New quinoline and isatin derivatives having the main characteristics of VEGFR-2 inhibitors was synthesised. The antiproliferative effects of these compounds were estimated against A549, Caco-2, ...HepG2, and MDA-MB-231. Compounds 13 and 14 showed comparable activities with doxorubicin against the Caco-2 cells. These compounds strongly inhibited VEGFR-2 kinase activity. The cytotoxic activities were evaluated against Vero cells. Compound 7 showed the highest value of safety and selectivity. Cell migration assay displayed the ability of compound 7 to prevent healing and migration abilities in the cancer cells. Furthermore, compound 7 induced apoptosis in Caco-2 through the expressive down-regulation of the apoptotic genes, Bcl2, Bcl-xl, and Survivin, and the upregulation of the TGF gene. Molecular docking against VEGFR-2 emerged the interactions of the synthesised compounds in a similar way to sorafenib. Additionally, seven molecular dynamics simulations studies were applied and confirmed the stability of compound 13 in the active pocket of VEGFR-2 over 100 ns.
A new series of pyrimidine-5-carbonitrile derivatives has been designed as ATP mimicking tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR). These compounds were synthesized ...and evaluated for their
in vitro
cytotoxic activities against a panel of four human tumor cell lines, namely colorectal carcinoma (HCT-116), hepatocellular carcinoma (HepG-2), breast cancer (MCF-7), and non-small cell lung cancer cells (A549). Five of the synthesized compounds,
11
a
,
11
b
,
12
b
,
15
b
and
16
a
, were found to exhibit moderate antiproliferative activity against the tested cell lines and were more active than the EGFR inhibitor erlotinib. In particular, compound
11
b
showed 4.5- to 8.4-fold erlotinib activity against HCT-116, HepG-2, MCF-7, and A549 cells with IC
50
values of 3.37, 3.04, 4.14, and 2.4 μM respectively. Moreover, the most cytotoxic compounds that showed promising IC
50
values against the four cancer cell lines were subjected to further investigation for their kinase inhibitory activities against EGFR
WT
and EGFR
T790M
using homogeneous time resolved fluorescence (HTRF) assay. Compound
11
b
was also found to be the most active compound against both EGFR
WT
and mutant EGFR
T790M
, exhibiting IC
50
values of 0.09 and 4.03 μM, respectively. The cell cycle and apoptosis analyses revealed that compound
11
b
can arrest the cell cycle at the G2/M phase and induce significant apoptotic effects in HCT-116, HepG-2, and MCF-7 cells. Additionally, compound
11
b
upregulated the level of caspase-3 by 6.5 fold in HepG-2 when compared with the control. Finally, molecular docking studies were carried out to examine the binding mode of the synthesized compounds against the proposed targets; EGFR
WT
and EGFR
T790M
. Additional
in silico
ADMET studies were performed to explore drug-likeness properties.
A new series of pyrimidine-5-carbonitrile derivatives has been designed as ATP mimicking tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR).
A new series of pyrimidine-5-carbonitrile derivatives has been designed as ATP mimicking tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR). These compounds were synthesized ...and evaluated for their in vitro cytotoxic activities against a panel of four human tumor cell lines, namely colorectal carcinoma (HCT-116), hepatocellular carcinoma (HepG-2), breast cancer (MCF-7), and non-small cell lung cancer cells (A549). Five of the synthesized compounds, 11a, 11b, 12b, 15b and 16a, were found to exhibit moderate antiproliferative activity against the tested cell lines and were more active than the EGFR inhibitor erlotinib. In particular, compound 11b showed 4.5- to 8.4-fold erlotinib activity against HCT-116, HepG-2, MCF-7, and A549 cells with IC50 values of 3.37, 3.04, 4.14, and 2.4 μM respectively. Moreover, the most cytotoxic compounds that showed promising IC50 values against the four cancer cell lines were subjected to further investigation for their kinase inhibitory activities against EGFRWT and EGFRT790M using homogeneous time resolved fluorescence (HTRF) assay. Compound 11b was also found to be the most active compound against both EGFRWT and mutant EGFRT790M, exhibiting IC50 values of 0.09 and 4.03 μM, respectively. The cell cycle and apoptosis analyses revealed that compound 11b can arrest the cell cycle at the G2/M phase and induce significant apoptotic effects in HCT-116, HepG-2, and MCF-7 cells. Additionally, compound 11b upregulated the level of caspase-3 by 6.5 fold in HepG-2 when compared with the control. Finally, molecular docking studies were carried out to examine the binding mode of the synthesized compounds against the proposed targets; EGFRWT and EGFRT790M. Additional in silico ADMET studies were performed to explore drug-likeness properties.
•New nicotinamide derivatives were designed and synthesized as VEGFR-2 inhibitors.•Cytotoxicity against MCF-7, HepG2, and HCT-116 cells was evaluated.•Evaluation of VEGFR-2 inhibition, apoptotic ...effect, and cell cycle analyses were carried out.•The effect on caspase-3, TNF-, and IL-6 were assessed.•In silico docking, MD simulations, ADMET, and toxicity studies were performed.
