Discovery of thieno[2,3-d]pyrimidine-based derivatives as potent VEGFR-2 kinase inhibitors and anti-cancer agents

Abnormal vascular smooth muscle cell (VSMC) proliferation has an important role in the pathogenesis of both atherosclerosis restenosis and hypertension. Vascular endothelial growth factor (VEGF) has been shown to stimulate VSMC proliferation. In addition, angiogenesis is one of the hallmarks of cancerous growth. VEGF is the key modulator for the initial stages of angiogenesis that acts through the endothelial-specific receptor tyrosine kinases (VEGFRs). VEGFR-2 blockage is a good approach for suppression of angiogenesis. In order to discover novel VEGFR-2 TK inhibitors, we have designed and synthesized three new series of pyridine-containing compounds. The new compounds were all screened against a panel of three cell lines (HepG-2, HCT-116, and MCF-7). Promising results encouraged us to additionally evaluate the most active members for their in vitro VEGFR-2 inhibitory effect. Compound 7a, which is the most potent candidate, revealed a significant increase in caspase-3 level by 7.80-fold when compared to the control. In addition, Bax and Bcl-2 concentration levels showed an increase in the proapoptotic protein Bax (261.4 Pg/ml) and a decrease of the antiapoptotic protein Bcl-2 (1.25 Pg/ml) compared to the untreated cells. Furthermore, compound 7a arrested the cell cycle in the G2/M phase with induction of apoptosis. The immunomodulatory effect of compound 7a, the most active member, showed a reduction in TNF-α by 87%. Also, compound 7a caused a potent inhibitory effect on smooth muscle proliferation. Docking studies were also performed to get better insights into the possible binding mode of the target compounds with VEGFR-2 active sites.

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“…Discovery Studio 2.5 software was used to perform docking and visualization according to the described protocol [ 63 – 66 ] (Supplementary data).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Vascular Smooth Muscle and Cancer Cell Proliferation by New VEGFR Inhibitors and Their Immunomodulator Effect: Design, Synthesis, and Biological Evaluation

Ran

Qin

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…These approaches are essential contributors to the development of new bioactive agents [2][3][4][5][6][7][8]. Computer-assisted drug design has been applied in drug discovery [9][10][11], computational chemistry [12,13], toxicity prediction [14][15][16], ADMET assessment [17][18][19], molecular modeling [20], molecular design [21,22], and rational drug design [23][24][25][26][27]. All these techniques have great popularity and have been used in both academic fields in addition to the pharmaceutical industries [28].…”

Section: Introductionmentioning

confidence: 99%

In Silico Exploration of Potential Natural Inhibitors against SARS-Cov-2 nsp10

et al. 2021

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In continuation of our previous effort, different in silico selection methods were applied to 310 naturally isolated metabolites that exhibited antiviral potentialities before. The applied selection methods aimed to pick the most relevant inhibitor of SARS-CoV-2 nsp10. At first, a structural similarity study against the co-crystallized ligand, S-Adenosyl Methionine (SAM), of SARS-CoV-2 nonstructural protein (nsp10) (PDB ID: 6W4H) was carried out. The similarity analysis culled 30 candidates. Secondly, a fingerprint study against SAM preferred compounds 44, 48, 85, 102, 105, 182, 220, 221, 282, 284, 285, 301, and 302. The docking studies picked 48, 182, 220, 221, and 284. While the ADMET analysis expected the likeness of the five candidates to be drugs, the toxicity study preferred compounds 48 and 182. Finally, a density-functional theory (DFT) study suggested vidarabine (182) to be the most relevant SARS-Cov-2 nsp10 inhibitor.

