Anti-proliferative 2,3-dihydro-1,3,4-thiadiazoles targeting VEGFR-2: Design, synthesis, in vitro, and in silico studies.

In this study, we present the design, synthesis, and evaluation of six new thiadiazole derivatives designed as VEGFR-2 inhibitors. The most promising compound, 18b, demonstrated promising inhibitory activity against VEGFR-2, with an IC50 value of 0.165 µg/mL. The in vitro assessments on MCF-7 and HepG2 cell lines revealed the superior anti-proliferative effects of compound 18b, exhibiting IC50 values of 0.06 and 0.17 µM, respectively. Further investigations into the cell cycle distribution of compound 18b on MCF-7 cells exhibited a cell cycle arrest at the S phase (52.96 %) and significantly reducing the percentage of cells in the G0-G1 and G2/M phases. Additionally, compound 18b demonstrated a remarkable pro-apoptotic effect, with 45.29 % total apoptosis, characterized by both early and late apoptosis, and minimal necrosis. These findings were corroborated by RT-PCR analysis, revealing a significant downregulation of the anti-apoptotic gene Bcl2 and upregulation of the pro-apoptotic gene BAX in compound 18b-treated cells compared to control MCF-7 cells. Moreover, in silico studies involving molecular docking, Density Functional Theory (DFT) calculations, Molecular Dynamics (MD) simulations, MM-GBSA, Principle Component Analysis of Trajectories (PCAT), in addition to Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) predictions underscored the molecular interactions, energetics, and pharmacokinetic properties of compound 18b and the other derivatives further supporting its potential. Our integrated approach, combining in vitro experimens with in silico predictions provides valuable insights into the therapeutic potential of compound 18b as a robust VEGFR-2 inhibitor and lays the groundwork for future optimization.

New Thieno[2,3-d]pyrimidines as Anticancer VEGFR-2 Inhibitors with Apoptosis Induction: Design, Synthesis, and Biological and In Silico Studies.

BACKGROUND: Vascular endothelial growth factor receptor-2 (VEGFR-2) is a critical protein involved in tumor progression, making it an attractive target for cancer therapy. OBJECTIVE: This study aimed to synthesize and evaluate novel thieno[2,3-d]pyrimidine analogues as potential anticancer VEGFR-2 inhibitors. METHODS: The thieno[2,3-d]pyrimidine analogues were synthesized following the pharmacophoric features of VEGFR-2 inhibitors. The anticancer potential was assessed against PC3 and HepG2 cell lines. The VEGFR-2 inhibition was evaluated through IC50 determination. Cell cycle analysis and apoptosis assays were performed to elucidate the mechanisms of action. Molecular docking, molecular dynamics simulations, MM-GBSA, and PLIP studies were conducted to investigate the binding affinities and interactions with VEGFR-2. Additionally, in silico ADMET studies were performed. RESULTS: Compound 8b demonstrated significant anti-proliferative activities with IC50 values of 16.35 µM and 8.24 µM against PC3 and HepG2 cell lines, respectively, surpassing sorafenib and exhibiting enhanced selectivity indices. Furthermore, compound 8b showed an IC50 value of 73 nM for VEGFR-2 inhibition. Cell cycle analysis revealed G2-M phase arrest, while apoptosis assays demonstrated increased apoptosis in HepG2 cells. Molecular docking and dynamic simulations confirmed the binding affinity and interaction of compound 8b with VEGFR-2, supported by MMGBSA and PLIP studies. In silico ADMET studies indicated the drug development potential of the synthesized thieno[2,3-d]pyrimidines. CONCLUSION: The study highlights compound 8b as a promising VEGFR-2 inhibitor with potent anti-proliferative activities. Its mechanism of action involves cell cycle arrest and induction of apoptosis. Further, molecular docking and dynamic simulations support the strong binding affinity of compound 8b to VEGFR-2.

Synthesis, docking study, and antitumor evaluation of benzamides and oxadiazole derivatives of 3-phenoxybenzoic acid as VEGFR-2 inhibitors.

