1,2-Benzisothiazole Derivatives Bearing 4-, 5-, or 6-Alkyl/arylcarboxamide Moieties Inhibit Carbonic Anhydrase Isoform IX (CAIX) and Cell Proliferation under Hypoxic Conditions

Coviello, Vito; Marchi, Beatrice; Sartini, Stefania; Quattrini, Luca; Marini, Anna María; Simorini, Francesca; Taliani, Sabrina; Salerno, Silvia; Orlandi, Paola; Fioravanti, Anna; Desidero, Teresa Di; Vullo, Daniela; Settimo, Federico Da; Supuran, Claudiu T.; Bocci, Guido; Motta, Concettina La

doi:10.1021/acs.jmedchem.6b00616

Cited by 24 publications

(21 citation statements)

References 40 publications

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“…Carbonic anhydrase IX (CAIX) plays an important role in the growth and metastasis of numerous tumors (including renal cancer, cervical cancer, colon cancer, prostate cancer, breast cancer, head and neck tumors, and so on), and has been used for the diagnosis, treatment, and prognosis of malignant tumors. [18][19][20][21][22][23] Targeted ligands against CAIX include monoclonal antibodies, nanobodies, and affibodies, as well as polypeptides that we studied earlier. 18,22,24,25 Aptamers are single-stranded DNA or RNA oligonucleotides that specifically bind to biological macromolecules or cells through a specific spatial structure.…”

Section: Introductionmentioning

confidence: 99%

CAIX aptamer-functionalized targeted nanobubbles for ultrasound molecular imaging of various tumors

Zhu¹,

Wang²,

Liu³

et al. 2018

IJN

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PurposeTargeted nanobubbles can penetrate the tumor vasculature and achieve ultrasound molecular imaging (USMI) of tumor parenchymal cells. However, most targeted nanobubbles only achieve USMI of tumor parenchymal cells from one organ, and their distribution, loading ability, and binding ability in tumors are not clear. Therefore, targeted nanobubbles loaded with carbonic anhydrase IX (CAIX) aptamer were fabricated for USMI of various tumors, and the morphological basis of USMI with targeted nanobubbles was investigated.Materials and methodsThe specificity of CAIX aptamer at the cellular level was measured by immunofluorescence and flow cytometry. Targeted nanobubbles loaded with CAIX aptamer were prepared by a maleimidethiol coupling reaction, and their binding ability to CAIX-positive tumor cells was analyzed in vitro. USMI of targeted and non-targeted nanobubbles was performed in tumor-bearing nude mice. The distribution, loading ability, and binding ability of targeted nanobubbles in xenograft tumor tissues were demonstrated by immunofluorescence.ResultsCAIX aptamer could specifically bind to CAIX-positive 786-O and Hela cells, rather than CAIX-negative BxPC-3 cells. Targeted nanobubbles loaded with CAIX aptamer had the advantages of small size, uniform distribution, regular shape, and high safety, and they could specifically accumulate around 786-O and Hela cells, while not binding to BxPC-3 cells in vitro. Targeted nanobubbles had significantly higher peak intensity and larger area under the curve than non-targeted nanobubbles in 786-O and Hela xenograft tumor tissues, while there was no significant difference in the imaging effects of targeted and non-targeted nanobubbles in BxPC-3 xenograft tumor tissues. Immunofluorescence demonstrated targeted nanobubbles could still load CAIX aptamer after penetrating the tumor vasculature and specifically binding to CAIX-positive tumor cells in xenograft tumor tissues.ConclusionTargeted nanobubbles loaded with CAIX aptamer have a good imaging effect in USMI of tumor parenchymal cells, and can improve the accuracy of early diagnosis of malignant tumors from various organs.

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Section: Introductionmentioning

confidence: 99%

CAIX aptamer-functionalized targeted nanobubbles for ultrasound molecular imaging of various tumors

Zhu¹,

Wang²,

Liu³

et al. 2018

IJN

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“…Several potent and selective hCA IX and hCA XII inhibitors have been tested for their anticancer activity in various in vitro and in vivo models. Studies revealed that numerous potent hCA IX and hCA XII inhibitors have shown promising anticancer activity in preclinical investigation [327][328][329][330][331][332]. In this line,Winum et al evaluated anticancer effect of potent and selective hCA IX as well as hCA XII inhibitors belonging to sulfamate class.…”

mentioning

confidence: 99%

Progress in the development of human carbonic anhydrase inhibitors and their pharmacological applications: Where are we today?

