

Carbonic anhydrase inhibitors: Design, synthesis and structural characterization of new heteroaryl-N-carbonylbenzenesulfonamides targeting druggable human carbonic anhydrase isoforms

Buemi

Luca

Ferro

et al. 2015

European Journal of Medicinal Chemistry

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“…Moreover, by searching for CA isoform selectivity we designed and synthesized a series of isoquinoline sulfonamides. The synthetic procedures employed to obtain designed isoquinoline–sulfonamides 4 – 22 as racemic mixtures are described in Scheme . The experimental details as well as careful structural characterization of compounds 4 – 22 can be found in the Supporting Information.…”

Section: Resultsmentioning

confidence: 99%

“…The active zinc ion is coordinated by three histidine residues (i.e., His94, His96, and His119) and water/hydroxide ions react with carbon dioxide to give bicarbonate. The classical CAIs such as compounds 1 – 3 (Figure ) contain a sulfamide, sulfonamide, or sulfamate moiety able to coordinate the zinc ion within the catalytic binding site, which thus blocks the enzymatic activity of the CA . X‐ray crystallography has confirmed that the selectivity of the hCA isoform is generally controlled by the remaining molecular frame .…”

Section: Introductionmentioning

confidence: 99%

In Vivo Evaluation of Selective Carbonic Anhydrase Inhibitors as Potential Anticonvulsant Agents

et al. 2016

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Epilepsy is a common neurological disorder caused by an imbalance between inhibitory and excitatory neurotransmission. It is well known that neuronal excitability is related to γ-aminobutyric acid (GABA)ergic depolarization. HCO3 (-) -dependent depolarization can be suppressed by membrane-permeable inhibitors of carbonic anhydrase. We previously identified some isoquinoline sulfonamides as potent and selective inhibitors of the human carbonic anhydrase II and VII (hCA II and hCA VII) isoforms. Given that hCA II and hCA VII are specific isoforms involved in GABA-mediated neuronal excitation, we hypothesized that they could represent the biological target for the development of new anticonvulsant agents. Therefore, for selected isoquinoline sulfonamides, we preliminarily tested their ability to prevent audiogenic seizures in DBA/2 mice. All compounds were evaluated after intraperitoneal administration, and some of them proved to protect the mice against convulsions. Among this series of compounds, several derivatives showed combined in vivo efficacy with inhibitory effects toward the targeted carbonic anhydrases (i.e., hCA II and hCA VII). Specifically, the most interesting molecule was 1-(4-aminophenyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-sulfonamide (6), which proved to be a more active and selective hCA VII inhibitor than the reference compound topiramate. Further studies to explore the in vivo pharmacokinetic profile of the most active compounds may help to provide insight into the future design of selective hCA VII inhibitors.

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Identification of Potent and Selective Human Carbonic Anhydrase VII (hCA VII) Inhibitors

Cited by 26 publications

References 24 publications

Carbonic anhydrase VII–a potential prognostic marker in gliomas

Carbonic anhydrase VII–a potential prognostic marker in gliomas

Carbonic anhydrase inhibitors: Design, synthesis and structural characterization of new heteroaryl-N-carbonylbenzenesulfonamides targeting druggable human carbonic anhydrase isoforms

In Vivo Evaluation of Selective Carbonic Anhydrase Inhibitors as Potential Anticonvulsant Agents

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