Current chemotherapeutic agents have several limitations, including lack of selectivity, the development of undesirable side effects, and chemoresistance. As a result, there is an unmet need for the development of novel small molecules with minimal side effects and the ability to specifically target tumor cells. A new series of 3-phenoxybenzoic acid derivatives, including 1,3,4-oxadiazole derivatives (4a-d) and benzamides derivatives (5a-e) were synthesized; their chemical structures were confirmed by Fourier-transform infrared spectroscopy, 1H nuclear magnetic resonance (NMR), 13C NMR, and mass spectra; and various physicochemical properties were determined. The antiproliferative activities of the new derivatives were evaluated by means of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Three compounds (4b, 4c, and 4d) exhibited cytotoxicity against two of the three cell lines tested, five compounds (3, 4a, 5a, 5b, and 5e) were toxic to one cell line, while two compounds (5c and 5d) were not cytotoxic to any of the three cell lines tested in the current study. Based on docking scores, MTT assay findings, and vascular endothelial growth factor receptor 2 (VEGFR-2) kinase activity data, Compound 4d was selected for further biological investigation. Flow cytometry was used to determine the mode of cell death (apoptosis vs. necrosis) and the effect on cell cycle progression. Compound 4d arrested HepG2 hepatocellular carcinoma cells in the G2/M phase and activated both the intrinsic and extrinsic apoptosis pathways. In conclusion, Compound 4d has shown promising results for future research as a potent VEGFR-2 tyrosine kinase inhibitor.

Synthesis of Bis-thiazoles Tethered 1,4-Dihydropyridine and Pyridine Linkers via Simple Oxidation and their Molecular Docking as VEGFR -TK Inhibitors.

AIM: In this study, a neoteric and expedient oxidation method is applied for a variety of Hantzsch 1,4-dihydropyridine derivatives such as 1,4-dihydro- 2,6-dimethyl-3,5-diacetylpyridine, 3,5-bis-hydrazono--2,6-dimethyl-1,4-dihydropyridine, and 3,5-bis-thiazoly-2,6-dimethyl-1,4-dihydro pyridine. METHOD: This simple oxidation is based upon the in situ generation of nitrous acid from an aqueous sodium nitrite and acetic acid mixture and could be used to downgrade costs, sustain resources, and minimize chemical wastes. Also, a molecular modeling strategy was used to study the mechanism of action for various derivatives of bis-hydrazinylidene- thiazole as the protein Vascular Endothelial Growth Factor Receptor Tyrosine Kinase (VEGFR TK) inhibitor through evaluating their binding scores and modes compared with Sorafenib as a reference standard. RESULT: The results revealed that the interaction of hydrazinylidene and thiazole as an anticancer Tyrosine Kinase inhibitor has been improved. CONCLUSION: Additionally, the compounds exhibiting the highest activity were assessed for their potential anticancer effects against HepG-2, MCF-7, and WI-38 cells, and the outcomes demonstrated encouraging activity against cancer.

Design, synthesis, and anticancer evaluation of N-sulfonylpiperidines as potential VEGFR-2 inhibitors, apoptotic inducers.

A new panel of N-sulfonylpiperidine derivatives has been designed and synthesized as vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors. Anti-proliferative activities of the synthesized members were tested against colorectal carcinoma (HCT-116), hepatocellular carcinoma (HepG-2), and breast cancer (MCF-7) cell lines. Compounds 3a, 4, 8, and 9 showed the highest activities against the tested cell lines. In particular, compound 8 showed excellent activities against HCT-116, HepG-2, and MCF-7 with IC50 values of 3.94, 3.76, and 4.43 µM, respectively. Such IC50 values are comparable to vinblastine (IC50 = 3.21, 7.35, 5.83 µM, respectively) and doxorubicin (IC50 = 6.74, 7.52, 8.19 µM, respectively). In vitro VEGFR-2 inhibitory activity of the most promising molecules (3a, 4, 8, and 9) indicated that compound 8 is the highest VEGFR-2 inhibitor with an IC50 of 0.0554 µM, compared to sorafenib (IC50 = 0.0416 µM). The most promising candidates (3a, 4, 8, and 9) were subjected to flow cytometry analyses to assess their effects on the cell cycle behavior and the apoptotic power against the three tested cell lines (HCT-116, HepG-2, and MCF-7). The tested compound arrested the tumor cells at both the G2/M and Pre-G1 phases. In addition, compound 9 was proved as the most effective apoptotic inducer among the tested compounds against the tested cells. Molecular docking studies against VEGFR-2 (PDB ID: 2OH4) revealed good binding modes of the synthesized compound similar to that of sorafenib. Computational investigation of ADMET parameters revealed the drug-likeness of the synthesized compounds.

