Novel 1,3,5-triazine-based pyrazole derivatives as potential antitumor agents and EFGR kinase inhibitors: synthesis, cytotoxicity, DNA binding, molecular docking and DFT studies

Raghu, M.S.; Kumar, C.B. Pradeep; Prashanth, M.K.; Kumar, K. Deva Arun; Prathibha, B.S.; Kanthimathi, G.; Alissa, Siham A.; Al-Ghulikah, Hanan A.; Osman, Sameh M.

doi:10.1039/d1nj02419a

Cited by 82 publications

(21 citation statements)

References 42 publications

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“…The EGFR/PI3K/AKT/mTOR signaling cascade is important in many cellular processes, including cell growth and proliferation, apoptosis, survival, and metabolism, all of which contribute to tumor progression. – To study the effective molecular targets of the promising 4f , 5d , and 5c , which showed the highest cytotoxic activity against HCT-116 cells and promising EGFR inhibition, these compounds were tested against the PI3K/AKT/mTOR pathway.…”

Section: Resultsmentioning

confidence: 99%

“…8 Other examples of commercial drugs based on the s-triazine moiety include Enasidenib (Idhifa) (Figure 1, compound II), which is used to treat IDH2-positive acute leukemia and was first approved by the U.S. FDA in 2017, 9 and Gedatolisib (Figure 1, compound III), a first-in-class PI3K/mTOR inhibitor used to treat breast cancer. 10 Many other compounds carrying an s-triazine scaffold, including compounds IV 11 and V 12 for EGFR-TK inhibitors, compound VI ZSTK474 (PI3K/MEK dual inhibitors), 1 3 compound VII, named Bimiralisib (PQR309), 14−16 and compound VIII as a dual inhibitor of PI3K/mTOR, have been reported as anticancer agents targeting EGFR/PI3K/AKT/mTOR cascades (Figure 1). 17 The literature has reported other biological activities of striazine derivatives, 18 including antimicrobial, 19 antimalarial, 20 anti-inflammatory, 21,22 antibacterial and antifungal, 11 antioxidant, anticholinesterase, 23,24 and antiviral activity.…”

Section: ■ Introductionmentioning

confidence: 99%

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Synthesis and Antiproliferative Activity of a New Series of Mono- and Bis(dimethylpyrazolyl)-s-triazine Derivatives Targeting EGFR/PI3K/AKT/mTOR Signaling Cascades

et al. 2022

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Here, we synthesized a newseries of mono - and bis (dimethylpyrazolyl)- s -triazine derivatives. The synthetic methodology involved the reaction of different mono- and dihydrazinyl- s -triazine derivatives with acetylacetone in the presence of triethylamine to produce the corresponding target products in high yield and purity. The antiproliferative activity of the novel mono - and bis (dimethylpyrazolyl)- s -triazine derivatives was studied against three cancer cell lines, namely, MCF-7, HCT-116, and HepG2. N -(4-Bromophenyl)-4-(3,5-dimethyl-1 H -pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-amine 4f , N -(4-chlorophenyl)-4,6-bis(3,5-dimethyl-1 H -pyrazol-1-yl)-1,3,5-triazin-2-amine 5c , and 4,6- bis (3,5-dimethyl-1 H -pyrazol-1-yl)- N -(4-methoxyphenyl)-1,3,5-triazin-2-amine 5d showed promising activity against these cancer cells: 4f [(IC 50 = 4.53 ± 0.30 μM (MCF-7); 0.50 ± 0.080 μM (HCT-116); and 3.01 ± 0.49 μM (HepG2)]; 5d [(IC 50 = 3.66 ± 0.96 μM (HCT-116); and 5.42 ± 0.82 μM (HepG2)]; and 5c [(IC 50 = 2.29 ± 0.92 μM (MCF-7)]. Molecular docking studies revealed good binding affinity with the receptor targeting EGFR/PI3K/AKT/mTOR signaling cascades. Compound 4f exhibited potent EGFR inhibitory activity with an IC 50 value of 61 nM compared to that of Tamoxifen (IC 50 value of 69 nM), with EGFR inhibition of 83 and 84%, respectively, at a concentration of 10 μM. Interestingly, 4f showed remarkable PI3K/AKT/mTOR inhibitory activity with 0.18-, 0.27-, and 0.39-fold decrease in their concentration (reduction in controls from 6.64, 45.39, and 86.39 ng/mL to 1.24, 12.35, and 34.36 ng/mL, respectively). Hence, the synthetic 1,3,5-triazine derivative 4f exhibited promising antiproliferative activity in HCT-116 cells through apoptosis induction by targeting the EGFR and its downstream pathway.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Synthesis and Antiproliferative Activity of a New Series of Mono- and Bis(dimethylpyrazolyl)-s-triazine Derivatives Targeting EGFR/PI3K/AKT/mTOR Signaling Cascades

et al. 2022

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“…Additionally, Pyrazole moiety has been inserted in many FDA-approved drugs such as Pazopanib, which offered more potent inhibitors. These pyrazole derivatives exhibited potent tumoricidal action against EGFR-tyrosine kinase with an IC 50 of 395.1, 286.9, and 229.4 nM, respectively, compared to the standard drug, erlotinib [ 86 ]. The pyrazoline derivatives consisting of carbothioamide group showed significant EGFR inhibition, showing IC 50 values ranging from 1.66 to 1.9 μM, and halted the growth of cancer cells [ 87 ].…”

Section: Recent Updates On Selective Tyrosine Kinase Inhibitors In Pre-clinical Studiesmentioning

confidence: 99%

Emerging Importance of Tyrosine Kinase Inhibitors against Cancer: Quo Vadis to Cure?