As an extension to our preceding studies on nicotinamide derivatives as anticancer agents, new nicotinamide-based candidates were designed and synthesized as VEGFR-2 inhibitors. The in vitro cytotoxic activity of the synthesized compounds was evaluated against three human cancer cell lines (MCF-7, HepG-2 and HCT-116). The IC50 values for compound 17 were 2.61± 0.01, 3.20 ± 0.02, and 2.46 ± 0.01 µM, respectively, compared to sorafenib (4.21±0.03, 3.40 ± 0.02, and 5.30 ± 0.04 µM) against MCF-7, HePG-2, and HCT-116. This indicated that compound 17 possess double strength relative to sorafenib against both MCF-7 and HCT-116. Compound 17 was the most promising VEGFR-2 inhibitor with IC50 value of 0.34 μM that was slightly better than that of sorafenib (0.38 μM). Further studies displayed the ability of compound 17 to arrest the growth of HCT-116 cells at the Pre-G1 and S phases. Additionally, compound 17 induced a significant increase in the total apoptosis rate of HCT-116 cells from 1.82 % to 26.69 %. Moreover, it showed high selectivity indices against HCT-116, HepG2, and MCF-7 cancer cells. Furthermore, compound 17 showed potent inhibitory activities on TNF-α and IL-6 and showed a notable rise in caspase-3 level. In addition, the potentiality of the designed derivatives to bind with and inhibit the VEGFR-2 enzyme was indicated by molecular docking assessments. MD simulation studies revealed the stability of compound 17 in the active site of VEGFR-2 for 100 ns. Based on the previous findings, compound 17 appears to be a promising apoptotic VEGFR-2 inhibitor and could potentially direct future efforts towards the development of novel anticancer medications.
A new series of pyrimidine-5-carbonitrile derivatives has been designed as ATP mimicking tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR). These compounds were synthesized ...and evaluated for their in vitro cytotoxic activities against a panel of four human tumor cell lines, namely colorectal carcinoma (HCT-116), hepatocellular carcinoma (HepG-2), breast cancer (MCF-7), and non-small cell lung cancer cells (A549). Five of the synthesized compounds, 11a, 11b, 12b, 15b and 16a, were found to exhibit moderate antiproliferative activity against the tested cell lines and were more active than the EGFR inhibitor erlotinib. In particular, compound 11b showed 4.5- to 8.4-fold erlotinib activity against HCT-116, HepG-2, MCF-7, and A549 cells with IC50 values of 3.37, 3.04, 4.14, and 2.4 μM respectively. Moreover, the most cytotoxic compounds that showed promising IC50 values against the four cancer cell lines were subjected to further investigation for their kinase inhibitory activities against EGFRWT and EGFRT790M using homogeneous time resolved fluorescence (HTRF) assay. Compound 11b was also found to be the most active compound against both EGFRWT and mutant EGFRT790M, exhibiting IC50 values of 0.09 and 4.03 μM, respectively. The cell cycle and apoptosis analyses revealed that compound 11b can arrest the cell cycle at the G2/M phase and induce significant apoptotic effects in HCT-116, HepG-2, and MCF-7 cells. Additionally, compound 11b upregulated the level of caspase-3 by 6.5 fold in HepG-2 when compared with the control. Finally, molecular docking studies were carried out to examine the binding mode of the synthesized compounds against the proposed targets; EGFRWT and EGFRT790M. Additional in silico ADMET studies were performed to explore drug-likeness properties.
Eleven novel benzoxazole/benzothiazole‐based thalidomide analogs were designed and synthesized to obtain new effective antitumor immunomodulatory agents. The synthesized compounds were evaluated for ...their cytotoxic activities against HepG‐2, HCT‐116, PC3, and MCF‐7 cells. Generally, the open analogs with semicarbazide and thiosemicarbazide moieties (10, 13a–c, 14, and 17a,b) exhibited higher cytotoxic activities than derivatives with closed glutarimide moiety (8a–d). In particular, compound 13a (IC50 = 6.14, 5.79, 10.26, and 4.71 µM against HepG‐2, HCT‐116, PC3, and MCF‐7, respectively) and 14 (IC50 = 7.93, 8.23, 12.37, and 5.43 µM, respectively) exhibited the highest anticancer activities against the four tested cell lines. The most active compounds 13a and 14 were further evaluated for their in vitro immunomodulatory activities on tumor necrosis factor‐alpha (TNF‐α), caspase‐8 (CASP8), vascular endothelial growth factor (VEGF), and nuclear factor kappa‐B p65 (NF‐κB p65) in HCT‐116 cells. Compounds 13a and 14 showed a remarkable and significant reduction in TNF‐α. Furthermore, they showed significant elevation in CASP8 levels. Also, they significantly inhibited VEGF. In addition, compound 13a showed significant decreases in the level of NF‐κB p65 while compound 14 demonstrated an insignificant decrease with respect to thalidomide. Moreover, our derivatives exhibited good in silico absorption, distribution, metabolism, elimination, toxicity (ADMET) profiles.
