Novel thienopyrimidine derivatives as dual EGFR and VEGFR-2 inhibitors: design, synthesis, anticancer activity and effect on cell cycle profile

Mghwary, Aml E.-S.; Gedawy, Ehab M.; Kamal, Amr; Abuel‐Maaty, Suzan M.

doi:10.1080/14756366.2019.1593160

Cited by 45 publications

(31 citation statements)

References 35 publications

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“…The inhibition of the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR-2) plays a crucial role in tumor suppression, angiogenesis, and metastasis (Alferez et al, 2008;Mghwary et al, 2019). The two share common signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

Novel Anticancer Fused Pyrazole Derivatives as EGFR and VEGFR-2 Dual TK Inhibitors

et al. 2020

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EGFR and VEGFR-2 represent promising targets for cancer treatment as they are very important in tumor development as well as in angiogenesis and metastasis. In this work, 6-amino-4-(2-bromophenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile 1 and (E)-4-(2-Bromobenzylidene)-5-methyl-2,4-dihydro-3H-pyrazol-3-one 11 were selected as starting materials to synthesize different fused pyrazole derivatives; dihydropyrano[2,3-c]pyrazole 1, 2, 7-9, and 15, pyrazolo[4 ′ ,3 ′ :5,6]pyrano[2,3d]pyrimidine 3-6, pyrazolo[3,4-d]pyrimidine 12 and 13, and pyrazolo[3,4-c]pyrazole 14 derivatives were synthesized to evaluate their anticancer activity against HEPG2 human cancer cell lines compared to erlotinib and sorafenib as reference drugs. Seven compounds 1, 2, 4, 8, 11, 12, and 15 showed nearly 10 fold higher activity than erlotinib (10.6 µM) with IC 50 ranging from 0.31 to 0.71 µM. In vitro EGFR and VEGFR-2 inhibitory activity were performed for the synthesized compounds, and the results identified compound 3 as the most potent EGFR inhibitor (IC 50 = 0.06 µM) and compound 9 as the most potent VEGFR-2 inhibitor (IC 50 = 0.22 µM). Moreover, compounds 9 and 12 revealed potent dual EGFR and VEGFR-2 inhibition, and these results were supported by docking studies of these two compounds within the active sites of both enzymes.

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Section: Introductionmentioning

confidence: 99%

Novel Anticancer Fused Pyrazole Derivatives as EGFR and VEGFR-2 Dual TK Inhibitors

et al. 2020

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“…The synthesis, reactions and biological effects of isomeric thienopyrimidines have been reviewed extensively [15][16][17][18][19][20][21][22][23][24]. Thieno pyrimidines have a great potential of application and were recognized as anticancer agents [25][26][27][28][29][30]. Earlier we have developed some original methods for the synthesis of functionalized thieno[2,3-d]pyrimidines [31][32][33].…”

Section: Resultsmentioning

confidence: 99%

Spirocyclic thienopyrimidines: synthesis, new rearrangements under Vilsmeier conditions and in silico prediction of anticancer activity

et al. 2020

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Aim. To find novel anticancer lead molecules among easily available spiro-fused thieno[2,3-d] pyrimidines. Methods. Organic synthesis, spectral methods and molecular docking. Results. New spiro heterocycles were synthesized by condensation of 2-aminothiophene-3-carbonitriles with cyclic ketones via Gevald reaction. Other model spirocyclic compounds were prepared by the reaction of 3-aminothieno[2,3-b]pyridine-2-carboxamides with cyclohexanone under acidic conditions. According to the docking studies against the EGFR WT the synthesized compounds revealed good binding energies ranging from-8.4 to-10.2 kcal/mol. The compounds were tested as inhibitors of protein kinase CK; 7',8',9',10'-tetrahydro-1'H-spiro[cyclohexane-1,2'-pyrimido[4',5':4,5]thieno[2,3-b]quinolin]-4'(3'H)-one showed the best binding energy while be bound by a hydrogen bond to Val66 amino acid residue. This compound also showed good results as a potential inhibitor of B-Raf kinase. Conclusion. New spiro-fused thieno[2,3d]pyrimidines have been synthesized. The inhibition activity of novel compounds as potential inhibitors of the EGFR, CK2, FGFR1 and B-raf kinases was examined. We found that spirofused thieno[2,3-d]pyrimidines undergo the rearrangement under Vilsmeier-Haack conditions to afford hitherto undescribed thienopyrimidines and-quinolines. The docking studies revealed that the rearranged products do not tend to form hydrogen bonds with the kinase amino acid residues and show moderate binding energies. Therefore, in contrast to the spiro-fused thieno[2,3-d]pyrimidines, the rearranged products cannot be considered as perspective targets for further screening.