Mongre

Mishra

Shukla

et al. 2021

IJMS

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GLOBOCAN 2020 estimated more than 19.3 million new cases, and about 10 million patients were deceased from cancer in 2020. Clinical manifestations showed that several growth factor receptors consisting of transmembrane and cytoplasmic tyrosine kinase (TK) domains play a vital role in cancer progression. Receptor tyrosine kinases (RTKs) are crucial intermediaries of the several cellular pathways and carcinogenesis that directly affect the prognosis and survival of higher tumor grade patients. Tyrosine kinase inhibitors (TKIs) are efficacious drugs for targeted therapy of various cancers. Therefore, RTKs have become a promising therapeutic target to cure cancer. A recent report shows that TKIs are vital mediators of signal transduction and cancer cell proliferation, angiogenesis, and apoptosis. In this review, we discuss the structure and function of RTKs to explore their prime role in cancer therapy. Various TKIs have been developed to date that contribute a lot to treating several types of cancer. These TKI based anticancer drug molecules are also discussed in detail, incorporating their therapeutic efficacy, mechanism of action, and side effects. Additionally, this article focuses on TKIs which are running in the clinical trial and pre-clinical studies. Further, to gain insight into the pathophysiological mechanism of TKIs, we also reviewed the impact of RTK resistance on TKI clinical drugs along with their mechanistic acquired resistance in different cancer types.

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“…pyrazole moiety as a potential anti-cancer agent targeting EFGR kinase inhibitors with IC50 = 229.4 nm (Compound III, Figure 1) [28]. Additionally, the Singh research team have reported a new series of hybrids derived from monastrol-1,3,5-triazine and were studied in vitro and in vivo for their anti-cancer activity.…”

Section: Introductionmentioning

confidence: 99%

“…Compound II was found to have significant activity compared to methotrexate against the A549 cancer cell line [27]. Prashanth et al, reported novel lead compounds based on s-triazine tethered pyrazole moiety as a potential anti-cancer agent targeting EFGR kinase inhibitors with IC 50 = 229.4 nm (Compound III, Figure 1) [28]. Additionally, the Singh research team have reported a new series of hybrids derived from monastrol-1,3,5-triazine and were studied in vitro and in vivo for their anti-cancer activity.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, and Molecular Structure Investigations of a New s-Triazine Derivatives Incorporating Pyrazole/Piperidine/Aniline Moieties

et al. 2021

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In this work, we synthesized two new s-triazine incorporates pyrazole/piperidine/aniline moieties. Molecular structure investigations in the light of X-ray crystallography combined with Hirshfeld and DFT calculations were presented. Intermolecular interactions controlling the molecular packing of 4-(3,5-dimethyl-1H-pyrazol-1-yl)-N-phenyl-6-(piperidin-1-yl)-1,3,5-triazin-2-amine; 5a and N-(4-bromophenyl)-4-(3,5-dimethyl-1H-pyrazol-1-yl)-6-(piperidin-1-yl)-1,3,5-triazin-2-amine; 5b were analyzed using Hirshfeld calculations. The most dominant interactions are the H...H, N...H and H...C contacts in both compounds. The N...H and H...C interactions in 5a and the N...H, Br...H and H...H interactions in 5b are the most important. In addition, DFT calculations were used to compute the molecular structures of 5a and 5b; then, their electronic properties, as well as the 1H- and 13C-NMR spectra, were predicted. Both compounds are polar where 5a (1.018 Debye) has lower dipole moment than 5b (4.249 Debye). The NMR chemical shifts were calculated and very good correlations between the calculated and experimental data were obtained (R2 = 0.938–0.997).

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Novel 1,3,5-triazine-based pyrazole derivatives as potential antitumor agents and EFGR kinase inhibitors: synthesis, cytotoxicity, DNA binding, molecular docking and DFT studies

Abstract: We herein report a design and synthesis of new 1,3,5-triazine based pyrazole derivatives (5a-i) for anticancer activity targeting epidermal growth factor (EGFR) tyrosine kinase. The newly synthesized compounds were characterized...

Cited by 82 publications

References 42 publications

Synthesis and Antiproliferative Activity of a New Series of Mono- and Bis(dimethylpyrazolyl)-s-triazine Derivatives Targeting EGFR/PI3K/AKT/mTOR Signaling Cascades

Synthesis and Antiproliferative Activity of a New Series of Mono- and Bis(dimethylpyrazolyl)-s-triazine Derivatives Targeting EGFR/PI3K/AKT/mTOR Signaling Cascades

Emerging Importance of Tyrosine Kinase Inhibitors against Cancer: Quo Vadis to Cure?

Synthesis, and Molecular Structure Investigations of a New s-Triazine Derivatives Incorporating Pyrazole/Piperidine/Aniline Moieties

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