Eleven benzoxazole/benzothiazole‐based thalidomide analogs were designed and synthesized. In vitro cytotoxic activities were evaluated against four human cell lines: MCF‐7, HCT‐116, HepG‐2, and PC3. In vitro immunomodulatory assays on tumor necrosis factor‐alpha and studies on the effects on human caspase 3 levels, vascular endothelial growth factor inhibition, and on nuclear factor kappa‐B p65 were carried out for 13a and 14.
Sixteen new thalidomide analogs were synthesized. The new candidates showed potent in vitro antiproliferative activities against three human cancer cell lines, namely hepatocellular carcinoma ...(HepG-2), prostate cancer (PC3), and breast cancer (MCF-7). It was found that compounds XII, XIIIa, XIIIb, XIIIc, XIIId, XIVa, XIVb, and XIVc showed IC
values ranging from 2.03 to 13.39 µg/mL, exhibiting higher activities than thalidomide against all tested cancer cell lines. Compound XIIIa was the most potent candidate, with an IC
of 2.03 ± 0.11, 2.51 ± 0.2, and 0.82 ± 0.02 µg/mL compared to 11.26 ± 0.54, 14.58 ± 0.57, and 16.87 ± 0.7 µg/mL for thalidomide against HepG-2, PC3, and MCF-7 cells, respectively. Furthermore, compound XIVc reduced the expression of NFκB P65 levels in HepG-2 cells from 278.1 pg/mL to 63.1 pg/mL compared to 110.5 pg/mL for thalidomide. Moreover, compound XIVc induced an eightfold increase in caspase-8 levels with a simultaneous decrease in TNF-α and VEGF levels in HepG-2 cells. Additionally, compound XIVc induced apoptosis and cell cycle arrest. Our results reveal that the new candidates are potential anticancer candidates, particularly XIIIa and XIVc. Consequently, they should be considered for further evaluation for the development of new anticancer drugs.
Nicotine
1 binds at nicotinic acetylcholinergic receptors (nAChRs) but relatively little is known regarding its structure–affinity relationships at central receptors. The present study focuses on the ...pyridine 6-position of nicotine. Earlier studies from our laboratories suggested that the electronic (σ) and/or lipophilic (π) nature of the 6-position substituent might influence nAChR affinity. To examine this in greater detail, we prepared and evaluated a series of 6-substituted nicotine analogs. The various analogs were found to bind at nAChRs with affinities (
K
i values) ranging from 0.45 to > 10000 nM. It was demonstrated, for fifteen of these analogs, that affinity could not be explained on the basis of either σ or π. However, a combination of π and Δ MOL VOL (representative of the volume of the 6-position substituent) accounted for affinity (
r = 0.970,
n = 15). The basicity of the pyridine nitrogen atom was also examined by determining the p
K
a values of several representative analogs. Consistent with the above studies examining σ, as well as with previously published studies on peripheral nAChR binding, p
K
a alone did not account for variation in affinity. It would appear that lipophilic substituents at the pyridine 6-position contribute to nAChR affinity of nicotine analogs, but that affinity is further modulated by the steric size of this substituent in that increased size results in decreased affinity.
The emerging resistance to antimicrobial drugs demands the synthesis of new remedies for microbial infections. Attempts have been made to prepare new compounds by modifications in the quinolone ...structure. An important method for the synthesis of new quinolone is using Vilsmeier approach but has its own limitations. The present work aimed to synthesize novel norfloxacin analogues using modified Vilsmeier approach and conduct preliminary investigations for the evaluation of their physicochemical properties, photochemical probe, and antimicrobial effects. In an effort to synthesize norfloxacin analogues, only 7-bromo-6-N-benzyl piperazinyl-4-oxoquinoline-3-carboxylic acid was isolated using Vilsmeier approach at high temperature, where N,N′-bis-(4-fluoro-3-nitrophenyl)-oxalamide and N,N′-bis-(3-chloro-4-fluorophenyl)-malonamide were obtained at low temperature. Correlation results showed that lipophilicity, molecular mass, and electronic factors might influence the activity. The synthesized compounds were evaluated for their antimicrobial effects against important pathogens, for their potential use in the inhibition of vitiligo.
Certain new nitrogen-substituted derivatives of cyclic imides phthalimide (a), 1,8-naphthalimide (b), and diphenimide (c), were synthesized aiming to obtain potent hypolipidemic agents. Thus, 2-(
N
...-imido) propanoic acids, 2-(
N
-phthalimido)-2-methylpropionic acid, and their ethyl esters were synthesized (Target derivative A). Also their corresponding
N
-substituted-2-(
N
-imido) propionamides and 2-(
N
-phthalimido)-2-methylpropionamides were prepared (Target derivative B). In addition,
N
-phthalimidomethyleneoxy acetate was prepared. Some of the newly prepared compounds were subjected to 3D studies and were found to be superimposed on Clofibrate, which is the first generation of fibrate drugs. The preliminary evaluation of hypolipidemic activity of the newly prepared compounds against triton WR-1339-induced hyperlipidemia in rat showed that several derivatives have demonstrated significant lowering of serum total cholesterol and triglyceride levels at dose of 150 mg/kg/i.p. comparing with Fenofibrate which is one of the second generations of fibrate drugs.
Graphical Abstract
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