A novel series of 2-thioacetamide linked benzoxazole-benzamide conjugates 1-15 was designed as potential inhibitors of the vascular endothelial growth factor receptor-2 (VEGFR-2). The prepared ...compounds were evaluated for their potential antitumor activity and their corresponding selective cytotoxicity was estimated using normal human fibroblast (WI-38) cells. Compounds 1, 9-12 and 15 showed good selectivity and displayed excellent cytotoxic activity against both HCT-116 and MCF-7 cancer cell lines compared to sorafenib, used as a reference compound. Furthermore, compounds 1 and 11 showed potent VEGFR-2 inhibitory activity. The cell cycle progression assay showed that 1 and 11 induced cell cycle arrest at G2/M phase, with a concomitant increase in the pre-G1 cell population. Further pharmacological studies showed that 1 and 11 induced apoptosis and inhibited the expression of the anti-apoptotic Bcl-2 and Bcl-xL proteins in both cell lines. Therefore, compounds 1 and 11 might serve as promising candidates for future anticancer therapy development.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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•Fifteen compounds of novel 1H-pyrazolo 3,4-bpyridine derivatives were designed and synthesized.•Molecular docking was carried out against DNA.•In vitro anti-proliferative activity ...against HePG-2, MCF-7, HCT-116, and PC-3 cell lines, DNA binding affinity and association constants assay were carried out.•A strong relationship exists between the anticancer activity and the DNA binding activity.
In trying to develop new anticancer agents, a series of 1H-pyrazolo3,4-bpyridine derivatives was designed and synthesized. Fifteen compounds were evaluated in vitro for their anti-proliferative activity against HePG-2, MCF-7, HCT-116, and PC-3 cell lines. Additionally, DNA binding affinity of the synthesized derivatives was investigated as a potential mechanism for the anticancer activity using DNA/methyl green assay and association constants assay. Compounds 19, 20, 21, 24 and 25 exhibited good activity against the four cancer cells comparable to that of doxorubicin. Interestingly, DNA binding assay results were in agreement with that of the cytotoxicity assays where the most potent anticancer compounds showed good DNA binding affinity comparable to that of doxorubicin and daunorubicin. Furthermore, a molecular docking of the tested compounds was carried out to investigate their binding pattern with the prospective target, DNA (PDB-code: 152d).
In the current work, some 1,3,4-oxadiazole-naphthalene hybrids were designed and synthesised as VEGFR-2 inhibitors. The synthesised compounds were evaluated in vitro for their antiproliferative ...activity against two human cancer cell lines namely, HepG-2 and MCF-7. Compounds that exhibited promising cytotoxicity (5, 8, 15, 16, 17, and 18) were further evaluated for their VEGFR-2 inhibitory activities. Compound 5 showed good antiproliferative activity against both cell lines and inhibitory effect on VEGFR-2. Besides, it induced apoptosis by 22.86% compared to 0.51% in the control (HepG2) cells. This apoptotic effect was supported by a 5.61-fold increase in the level of caspase-3 compared to the control cells. Moreover, it arrested the HepG2 cell growth mostly at the Pre-G1 phase. Several in silico studies were performed including docking, ADMET, and toxicity studies to predict binding mode against VEGFR-2 and to anticipate pharmacokinetic, drug-likeness, and toxicity of the synthesised compounds.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The huge global expansion of the COVID-19 pandemic caused by the novel SARS-corona virus-2 is an extraordinary public health emergency. The unavailability of specific treatment against SARS-CoV-2 ...infection necessitates the focus of all scientists in this direction. The reported antiviral activities of guanidine alkaloids encouraged us to run a comprehensive in silico binding affinity of fifteen guanidine alkaloids against five different proteins of SARS-CoV-2, which we investigated. The investigated proteins are COVID-19 main protease (M
