Medicinal Attributes of Thienopyrimidine Based Scaffold Targeting Tyrosine Kinases and Their Potential Anticancer Activities

Ghith, Amna; Ismail, Nasser S. M.; Youssef, Khairia M.; Abouzid, Khaled A. M.

doi:10.1002/ardp.201700242

Cited by 21 publications

(14 citation statements)

References 146 publications

(147 reference statements)

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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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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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“…Such a role is crucial to prevent ischaemic necrosis and facilitate the survival of the damaged tissues 5 . During the normal state, angiogenesis is controlled by some protein kinases (PKs), which comprise VEGFRs, FGFRs, and EGFRs 6 . PKs can be deregulated under pathological conditions, producing a disturbance in angiogenesis process.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, docking, ADMET studies, and anticancer evaluation of new 3-methylquinoxaline derivatives as VEGFR-2 inhibitors and apoptosis inducers

Alanazi

Eissa

Alsaif

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a critical role in cancer angiogenesis. Inhibition of VEGFR-2 activity proved effective suppression of tumour propagation. Accordingly, two series of new 3-methylquinoxaline derivatives have been designed and synthesised as VEGFR-2 inhibitors. The synthesised derivatives were evaluated in vitro for their cytotoxic activities against MCF-7and HepG2 cell lines. In addition, the VEGFR-2 inhibitory activities of the target compounds were estimated to indicate the potential mechanism of their cytotoxicity. To a great extent, the results of VEGFR-2 inhibition were highly correlated with that of cytotoxicity. Compound 27a was the most potent VEGFR-2 inhibitor with IC 50 of 3.2 nM very close to positive control sorafenib (IC 50 = 3.12 nM). Such compound exhibited a strong cytotoxic effect against MCF-7 and HepG2, respectively with IC 50 of 7.7 and 4.5 µM in comparison to sorafenib (IC 50 = 3.51 and 2.17 µM). In addition, compounds 28 , 30f , 30i , and 31b exhibited excellent VEGFR-2 inhibition activities (IC 50 range from 4.2 to 6.1 nM) with promising cytotoxic activity. Cell cycle progression and apoptosis induction were investigated for the most active member 27a . Also, the effect of 27a on the level of caspase-3, caspase-9, and BAX/Bcl-2 ratio was determined. Molecular docking studies were implemented to interpret the binding mode of the target compounds with the VEGFR-2 pocket. Furthermore, toxicity and ADMET calculations were performed for the synthesised compounds to study their pharmacokinetic profiles

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“…Thienopyrimidines, containing a thiophene ring fused to pyrimidine, are bioisosteres of purines that have been shown to have in vitro anticancer efficacy against certain cancer cell lines [13]. However, there are no previous reports regarding the potential antimetastatic efficacy of any thieno[2,3- d ]pyrimidine derivatives, nor the mechanism of action, of these compounds [14].…”

Section: Introductionmentioning

confidence: 99%

Novel Thienopyrimidine Derivative, RP-010, Induces β-Catenin Fragmentation and Is Efficacious against Prostate Cancer Cells

Amawi

Hussein

Boddu

et al. 2019

Cancers

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Thienopyrimidines containing a thiophene ring fused to pyrimidine are reported to have a wide-spectrum of anticancer efficacy in vitro. Here, we report for the first time that thieno[3,2-d]pyrimidine-based compounds, also known as the RP series, have efficacy in prostate cancer cells. The compound RP-010 was efficacious against both PC-3 and DU145 prostate cancer (PC) cells (IC50 < 1 µM). The cytotoxicity of RP-010 was significantly lower in non-PC, CHO, and CRL-1459 cell lines. RP-010 (0.5, 1, 2, and 4 µM) arrested prostate cancer cells in G2 phase of the cell cycle, and induced mitotic catastrophe and apoptosis in both PC cell lines. Mechanistic studies suggested that RP-010 (1 and 2 µM) affected the wingless-type MMTV (Wnt)/β-catenin signaling pathway, in association with β-catenin fragmentation, while also downregulating important proteins in the pathway, including LRP-6, DVL3, and c-Myc. Interestingly, RP-010 (1 and 2 µM) induced nuclear translocation of the negative feedback proteins, Naked 1 and Naked 2, in the Wnt pathway. In addition, RP-010 (0.5, 1, 2 and 4 µM) significantly decreased the migration of PC cells in vitro. Finally, RP-010 did not produce significant toxic effects in zebrafish at concentrations of up to 6 µM. In conclusion, RP-010 may be an efficacious and relatively nontoxic anticancer compound for prostate cancer. Future mechanistic and in vivo efficacy studies are needed to optimize the hit compound RP-010 for lead optimization and clinical use.

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Medicinal Attributes of Thienopyrimidine Based Scaffold Targeting Tyrosine Kinases and Their Potential Anticancer Activities

Cited by 21 publications

References 146 publications

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

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

Design, synthesis, docking, ADMET studies, and anticancer evaluation of new 3-methylquinoxaline derivatives as VEGFR-2 inhibitors and apoptosis inducers

Novel Thienopyrimidine Derivative, RP-010, Induces β-Catenin Fragmentation and Is Efficacious against Prostate Cancer Cells

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