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“…kinase inhibitors (TKIs) that have exhibited clinical benefit in treating NSCLC (6,7). Erlotinib treatment prolonged the progression-free survival of NSCLC patients, who harbor EGFR exon 19 deletion or L858R mutations (EGFR Mut+ NSCLC) (8).…”

Section: Combination Of Huanglian Jiedu Decoction and Erlotinib Delaymentioning

confidence: 99%

Combination of Huanglian Jiedu Decoction and erlotinib delays growth and improves sensitivity of EGFR‑mutated NSCLC cells in vitro and in vivo via STAT3/Bcl‑2 signaling

et al. 2020

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Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is widely used in the treatment of non-small cell lung cancer (NSCLC). However, erlotinib resistance leads to high mortality in patients with NSCLC, while the activation of STAT3 is closely related to erlotinib resistance. Studies have shown that the main components of Huanglian Jiedu Decoction (HJD) have antitumor effects. Therefore, the anticancer effect of HJD combined with erlotinib on NSCLC cells was investigated. The NSCLC HCC827, HCC827ER, and H1975 cell lines as well as xenograft nude mice were selected as models to study the effects of HJD. The proapoptotic effects of HJD were examined by CCK-8 and apoptosis assays. ELISA, immunostaining, and western blot analysis were also performed. HJD considerably enhanced the anticancer effect of erlotinib in both EGFR-TKI-resistant and -sensitive NSCLC cells. HJD promoted erlotinib-induced apoptosis and caspase 3 activity. The co-treatment also inhibited the expression of Bcl-XL, Bcl-2, and p-STAT3. In addition, siSTAT3 had similar functions with HJD. In particular, the apoptotic rates of erlotinib-stimulated HCC827, HCC827ER, and H1975 cells were enhanced by transfecting siSTAT3. Furthermore, overexpression of STAT3 significantly inhibited HJD-mediated erlotinib sensitization. The combined use of HJD with erlotinib significantly reduced tumor growth in erlotinib-resistant HCC827ER and H1975 ×enografts, induced caspase 3, and inhibited Ki67, STAT3, and Bcl-2 expression. HJD significantly alleviated erlotinib resistance by regulating the STAT3/Bcl-2 signaling pathway, which is a promising method to overcome the EGFR-TKI resistance of NSCLC.

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Novel thienopyrimidine derivatives as dual EGFR and VEGFR-2 inhibitors: design, synthesis, anticancer activity and effect on cell cycle profile

Cited by 45 publications

References 35 publications

Novel Anticancer Fused Pyrazole Derivatives as EGFR and VEGFR-2 Dual TK Inhibitors

Novel Anticancer Fused Pyrazole Derivatives as EGFR and VEGFR-2 Dual TK Inhibitors

Spirocyclic thienopyrimidines: synthesis, new rearrangements under Vilsmeier conditions and in silico prediction of anticancer activity

Combination of Huanglian Jiedu Decoction and erlotinib delays growth and improves sensitivity of EGFR‑mutated NSCLC cells in vitro and in vivo via STAT3/Bcl‑2 signaling

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