Discovery of new thiazolidine-2,4-dione derivatives as potential VEGFR-2 inhibitors: In vitro and in silico studies.

In this study, a series of seven novel 2,4-dioxothiazolidine derivatives with potential anticancer and VEGFR-2 inhibiting abilities were designed and synthesized as VEGFR-2 inhibitors. The synthesized compounds were tested in vitro for their potential to inhibit VEGFR-2 and the growth of HepG2 and MCF-7 cancer cell lines. Among the compounds tested, compound 22 (IC50 = 0.079 µM) demonstrated the highest anti-VEGFR-2 efficacy. Furthermore, it demonstrated significant anti-proliferative activities against HepG2 (IC50 = 2.04 ± 0.06 µM) and MCF-7 (IC50 = 1.21 ± 0.04 M). Additionally, compound 22 also increased the total apoptotic rate of the MCF-7 cancer cell lines with cell cycle arrest at S phase. As well, computational methods were applied to study the VEGFR-2-22 complex at the molecular level. Molecular docking and molecular dynamics (MD) simulations were used to investigate the complex's structural and kinetic characteristics. The DFT calculations further revealed the structural and electronic properties of compound 22. Finally, computational ADMET and toxicity tests were performed indicating the likeness of the proposed compounds to be drugs. The results suggest that compound 22 displays promise as an effective anticancer treatment and can serve as a model for future structural modifications and biological investigations in this field.

Computer-assisted drug discovery (CADD) of an anti-cancer derivative of the theobromine alkaloid inhibiting VEGFR-2.

VEGFR-2 is a significant target in cancer treatment, inhibiting angiogenesis and impeding tumor growth. Utilizing the essential pharmacophoric structural properties, a new semi-synthetic theobromine analogue (T-1-MBHEPA) was designed as VEGFR-2 inhibitor. Firstly, T-1-MBHEPA's stability and reactivity were indicated through several DFT computations. Additionally, molecular docking, MD simulations, MM-GPSA, PLIP, and essential dynamics (ED) experiments suggested T-1-MBHEPA's strong binding capabilities to VEGFR-2. Its computational ADMET profiles were also studied before the semi-synthesis and indicated a good degree of drug-likeness. T-1-MBHEPA was then semi-synthesized to evaluate the design and the in silico findings. It was found that, T-1-MBHEPA inhibited VEGFR-2 with an IC50 value of 0.121 ± 0.051 µM, as compared to sorafenib which had an IC50 value of 0.056 µM. Similarly, T-1-MBHEPA inhibited the proliferation of HepG2 and MCF7 cell lines with IC50 values of 4.61 and 4.85 µg/mL respectively - comparing sorafenib's IC50 values which were 2.24 µg/mL and 3.17 µg/mL respectively. Interestingly, T-1-MBHEPA revealed a noteworthy IC50 value of 80.0 µM against the normal cell lines exhibiting exceptionally high selectivity indexes (SI) of 17.4 and 16. 5 against the examined cell lines, respectively. T-1-MBHEPA increased the percentage of apoptotic MCF7 cells in early and late stages, respectively, from 0.71 % to 7.22 % and from 0.13 % to 2.72 %, while the necrosis percentage was increased to 11.41 %, in comparison to 2.22 % in control cells. Furthermore, T-1-MBHEPA reduced the production of pro-inflammatory cytokines TNF-α and IL-2 in the treated MCF7 cells by 33 % and 58 %, respectively indicating an additional anti-angiogenic mechanism. Also, T-1-MBHEPA decreased significantly the potentialities of MCF7 cells to heal and migrate from 65.9 % to 7.4 %. Finally, T-1-MBHEPA's oral treatment didn't show toxicity on the liver function (ALT and AST) and the kidney function (creatinine and urea) levels of mice.

