SLC-0111 enaminone analogs, 3/4-(3-aryl-3-oxopropenyl) aminobenzenesulfonamides, as novel selective subnanomolar inhibitors of the tumor-associated carbonic anhydrase isoform IX

Eldehna, Wagdy M.; Abo-Ashour, Mahmoud F.; Berrino, Emanuela; Vullo, Daniela; Ghabbour, Hazem A.; Al-Rashood, Sara T.; Hassan, Ghada S.; Alkahtani, Hamad M.; Almehizia, Abdulrahman A.; Alharbi, Amal; Abdel‐Aziz, Hatem A.

doi:10.1016/j.bioorg.2018.11.014

Cited by 53 publications

(31 citation statements)

References 43 publications

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“…The discovery of other SLC-0111 analogs was continued through two new studies that described the synthesis of novel sets of thioureido and selenoureido CAIs. In these studies, the SLC-0111 ureido oxygen was replaced with a sulfur or selenium atom (Compound 13 , Figure 3 ) [ 150 , 151 ]. The inhibition profile for both thioureido and selenoureido SLC-0111 congeners showed a loss of selectivity for the inhibition of the cancer-associated cytosolic h CA isoforms [ 150 , 151 ].…”

Section: Validation Of Ca Ix/xii As Anticancer Drug Targetsmentioning

confidence: 99%

“…In these studies, the SLC-0111 ureido oxygen was replaced with a sulfur or selenium atom (Compound 13 , Figure 3 ) [ 150 , 151 ]. The inhibition profile for both thioureido and selenoureido SLC-0111 congeners showed a loss of selectivity for the inhibition of the cancer-associated cytosolic h CA isoforms [ 150 , 151 ]. Moreover, Eldehna et al, in 2019, developed a series of 3/4-(3-aryl-3-oxopropenyl)aminobenzenesulfonamide derivatives as novel SLC-0111 enaminone analogs (Compound 14 , Figure 3 ).…”

Section: Validation Of Ca Ix/xii As Anticancer Drug Targetsmentioning

confidence: 99%

“…All the reported enaminones exhibited good selectivity toward hCA IX over hCA I and II. The structure-activity relationship (SAR) outcomes highlighted the significance of the incorporation of a bulkier aryl tail such as the 2-naphthyl ring [ 151 ].…”

Section: Validation Of Ca Ix/xii As Anticancer Drug Targetsmentioning

confidence: 99%

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Carbonic Anhydrase Inhibitors Targeting Metabolism and Tumor Microenvironment

et al. 2020

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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-1/2). In turn, the HIF pathway activates a number of genes including those involved in glucose metabolism, angiogenesis, and pH regulation. Several carbonic anhydrase (CA, EC 4.2.1.1) isoforms, such as CA IX and XII, actively participate in these processes and were validated as antitumor/antimetastatic drug targets. Here, we review the field of CA inhibitors (CAIs), which selectively inhibit the cancer-associated CA isoforms. Particular focus was on the identification of lead compounds and various inhibitor classes, and the measurement of CA inhibitory on-/off-target effects. In addition, the preclinical data that resulted in the identification of SLC-0111, a sulfonamide in Phase Ib/II clinical trials for the treatment of hypoxic, advanced solid tumors, are detailed.

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Section: Validation Of Ca Ix/xii As Anticancer Drug Targetsmentioning

confidence: 99%

Section: Validation Of Ca Ix/xii As Anticancer Drug Targetsmentioning

confidence: 99%

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Carbonic Anhydrase Inhibitors Targeting Metabolism and Tumor Microenvironment

et al. 2020

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“…CA IX is highly overexpressed in many types of cancer 39,40 . For example, its expression is increased considerably in solid tumours of uterus, kidney, lung, colon, breast, brain, and ovary [41][42][43][44] . Tumour cells decrease their extracellular pH by lactic acid production and CO 2 hydration, which is catalysed by CAs ( Figure 2).…”

