Expanding the anticancer potential of 1,2,3-triazoles via simultaneously targeting Cyclooxygenase-2, 15-lipoxygenase and tumor-associated carbonic anhydrases

Elzahhar, Perihan A.; Wahab, Shrouk M. Abd El; Elagawany, Mohamed; Daabees, Hoda G.; Belal, Ahmed S.F.; El‐Yazbi, Ahmed F.; Eid, Ali H.; Alaaeddine, Rana; Hegazy, Rehab; Allam, Rasha M.; Helmy, Maged W.; Elgendy, Bahaa; Angeli, Andrea; El-Hawash, Soad A.M.

doi:10.1016/j.ejmech.2020.112439

Cited by 48 publications

(36 citation statements)

References 59 publications

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“…These compounds were also docked within the active sites of the three enzymes, showing favourable interaction, but as for the preceding study, the docking with the CA IX active site was performed with the neutral and not the deprotonated sulphonamide. However, the interaction with the zinc ion was in this case observed, being in fact one of the main factors responsible for the effective inhibition of these enzymes 71 .…”

Section: Antitumor Hybrid Drugs Incorporating Cais Conjugated With Other Cheotypesmentioning

confidence: 65%

“…Some of the most widely used anticancer drugs nowadays are the tyrosine kinase inhibitors and the tubulin polymerisation inhibitors, with many new representatives of these classes being launched each year 69 . Thus, in this paragraph I will examine a set of hybridisation approaches which involve CAIs and several other, rather heterogeneous classes of antitumor agents, among which the epidermal growth factor receptor (EGFR) antagonists (this protein has kinase activity) 70 , the 15-lipoxygenase (15-LOX)/COX-2 (multitargeting of tree different proteins) inhibitors 71 , the telomerase inhibitors 72 , the P-glycoprotein (P-gp) inhibitors 73 , and the thioredoxin inhibitors 74 , 75 .…”

Section: Antitumor Hybrid Drugs Incorporating Cais Conjugated With Other Cheotypesmentioning

confidence: 99%

“…Elzahhar et al. 71 reported a multitargeting strategy involving three different targets: CAs, COX-2 and 15-LOX, all enzymes found to be overexpressed in some types of tumours. Some of the reported derivatives, such as 37 and 38 ( Figure 13 ) showed nanomolar CA IX/XII and COX-2 inhibitory action and micromolar inhibition of 15-LOX, and possessed effective antiproliferative action against hepatic (HepG2), breast (MCF7) and lung (A549) cancer cell lines 71 .…”

Section: Antitumor Hybrid Drugs Incorporating Cais Conjugated With Other Cheotypesmentioning

confidence: 99%

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Multitargeting approaches involving carbonic anhydrase inhibitors: hybrid drugs against a variety of disorders

Supuran

2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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Carbonic anhydrases (CAs, EC 4.2.1.1) are enzymes involved in a multitude of diseases, and their inhibitors are in clinical use as drugs for the management of glaucoma, epilepsy, obesity, and tumours. In the last decade, multitargeting approaches have been proposed by hybridisation of CA inhibitors (CAIs) of sulphonamide, coumarin, and sulphocoumarin types with NO donors, CO donors, prostaglandin analogs, β-adrenergic blockers, non-steroidal anti-inflammatory drugs, and a variety of anticancer agents (cytotoxic drugs, kinase/telomerase inhibitors, P-gp and thioredoxin inhibitors). Many of the obtained hybrids showed enhanced efficacy compared to the parent drugs, making multitargeting an effective and innovative approach for various pharmacological applications.

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Section: Antitumor Hybrid Drugs Incorporating Cais Conjugated With Other Cheotypesmentioning

confidence: 65%

Section: Antitumor Hybrid Drugs Incorporating Cais Conjugated With Other Cheotypesmentioning

confidence: 99%

Section: Antitumor Hybrid Drugs Incorporating Cais Conjugated With Other Cheotypesmentioning

confidence: 99%

See 1 more Smart Citation

Multitargeting approaches involving carbonic anhydrase inhibitors: hybrid drugs against a variety of disorders

Supuran

2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…The cells were supported by Dulbecco's modified Eagle medium containing penicillin, streptomycin, and fetal bovine serum in concentrations 100 U/mL, 100 mg/mL, and 10%, respectively. 26 Cell suspension (100 μL aliquots) was incubated at 37°C under carbon dioxide for 24 h in a 96-well plate. Samples of DLX solution, the optimized plain in situ cubo-gel, and the optimized DLX loaded in situ cubo-gel, 100 μL each, with different concentrations (0.01, 0.1, 1, 10, 100 μg/mL), were added to the cell suspensions.…”