Antitumor activity of the new tyrphostin briva against BRAFV600E-mutant colorectal carcinoma cells.

Because of a reduced sensitivity of BRAF-mutant colorectal cancers to BRAF inhibitor treatment when compared with BRAF-mutant melanoma, it is essential to develop efficient drugs to cope with this disease. The new 2-(4-bromophenyl)-3-arylacrylonitrile compound Briva was prepared in one step from commercially available starting compounds. Briva and two known thiophene analogs (Thio-Iva and Thio-Dam) were tested for their cytotoxic activity against various tumor cell lines including colorectal and breast cancer cells. The antitumor activities of the test compounds were assessed in vitro via the MTT assay, DAPI staining of nuclei, RT-PCR and immunoblotting, wound healing, clonogenic assay, collagen I adhesion assay, and kinase inhibition assays. A selective activity of Briva was observed against BRAFV600E-mutant HT-29 and COLO-201 colorectal carcinoma (CRC) cells. Briva caused inhibition of HT-29 clonogenic tumor growth and was found to induce cytotoxicity by activating the intrinsic apoptosis pathway. In addition, Briva reduced HT-29 cell adhesion and migration. Kinase inhibition experiments revealed that Briva inhibits VEGFR2. Thus, Briva can be considered as a promising antitumor compound against BRAFV600E-mutant colon carcinoma by targeting VEGFR2 tyrosine kinase and consequently reducing cell adhesion and metastasis formation.

Anti-breast cancer potential of a new xanthine derivative: In silico, antiproliferative, selectivity, VEGFR-2 inhibition, apoptosis induction and migration inhibition studies.

BACKGROUND: The overexpression of VEGFR-2 receptors in breast cancer provides a valuable approach to anticancer strategies. Targeting VEGFR-2, a new semisynthetic compound (T-1-MCPAB) has been designed. METHODS: Computational methods (ADMET, toxicity, DFT, Molecular Docking, Molecular Dynamics Simulations, MM-GBSA, PLIP, and PCAT) were conducted. In addition to the semi-synthesis, in vitro studies (anti-VEGFR-2, anti-proliferative, flow cytometry, and wound scratch assay) were employed. RESULTS: ADME and toxicity profiles of T-1-MCPAB studies indicated its overall drug-likeness showing results much better than Sorafenib. Then, T-1-MCPAB's exact 3D structure, stability, and reactivity were evoked by the DFT calculations. Molecular docking, molecular dynamics simulations, MM-GPSA, PLIP, and PCAT studies denoted the correct binding and inhibiting potential of T-1-MCPAB, towards VEGFR-2 protein. After the semisynthesis, T-1-MCPAB inhibited VEGFR-2 with an IC50 of 0.135 µM, which was comparable to sorafenib's IC50 of 0.0591 µM. T-1-MCPAB also showed a notable performance against MCF7 and T47D breast cancer cell lines with IC50 values of 30.95 µM and 63.64 µM, respectively, and had high selectivity index values of 3.7 and 1.8, respectively. Furthermore, T-1-MCPAB influenced early and late apoptosis and significantly decreased the potential of MCF7 cells to heal and migrate. CONCLUSION: T-1-MCPAB is a promising VEGFR-2 inhibitor with potential for breast cancer treatment. Further chemical and biological studies are needed to explore its potential as a therapeutic agent.

Natural products targeting tumour angiogenesis.