Section: Tumour-associated Ca IXmentioning

confidence: 99%

Carbonic anhydrase IX as a novel candidate in liquid biopsy

Guler

Supuran

Capasso

2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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Among the diagnostic techniques for the identification of tumour biomarkers, the liquid biopsy is considered one that offers future research on precision diagnosis and treatment of tumours in a non-invasive manner. The approach consists of isolating tumor-derived components, such as circulating tumour cells (CTC), tumour cell-free DNA (ctDNA), and extracellular vesicles (EVs), from the patient peripheral blood fluids. These elements constitute a source of genomic and proteomic information for cancer treatment. Within the tumour-derived components of the body fluids, the enzyme indicated with the acronym CA IX and belonging to the superfamily of carbonic anhydrases (CA, EC 4.2.1.1) is a promising aspirant for checking tumours. CA IX is a transmembrane-CA isoform that is strongly overexpressed in many cancers being not much diffused in healthy tissues except the gastrointestinal tract. Here, it is summarised the role of CA IX as tumour-associated protein and its putative relationship in liquid biopsyfor diagnosing and monitoring cancer progression. ARTICLE HISTORY

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“…β-Enaminones are an important building block for the synthesis of many compounds which have pharmacological features including antitumor [1,2], anti-inflammatory [3], anti-epileptic [4], anticonvulsant [5], antibacterial [6] and other therapeutic agents [7][8][9]. Some of the reported heterocycles which β-enaminones were utilized as precursors in the synthetic routes of pharmacologically active precursors such as pyrazoles, pyridinones, dibenzodiazepines, quinolines, oxazoles and tetrahydrobenzoxazines [10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

One-Pot Synthesis, X-ray Single Crystal and Molecular Insight of Enaminone-Based β-Morpholino-/N-Methylpiperazinyl-/Pyrrolidinylpropiophenone

et al. 2020

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One-pot synthesis of three enaminones, (E)-1-(4-chlorophenyl)-3-morpholinoprop-2-en-1-one 1, (E)-1-(4-chlorophenyl)-3-(4-methylpiperazin-1-yl)prop-2-en-1-one 2, and (E)-1-(4-chlorophenyl)-3-(pyrrolidin-1-yl)prop-2-en-1-one 3 were achieved. The synthetic protocol via three components reaction of p-chloroacetophenone with DMFDMA (N,N-dimethylformamid-dimethylacetal) and the corresponding secondary amines (morpholine/N-methylpiperazine/pyrrolidine) in dioxane under heating for 2.5–4 h at 102 °C yielded the requisite enaminones. This protocol has the advantage of no separation of intermediate, no need for column purification with quantitative yield for the target compounds. The chemical features of the β-enaminones 1–3 were assigned by NMR. β-Enaminones 1, and 2 were assigned by single crystal X-ray diffraction technique. The intermolecular interactions in the crystal structures were analyzed quantitatively using Hirshfeld analysis. The Cl…H and O…H hydrogen bonds are common in both compounds while the C-H…π and N…H contacts are more significant in 2 than 1. DFT studies were investigated to show the electronic and spectroscopic properties (NMR and UV-Vis) of the studied systems.

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SLC-0111 enaminone analogs, 3/4-(3-aryl-3-oxopropenyl) aminobenzenesulfonamides, as novel selective subnanomolar inhibitors of the tumor-associated carbonic anhydrase isoform IX

Cited by 53 publications

References 43 publications

Carbonic Anhydrase Inhibitors Targeting Metabolism and Tumor Microenvironment

Carbonic Anhydrase Inhibitors Targeting Metabolism and Tumor Microenvironment

Carbonic anhydrase IX as a novel candidate in liquid biopsy

One-Pot Synthesis, X-ray Single Crystal and Molecular Insight of Enaminone-Based β-Morpholino-/N-Methylpiperazinyl-/Pyrrolidinylpropiophenone

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