Mishra

Tiwari

Supuran

2020

Medicinal Research Reviews

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190

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Carbonic anhydrases (CAs, EC 4.2.1.1) are widely distributed metalloenzymes in both prokaryotes and eukaryotes. They efficiently catalyze the reversible hydration of carbon dioxide to bicarbonate and H + ions and play a crucial role in regulating many physiological processes. CAs are wellstudied drug target for various disorders such as glaucoma, epilepsy, sleep apnea, and high altitude sickness. In the past decades, a large category of diverse families of CA inhibitors (CAIs) have been developed and many of them showed effective inhibition toward specific isoforms, and effectiveness in pathological conditions in preclinical and clinical settings. The discovery of isoform-selective CAIs in the last decade led to diminished side effects associated with off-target isoforms inhibition. The many new classes of such compounds will be discussed in the review, together with strategies for their development. Pharmacological advances of the newly emerged CAIs in diseases not usually associated with CA inhibition (neuropathic pain, arthritis, cerebral ischemia, and cancer) will also be discussed.

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“…As mentioned above, the main problem with the drug design of CA IX inhibitors was to obtain compounds which should selectively inhibit CA IX without a significant inhibitory effect against the physiologically dominant, highly abundant isoforms CA I and II (and also other off‐target isoforms) . This goal seemed to be difficult to achieve initially, but several classes of sulfonamides and their isosteres (sulfamates, sulfamides), most of which were obtained using the tail approach, allowed to obtain compounds with these features . Only the most relevant studies will be mentioned here, as this class of CAIs is the most investigated one and a high number of drug design studies (>400) have been reported since 2003 .…”

Section: Development Of Agents Targeting Carbonic Anhydrase IXmentioning

confidence: 99%

“…Thus, these three subclasses of CAIs will be dealt with together here in this section. All these studies allowed the detailed understanding of the factors governing activity and selectivity for inhibiting CA IX over other CA isoforms, and are summarized below: the zinc‐binding group of the sulfonamide, sulfamate, and sulfamide is not highly influential for obtaining potent and CA IX‐selective inhibitors. In fact, many classes of such derivatives show similar CA IX inhibitory/selectivity profiles, such as various sulfonamides, sulfamates, and sulfamides …”

Section: Development Of Agents Targeting Carbonic Anhydrase IXmentioning

confidence: 99%

Inhibition of carbonic anhydrase IX targets primary tumors, metastases, and cancer stem cells: Three for the price of one

Supuran

Alterio

Fiore

et al. 2018

Medicinal Research Reviews

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220

160

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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 features for drug design purposes has been extensively carried out, with consequent development of several highly selective small molecule inhibitors and monoclonal antibodies to be used for different purposes. Aim of this review is to provide a comprehensive state-of-the-art of studies performed on this enzyme, regarding structural, functional, and biomedical aspects, as well as the development of molecules with diagnostic and therapeutic applications for cancer treatment. A brief description of additional pharmacologic applications for CA IX inhibition in other diseases, such as arthritis and ischemia, is also provided.

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1,2-Benzisothiazole Derivatives Bearing 4-, 5-, or 6-Alkyl/arylcarboxamide Moieties Inhibit Carbonic Anhydrase Isoform IX (CAIX) and Cell Proliferation under Hypoxic Conditions

Cited by 24 publications

References 40 publications

CAIX aptamer-functionalized targeted nanobubbles for ultrasound molecular imaging of various tumors

CAIX aptamer-functionalized targeted nanobubbles for ultrasound molecular imaging of various tumors

Progress in the development of human carbonic anhydrase inhibitors and their pharmacological applications: Where are we today?

Inhibition of carbonic anhydrase IX targets primary tumors, metastases, and cancer stem cells: Three for the price of one

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