Tumour angiogenesis is the formation of new blood vessels to support the growth of a tumour. This process is critical for tumour progression and metastasis, making it an attractive approach to cancer therapy. Natural products derived from plants, animals or microorganisms exert anti-angiogenic properties and can be used to inhibit tumour growth and progression. In this review, we comprehensively report on the current status of natural products against tumour angiogenesis from four perspectives until March 2023: (1) the role of pro-angiogenic factors and antiangiogenic factors in tumour angiogenesis; (2) the development of anti-tumour angiogenesis therapy (monoclonal antibodies, VEGFR-targeted small molecules and fusion proteins); (3) the summary of anti-angiogenic natural agents, including polyphenols, polysaccharides, alkaloids, terpenoids, saponins and their mechanisms of action, and (4) the future perspectives of anti-angiogenic natural products (bioavailability improvement, testing of dosage and side effects, combination use and discovery of unique natural-based compounds). Our review aims to better understand the potential of natural products for drug development in inhibiting tumour angiogenesis and further aid the effective transition of these outcomes into clinical trials.

Discovery of indolinone-bearing benzenesulfonamides as new dual carbonic anhydrase and VEGFR-2 inhibitors possessing anticancer and pro-apoptotic properties.

In the current medical era, the utilization of a single small molecule to simultaneously target two distinct molecular targets is emerging as a highly effective strategy in the battle against cancer. Carbonic Anhydrase (CA) and Vascular-Endothelial Growth Factor (VEGF) are genes that are activated in response to low oxygen levels (hypoxia) and play a role in the development and progression of tumors in hypoxic conditions. Herein we report the design, synthesis, and biological assessment of a series of novel indolinone-based benzenesulfonamides (8a-k, 11a-d, 15a-d, and 16) as potential dual inhibitors for cancer-associated hCA IX/XII and VEGFR-2. All the synthesized sulfonamides were assessed for their inhibitory effect against four CA isoforms I, II, IX, and XII where they displayed varying degrees of hCA inhibition. The most effective and selective hCA IX and XII inhibitors 8g, 8j and 15b were chosen to be tested for their in vitro inhibitory impact against VEGFR-2 as well as their antiproliferative impact against VEGFR-2 overexpressing MDA-MB-231 and MCF-7 breast cancer cells. Furthermore, molecular docking studies were conducted within the hCA IX, XII, and VEGFR-2 active sites to explain the observed inhibitory results.

Discovery of sulfonamide-tethered isatin derivatives as novel anticancer agents and VEGFR-2 inhibitors.

In this work, new isatin-based sulphonamides (6a-i, 11a-c, 12a-c) were designed and synthesised as potential dual VEGFR-2 and carbonic anhydrase inhibitors with anticancer activities. Firstly, all target isatins were examined for in vitro antitumor action on NCI-USA panel (58 tumour cell lines). Then, the most potent derivatives were examined for the potential CA inhibitory action towards the physiologically relevant hCA isoforms I, II, and tumour-linked hCA IX isoform, in addition, the VEGFR-2 inhibitory activity was evaluated. The target sulphonamides failed to inhibit the CA isoforms that could be attributable to the steric effect of the neighbouring methoxy group, whereas they displayed potent VEGFR-2 inhibitory effect. Following that, isatins 11b and 12b were tested for their influence on the cell cycle disturbance, and towards the apoptotic potential. Finally, detailed molecular modelling analyses, including docking and molecular dynamics, were carried out to assess the binding mode and stability of target isatins.

A novel thieno[2,3-d]pyrimidine derivative inhibiting vascular endothelial growth factor receptor-2: A story of computer-aided drug discovery.