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“…Hereupon, we used the above-mentioned reaction conditions albeit with one-pot, two-step domino strategy. First, base (1.0 equiv, 3a/3b)-catalyzed dimerization of malononitrile (2.0 equiv, 2b) into non-isolated 2-amino-1,1,3-tricyanopropene (7) [46] that has drawn tremendous attention of interest due to its comprehensive implementations in the synthesis of heterocyclic compounds that manifest diverse biological and pharmaceutical properties [47]. At the same time, in another conical flask, suspension solution of 4-(pyrrolidin-1-yl)-3-formylcoumarin (5a)/ 4-(piperidin-1-yl)-3-formylcoumarin (5b) in MeOH (2 mL) were prepared from direct amination of 1a (1.0 equiv) and 3a/3b (1.5 equiv).…”

Section: Chemistrymentioning

confidence: 99%

“…VEGFR-2 type II inhibitors shared essential pharmacophoric features encompassing: (i) terminal heteroaromatic ring that occupies the ATP binding pocket (hinge region) via H-bond with cysteine acid (like Cys917); (ii) oxygen (N or S) linker that occupies the gatekeeper region between the hinge and DFG domains; (iii) urea or amide moiety spacer as H-bond acceptor-donor pair (HBA-HBD) that binds to DFG motif via H-bonds with glutamic (Glu833) and aspartic (Asp1044) acids; (iv) terminal lipophilic group that occupies the allosteric hydrophobic pocket (DFG-out) via hydrophobic interactions [7][8][9][10][11]. The well-defined EGFR inhibitors consists of: (i) central hetero aromatic unit that fits the adenine binding site through H-bond with methionine amino acid residue (Met793); (ii) hydrophobic head is a phenyl binding group with various hydrophobic substituents to interact with the hydrophobic region I; (iii) nitrogen spacer to link the hinge-binding central moiety with the terminal fragment that occupies the hydrophobic region I; (iv) hydrophobic tail is directly linked to the central heteroaromatic core and induced fit to the hydrophobic region II [12].…”

Section: Introductionmentioning

confidence: 99%

Metal-free domino amination-Knoevenagel condensation approach to access new coumarins as potent nanomolar inhibitors of VEGFR-2 and EGFR

Eliwa

Frese

Halawa

et al. 2021

Green Chemistry Letters and Reviews

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A metal-free, atom-economy and simple work-up domino amination-Knoevenagel condensation approach to construct new coumarin analogous (4a-f and 8a-e) was described. Further, new formyl (5a,d-f) and nitro (9a,d-f) coumarin derivatives were synthesized via C-N coupling reaction of various cyclic secondary amines and 4-chloro-3-(formyl-/nitro)coumarins (1a,c), respectively. The confirmed compounds were screened for their in vitro anti-proliferative activity against KB-3-1, A549 and PC3 human cancer cell lines using resazurin cellular-based assay. Among them, coumarin derivatives 4e and 8e displayed the best anti-cervical cancer potency (KB-3-1) with IC 50 values of 15.5 ± 3.54 and 21 ± 4.24 µM, respectively. Also, 4e showed the most promising cytotoxicity toward A549 with IC 50 value of 12.94 ± 1.51 µM. As well, 9d presented a more significant impact of potency against PC3 with IC 50 7.31 ± 0.48 µM. Moreover, 8d manifested selectivity against PC3 (IC 50 = 20.16 ± 0.07 µM), while 8e was selective toward KB-3-1 cell line (IC 50 = 21 ± 4.24 µM). Matching with docking profile, the enzymatic assay divulged that 8e is a dual potent single-digit nanomolar inhibitor of VEGFR-2 and EGFR with IC 50 values of 24.67 nM and 31.6 nM that were almost equipotent to sorafenib (31.08 nM) and erlotinib (26.79 nM), respectively.

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Discovery of thieno[2,3-d]pyrimidine-based derivatives as potent VEGFR-2 kinase inhibitors and anti-cancer agents

Cited by 87 publications

References 76 publications

Inhibition of Vascular Smooth Muscle and Cancer Cell Proliferation by New VEGFR Inhibitors and Their Immunomodulator Effect: Design, Synthesis, and Biological Evaluation

Inhibition of Vascular Smooth Muscle and Cancer Cell Proliferation by New VEGFR Inhibitors and Their Immunomodulator Effect: Design, Synthesis, and Biological Evaluation

In Silico Exploration of Potential Natural Inhibitors against SARS-Cov-2 nsp10

Metal-free domino amination-Knoevenagel condensation approach to access new coumarins as potent nanomolar inhibitors of VEGFR-2 and EGFR

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