Section: Cytotoxicity Assaymentioning

confidence: 99%

<p>Brain Targeting of Duloxetine HCL via Intranasal Delivery of Loaded Cubosomal Gel: In vitro Characterization, ex vivo Permeation, and in vivo Biodistribution Studies</p>

Elsenosy¹,

Abdelbary²,

Elshafeey³

et al. 2020

IJN

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Purpose: Duloxetine (DLX) is dual serotonin and norepinephrine reuptake inhibitor suffering from limited bioavailability (≈ 40%) due to extensive hepatic metabolism. This work aims to formulate and evaluate DLX intranasal thermoreversible cubosomal gels to enhance its bioavailability and ensure efficient brain targeting. Materials and Methods: Cubo-gels were prepared by 3 3 central composite design with three independent factors, lipid ratio (glycerol monooleate: glycerol tripalmitate), Pluronic F127%, and Pluronic F68%. The prepared formulations were evaluated for their particle size (PS), gelling temperature (GT), entrapment efficiency (EE%), and in vitro release. The cubogel with the highest desirability (0.88) was chosen as the optimized formulation. DLX cubogel was evaluated using differential scanning calorimetry, Fourier-transform infrared spectroscopy, X-ray powder diffraction, and transmission electron microscopy. Cytotoxicity study, ex vivo permeation study and in vivo bio-distribution study were conducted to evaluate the safety and efficacy of brain targeting. Results: The optimum cubo-gel was composed of 3.76 lipid ratio, 20% w/v PF127, and 5% w/v PF68. It had PS of 265.13 ± 9.85 nm, GT of 32 ± 0.05°C, EE% of 98.13 ± 0.50%, and showed controlled release behavior where 33% DLX was released within 6 hrs. The plain in situ cubo-gel had a significantly higher IC 50 compared to DLX solution and DLX-loaded in situ cubo-gel. The ex vivo permeation study showed 1.27 enhancement in the drug permeation from DLX in situ cubo-gel. According to the in vivo bio-distribution study in plasma and brain, the intranasal DLX in situ cubo-gel showed a 1.96 fold improvement in brain bioavailability compared to the intranasal solution. Its BTE% and DTP% were 137.77 and 10.5, respectively, indicating efficient brain targeting after intranasal administration. Conclusion: Accordingly, intranasal DLX in situ cubo-gel can be considered as an innovative nano-carrier delivery system for bioavailability enhancement and efficient brain targeting of DLX to maximize its effect.

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“…The presence of the numerous binding interactions between the functional groups on test compounds and the active site residues lining the COX‐2 isoenzyme resulted in the inhibition of the latter (Elzahhar et al, 2020).…”

Section: Selective Cox‐2 Inhibitors Based On Azole Nucleusmentioning

confidence: 99%

“Azole” as privileged heterocycle for targeting the inducible cyclooxygenase enzyme

Prasher

Sharma

2020

Drug Development Research

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An over‐expression of COX‐2 isoenzyme belonging to the Cyclooxygenase Enzyme Family triggers the overproduction of pro‐inflammatory prostaglandins that instigate the development of chronic inflammation and related disorders. Hence, the rationally designed drugs for mitigating over‐activity of COX‐2 isoenzyme play a regulatory role toward the alleviation of the progression of these disorders. However, a selective COX‐2 inhibition chemotherapy prompts several side effects that necessitate the identification of novel molecular scaffolds for deliberating state‐of‐the‐art drug designing strategies. The heterocyclic “azole” scaffold, being polar and hydrophilic, possesses remarkable physicochemical advantages for designing physiologically active molecules capable of interacting with a wide range of biological components, including enzymes, peptides, and metabolites. The substituted derivatives of azole nuclei enable a comprehensive SAR analysis for the appraisal of bioactive profile of the deliberated molecules for obtaining the rationally designed compounds with prominent activities. The comprehensive SAR analysis readily prompted the identification of Y‐shaped molecules and the eminence of bulkier group for COX‐2 selective inhibition. This review presents an epigrammatic collation of the pharmacophore‐profile of the chemotherapeutics based on azole motif for a selective targeting of the COX‐2 isoenzyme.

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Expanding the anticancer potential of 1,2,3-triazoles via simultaneously targeting Cyclooxygenase-2, 15-lipoxygenase and tumor-associated carbonic anhydrases

Cited by 48 publications

References 59 publications

Multitargeting approaches involving carbonic anhydrase inhibitors: hybrid drugs against a variety of disorders

Multitargeting approaches involving carbonic anhydrase inhibitors: hybrid drugs against a variety of disorders

<p>Brain Targeting of Duloxetine HCL via Intranasal Delivery of Loaded Cubosomal Gel: In vitro Characterization, ex vivo Permeation, and in vivo Biodistribution Studies</p>

“Azole” as privileged heterocycle for targeting the inducible cyclooxygenase enzyme

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