Following the pharmacophoric features of vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitors, a novel thieno[2,3-d]pyrimidine derivative has been designed and its activity against VEGFR-2 has been demonstrated by molecular docking studies that showed an accurate binding mode and an excellent binding energy. Furthermore, the recorded binding was confirmed by a series of molecular dynamics simulation studies, which also revealed precise energetic, conformational, and dynamic changes. Additionally, molecular mechanics with generalized Born and surface area solvation and polymer-induced liquid precursors studies were conducted and verified the results of the MD simulations. Next, in silico absorption, distribution, metabolism, excretion, and toxicity studies have also been conducted to examine the general drug-like nature of the designed candidate. According to the previous results, the thieno[2,3-d]pyrimidine derivative was synthesized. Fascinatingly, it inhibited VEGFR-2 (IC50 = 68.13 nM) and demonstrated strong inhibitory activity toward human liver (HepG2), and prostate (PC3) cell lines with IC50 values of 6.60 and 11.25 µM, respectively. As well, it was safe and showed a high selectivity index against normal cell lines (WI-38). Finally, the thieno[2,3-d]pyrimidine derivative arrested the growth of the HepG2 cells at the G2/M phase inducing both early and late apoptosis. These results were further confirmed through the ability of the thieno[2,3-d]pyrimidine derivative to induce significant changes in the apoptotic genes levels of caspase-3, caspase-9, Bcl-2 associated X-protein, and B-cell lymphoma 2.

Novel 2-oxo-2-phenylethoxy and benzyloxy diaryl urea hybrids as VEGFR-2 inhibitors: Design, synthesis, and anticancer evaluation.

Two series of diaryl urea derivatives, 6a-k and 7a-n, were synthesized. All the newly synthesized compounds were tested against the NCI (US) cancer cell lines via SRB assay. The p-chloro-m-trifluoromethyl phenyl derivatives 6e-g and 7e-g showed the most potent cytotoxic activity with a GI50 value range of 1.2-15.9 µM. Furthermore, the p-fluorobenzyloxy diaryl urea derivative 7g revealed the most potent cytotoxicity against eight cancer cell lines in the MTT assay with IC50 values below 5 µM. Compounds 6a-k and 7a-n were tested for their vascular endothelial growth factor receptor-2 (VEGFR-2) kinase inhibitory activities. The p-chloro-m-trifluoromethyl diaryl urea benzyloxy derivatives 7e-i and the p-methoxydiaryl urea benzyloxy derivatives 7k, 7l, and 7n were found to be the most active compounds as VEGFR-2 inhibitors in the benzyloxy series 7, with an IC50 range of 0.09-4.15 µM. In the 2-oxo-2-phenylethoxy series 6, compounds 6e-g and 6i were reported with IC50 values of 0.94, 0.54, 2.71, and 4.81 µM, respectively. Moreover, compounds 7e and 7g induced apoptosis, causing cell cycle arrest in the G2/M phase. In addition, 7g showed an antimigratory effect in A-375 cells and inhibited the VEGFR-2 expression in an immunohistofluorescence study. Molecular docking simulations on VEGFR-2 as well as ADME properties prediction were also performed.

Design, Synthesis, Molecular Modeling, and Anticancer Evaluation of New VEGFR-2 Inhibitors Based on the Indolin-2-One Scaffold.

A new series of indoline-2-one derivatives was designed and synthesized based on the essential pharmacophoric features of VEGFR-2 inhibitors. Anti-proliferative activities were assessed for all derivatives against breast (MCF-7) and liver (HepG2) cancer cell lines, using sunitinib as a reference agent. The most potent anti-proliferative derivatives were evaluated for their VEGFR-2 inhibition activity. The effects of the most potent inhibitor, 17a, on cell cycle, apoptosis, and expression of apoptotic markers (caspase-3&-9, BAX, and Bcl-2) were studied. Molecular modeling studies, such as docking simulations, physicochemical properties prediction, and pharmacokinetic profiling were performed. The results revealed that derivatives 5b, 10e, 10g, 15a, and 17a exhibited potent anticancer activities with IC50 values from 0.74-4.62 µM against MCF-7 cell line (sunitinib IC50 = 4.77 µM) and from 1.13-8.81 µM against HepG2 cell line (sunitinib IC50 = 2.23 µM). Furthermore, these compounds displayed potent VEGFR-2 inhibitory activities with IC50 values of 0.160, 0.358, 0.087, 0.180, and 0.078 µM, respectively (sunitinib IC50 = 0.139 µM). Cell cycle analysis demonstrated the ability of 17a to induce a cell cycle arrest of the HepG2 cells at the S phase and increase the total apoptosis by 3.5-fold. Moreover, 17a upregulated the expression levels of apoptotic markers caspase-3 and -9 by 6.9-fold and 3.7-fold, respectively. In addition, 17a increased the expression level of BAX by 2.7-fold while decreasing the expression level of Bcl-2 by 1.9-fold. The molecular docking simulations displayed enhanced binding interactions and similar placement as sunitinib inside the active pocket of VEGFR-2. The molecular modeling calculations showed that all the test compounds were in accordance with Lipinski and Veber rules for oral bioavailability and had promising drug-likeness behavior.

