Development of new thieno[2,3-d]pyrimidines as dual EGFR and STAT3 inhibitors endowed with anticancer and pro-apoptotic activities

Elsebaie, Heba A.; El-Moselhy, Tarek F.; El-Bastawissy, Eman A.; Elberembally, Kamel M.; Badi, Rehab Mustafa; Elkaeed, Eslam B.; Shaldam, Moataz A.; Eldehna, Wagdy M.; Tawfik, Haytham O.

doi:10.1016/j.bioorg.2024.107101

Cited by 8 publications

(3 citation statements)

References 64 publications

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“…When the ratio of proapoptotic proteins exceeds that of antiapoptotic proteins, several processes are triggered, and the outer mitochondrial membrane becomes permeable. − A critical tumor suppressor gene associated with apoptosis is p53. Apoptosis mediated by p53 may be brought on by decreased Bcl-2 expression and activation of caspases 3 and 9.…”

Section: Resultsmentioning

confidence: 99%

Discovery and Mechanistic Studies of Dual-Target Hits for Carbonic Anhydrase IX and VEGFR-2 as Potential Agents for Solid Tumors: X-ray, In Vitro, In Vivo, and In Silico Investigations of Coumarin-Based Thiazoles

Hefny,

El-Moselhy,

El-Din

et al. 2024

J. Med. Chem.

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A dual-targeting approach is predicted to yield better cancer therapy outcomes. Consequently, a series of coumarin-based thiazoles (5a−h, 6, and 7a−e) were designed and constructed as potential carbonic anhydrase (CA) and VEGFR-2 suppressors. The inhibitory actions of the target compounds were assessed against CA isoforms IX and VEGFR-2. The assay results showed that coumarin-based thiazoles 5a, 5d, and 5e can effectively inhibit both targets. 5a, 5d, and 5e cytotoxic effects were tested on pancreatic, breast, and prostate cancer cells (PANC1, MCF7, and PC3). Further mechanistic investigation disclosed the ability of 5e to interrupt the PANC1 cell progression in the S stage by triggering the apoptotic cascade, as seen by increased levels of caspases 3, 9, and BAX, alongside the Bcl-2 decline. Moreover, the in vivo efficacy of compound 5e as an antitumor agent was evaluated. Also, molecular docking and dynamics displayed distinctive interactions between 5e and CA IX and VEGFR-2 binding pockets.

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Section: Resultsmentioning

confidence: 99%

Discovery and Mechanistic Studies of Dual-Target Hits for Carbonic Anhydrase IX and VEGFR-2 as Potential Agents for Solid Tumors: X-ray, In Vitro, In Vivo, and In Silico Investigations of Coumarin-Based Thiazoles

Hefny,

El-Moselhy,

El-Din

et al. 2024

J. Med. Chem.

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“…These compounds have garnered attention due to their unique structural similarity to purines and their versatile pharmacological properties. They have been shown to possess antimicrobial [ 1 ], antiviral [ 2 ], and anti-inflammatory [ 3 , 4 ] properties, serve as β3-adrenoceptor agonists [ 5 ], exhibit anti-tuberculosis properties [ 6 ], antiprotozoal activity [ 7 ], and kinase inhibition [ 8 , 9 , 10 , 11 , 12 ], act as antioxidants [ 13 , 14 , 15 , 16 ], and possess anticancer activity [ 17 , 18 , 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Antimicrobial Evaluation of Sulfonamides after Coupling with Thienopyrimidine Coplanar Structure

Elmongy,

Alanazi,

Aldawsari

et al. 2024

Pharmaceuticals

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This work describes the design and synthesis of three series of hybrids of thienopyrimidines and sulfonamides. Dihydrofolate reductase enzyme was selected as a target for the in-silico screening of the synthesized thienopyrimidine–sulfonamide hybrid as an antibacterial, while squalene epoxidase was selected as an antifungal target protein. All screened compounds showed promising binding affinity ranges, with perfect fitting not exceeding 1.9 Å. The synthesized compounds were tested for their antimicrobial activity using agar well diffusion and minimum inhibitory concentration tests against six bacterial strains in addition to two Candida strains. Compounds 8iii and 12ii showed varying degrees of inhibition against Staphylococcus aureus and Escherichia coli bacterial strains, whereas the best antifungal activity against Candida was displayed by compound 8iii. Compound 12ii, the cyclohexathienopyrimidine coupled with sulfadiazine at position 3, has the best antibacterial activity, which is consistent with molecular docking results at the active site of the oxidoreductase protein. Interestingly, compound 12ii also has the highest docking binding energy at the antifungal squalene epoxidase active site. Investigating the physicochemical properties of the synthesized hybrids revealed their high tolerability with cell membranes, and moderate to poor oral bioavailability, and that all are drug-like candidates, among which 4i, the cyclohexathieno[2,3-d] pyrimidine core with sulphaguanidine incorporated at position 4, recorded the best score (1.58).

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“…Dual inhibitors of the two targets are considered promising scaffolds for treatment of solid tumors. 18–20 Cabozantinib is a potent inhibitor of c-MET and VEGFR-2 for patients with medullary thyroid cancer. 21 Recently, clinical trials showed a small-molecule dual inhibitor, tivozanib.…”

Section: Introductionmentioning

confidence: 99%

Discovery of new 1,3-diphenylurea appended aryl pyridine derivatives as apoptosis inducers through c-MET and VEGFR-2 inhibition: design, synthesis, in vivo and in silico studies

Elsebaie,

Nafie,

Tawfik

et al. 2024

RSC Med. Chem.

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Development of new thieno[2,3-d]pyrimidines as dual EGFR and STAT3 inhibitors endowed with anticancer and pro-apoptotic activities

Cited by 8 publications

References 64 publications

Discovery and Mechanistic Studies of Dual-Target Hits for Carbonic Anhydrase IX and VEGFR-2 as Potential Agents for Solid Tumors: X-ray, In Vitro, In Vivo, and In Silico Investigations of Coumarin-Based Thiazoles

Discovery and Mechanistic Studies of Dual-Target Hits for Carbonic Anhydrase IX and VEGFR-2 as Potential Agents for Solid Tumors: X-ray, In Vitro, In Vivo, and In Silico Investigations of Coumarin-Based Thiazoles

Antimicrobial Evaluation of Sulfonamides after Coupling with Thienopyrimidine Coplanar Structure

Discovery of new 1,3-diphenylurea appended aryl pyridine derivatives as apoptosis inducers through c-MET and VEGFR-2 inhibition: design, synthesis, in vivo and in silico studies

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