(E)-N-(3-(1-(2-(4-(2,2,2-Trifluoroacetamido)benzoyl)hydrazono)ethyl)phenyl)nicotinamide: A Novel Pyridine Derivative for Inhibiting Vascular Endothelial Growth Factor Receptor-2: Synthesis, Computational, and Anticancer Studies.

(E)-N-(3-(1-(2-(4-(2,2,2-Trifluoroacetamido)benzoyl)hydrazono)ethyl)phenyl)nicotinamide (compound 10) was designed as an antiangiogenic VEGFR-2 inhibitor with the essential pharmacophoric structural properties to interact with the catalytic pocket of VEGFR-2. The designed derivative was synthesized, and its structure was confirmed through Ms, elemental, 1H, and 13C spectral data. The potentiality of the designed pyridine derivative to bind with and inhibit the vascular endothelial growth factor receptor-2 (VEGFR-2) enzyme was indicated by molecular docking assessments. In addition, six molecular dynamic (MD) experiments proved its correct binding with VEGFR-2 over 100 ns. Additionally, the molecular mechanics energies, combined with the generalized born and surface area (MM-GBSA) analysis, identified the precise binding with optimum energy. To explore the stability and reactivity of the designed pyridine derivative, density functional theory (DFT) calculations, including electrostatic potential maps and total electron density, were carried out. Additionally, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis demonstrated its general likeness and its safety. The designed compound was synthesized to evaluate its effects against VEGFR-2 protein, cancer, and normal cells. The in vitro results were concordant with the in silico results, because the new pyridine derivative (compound 10) displayed VEGFR-2 inhibition with an IC50 value of 65 nM and displayed potent cytotoxic properties against hepatic (HepG2) and breast (MCF-7) cancer cell lines with IC50 values of 21.00 and 26.10 µM, respectively; additionally, it exhibited high selectivity indices against the normal cell lines (W-38) of 1.55 and 1.25, respectively. The obtained results present compound 10 as a new lead VEGFR-2 inhibitor for further biological investigation and chemical modifications.

New Oxazolo[5,4-d]pyrimidines as Potential Anticancer Agents: Their Design, Synthesis, and In Vitro Biological Activity Research.

Cancer is a large group of diseases in which the rapid proliferation of abnormal cells generally leads to metastasis to surrounding tissues or more distant ones through the lymphatic and blood vessels, making it the second leading cause of death worldwide. The main challenge in designing a modern anticancer therapy is to develop selective compounds that exploit specific molecular targets. In this work, novel oxazolo[5,4-d]pyrimidine derivatives were designed, synthesized, and evaluated in vitro for their cytotoxic activity against a panel of four human cancer cell lines (lung carcinoma: A549, breast adenocarcinoma: MCF7, metastatic colon adenocarcinoma: LoVo, primary colon adenocarcinoma: HT29), along with their P-glycoprotein-inhibitory ability and pro-apoptotic activity. These oxazolo[5,4-d]pyrimidine derivatives, which are structurally similar to nucleic purine bases in general, are characterized by the presence of a pharmacologically favorable isoxazole substituent at position 2 and aliphatic amino chains at position 7 of the condensed heterocyclic system. In silico analysis of the obtained compounds identified their potent inhibitory activity towards human vascular endothelial growth factor receptor-2 (VEGFR-2). Molecular docking was performed to assess the binding mode of new derivatives to the VEGFR-2 active site. Then, their physicochemical, pharmacokinetic, and pharmacological properties (i.e., ADME-administration, distribution, metabolism, and excretion) were also predicted to assess their druglikeness. In particular, compound 3g (with a 3-(N,N-dimethylamino)propyl substituent) was found to be the most potent against the HT29 cell line, with a 50% cytotoxic concentration (CC50) of 58.4 µM, exceeding the activity of fluorouracil (CC50 = 381.2 µM) and equaling the activity of cisplatin (CC50 = 47.2 µM), while being less toxic to healthy human cells (such as normal human dermal fibroblasts (NHDFs)) than these reference drugs. The results suggest that compound 3g is a potentially promising candidate for the treatment of primary colorectal cancer.

Discovery of New VEGFR-2 Inhibitors: Design, Synthesis, Anti-Proliferative Evaluation, Docking, and MD Simulation Studies.

Four new nicotinamide-based derivatives were designed as antiangiogenic VEGFR-2 inhibitors. The congeners were synthesized possessing the pharmacophoric essential features to bind correctly with the VEGFR-2 active pocket. All members were evaluated for their cytotoxic and VEGFR-2 inhibitory potentialities. Compound 6 was the most potent showingIC50 values of 9.3 ± 0.02 and 7.8 ± 0.025 µM against HCT-116 and HepG-2 cells, respectively, and IC50 of 60.83 nM regarding VEGFR-2 enzyme inhibition. Compound 6 arrested the growth of HCT-116 cells at the pre-G1 and G2-M phases. Further, it induced both early and late apoptosis. Additionally, compound 6 caused a significant decrease in TNF-α and IL6 by 66.42% and 57.34%, respectively. The considered compounds had similar docking performances to that of sorafenib against the VEGFR-2 (PDB ID: 2OH4). The correct binding of compound 6 with VEGFR-2 was validated using MD simulations, and MM-GPSA calculations.

New application of novel tetrazine derivatives as potent VEGFR-2 kinase inhibitors and anti-cancer agents.

Background: A novel series of s-tetrazine derivatives was designed as a new scaffold and synthesized efficiently as VEGFR-2 inhibitors for the first time. Methodology & results: The inhibitory activities of the new compounds were tested by MTT assay and enzyme assay, respectively. Western blot assay, cell apoptosis assay and cell migration assay were carried out to study the action mechanism of them. All the synthesized compounds showed evident VEGFR-2 inhibitory activities (IC50 in the range of 88.53-257.55 nM). Compounds 23h, 25d, 26e and 27c showed excellent anti-proliferative activities against the four tested cell lines and were better than sorafenib basically. Conclusion: Compounds with good activities based on this novel scaffold can be screened successfully.

Discovery of novel thiazolyl-pyrazolines as dual EGFR and VEGFR-2 inhibitors endowed with in vitro antitumor activity towards non-small lung cancer.

New series of thiazolyl-pyrazoline derivatives (7a-7d, 10a-10d and 13a-13f) have been synthesised and assessed for their potential EGFR and VEGFR-2 inhibitory activities. Compounds 10b and 10d exerted potent and selective inhibitory activity towards the two receptor tyrosine kinases; EGFR (IC50 = 40.7 ± 1.0 and 32.5 ± 2.2 nM, respectively) and VEGFR-2 (IC50 = 78.4 ± 1.5 and 43.0 ± 2.4 nM, respectively). The best anti-proliferative activity for the examined thiazolyl-pyrazolines was observed against the non-small lung cancer cells (NSCLC). Compounds 10b and 10d displayed pronounced efficacy against A549 (IC50 = 4.2 and 2.9 µM, respectively) and H441 cell lines (IC50 = 4.8 and 3.8 µM, respectively). Moreover, our results indicated that 10b and 10d were much more effective towards EGFR-mutated NSCLC cell lines (NCI-H1650 and NCI-H1975 cells) than gefitinib. Finally, compounds 10b and 10d induce G2/M cell cycle arrest and apoptosis and inhibit migration in A549 cancerous cells.