) (PDB ID: 6lu7), spike glycoprotein (PDB ID: 6VYB), nucleocapsid phosphoprotein (PDB ID: 6VYO), membrane glycoprotein (PDB ID: 6M17), and a non-structural protein (nsp10) (PDB ID: 6W4H). The binding energies for all tested compounds indicated promising binding affinities. A noticeable superiority for the pentacyclic alkaloids particularly, crambescidin 786 (
) and crambescidin 826 (
) has been observed. Compound
exhibited very good binding affinities against Mpro (ΔG = -8.05 kcal/mol), nucleocapsid phosphoprotein (ΔG = -6.49 kcal/mol), and nsp10 (ΔG = -9.06 kcal/mol). Compound
showed promising binding affinities against M
(ΔG = -7.99 kcal/mol), spike glycoproteins (ΔG = -6.95 kcal/mol), and nucleocapsid phosphoprotein (ΔG = -8.01 kcal/mol). Such promising activities might be attributed to the long ω-fatty acid chain, which may play a vital role in binding within the active sites. The correlation of c Log P with free binding energies has been calculated. Furthermore, the SAR of the active compounds has been clarified. The Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) studies were carried out in silico for the 15 compounds; most examined compounds showed optimal to good range levels of ADMET aqueous solubility, intestinal absorption and being unable to pass blood brain barrier (BBB), non-inhibitors of CYP2D6, non-hepatotoxic, and bind plasma protein with a percentage less than 90%. The toxicity of the tested compounds was screened in silico against five models (FDA rodent carcinogenicity, carcinogenic potency TD
, rat maximum tolerated dose, rat oral LD
, and rat chronic lowest observed adverse effect level (LOAEL)). All compounds showed expected low toxicity against the tested models. Molecular dynamic (MD) simulations were also carried out to confirm the stable binding interactions of the most promising compounds,
and
with their targets. In conclusion, the examined 15 alkaloids specially
and
showed promising docking, ADMET, toxicity and MD results which open the door for further investigations for them against SARS-CoV-2.
In this study, a set of novel benzoxazole derivatives were designed, synthesised, and biologically evaluated as potential VEGFR-2 inhibitors. Five compounds (12d, 12f, 12i, 12l, and 13a) displayed ...high growth inhibitory activities against HepG2 and MCF-7 cell lines and were further investigated for their VEGFR-2 inhibitory activities. The most potent anti-proliferative member 12 l (IC
50
= 10.50 μM and 15.21 μM against HepG2 and MCF-7, respectively) had the most promising VEGFR-2 inhibitory activity (IC
50
= 97.38 nM). A further biological evaluation revealed that compound 12l could arrest the HepG2 cell growth mainly at the Pre-G1 and G1 phases. Furthermore, compound 12l could induce apoptosis in HepG2 cells by 35.13%. likely, compound 12l exhibited a significant elevation in caspase-3 level (2.98-fold) and BAX (3.40-fold), and a significant reduction in Bcl-2 level (2.12-fold). Finally, docking studies indicated that 12l exhibited interactions with the key amino acids in a similar way to sorafenib.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
A new dicoumarin, jusan coumarin, (
), has been isolated from
aerial parts. The chemical structure of jusan coumarin was estimated, by 1D, 2D NMR as well as HR-Ms spectroscopic methods, to be ...7-hydroxy-6-methoxy-3-(2-oxo-2H-chromen-6-yl)oxy-2H-chromen-2-one. As the first time to be introduced in nature, its potential against SARS-CoV-2 has been estimated using various in silico methods. Molecular similarity and fingerprints experiments have been utilized for
against nine co-crystallized ligands of COVID-19 vital proteins. The results declared a great similarity between Jusan Coumarin and
, the ligand of COVID-19 main protease (PDB ID: 6W63), M
. To authenticate the obtained outputs, a DFT experiment was achieved to confirm the similarity of
and
. Consequently,
was docked against M
. The results clarified that
bonded in a correct way inside M
active site, with a binding energy of -18.45 kcal/mol. Furthermore, the ADMET and toxicity profiles of
were evaluated and showed the safety of
and its likeness to be a drug. Finally, to confirm the binding and understand the thermodynamic characters between
and M
, several molecular dynamics (MD) simulations studies have been administered. Additionally, the known coumarin derivative, 7-isopentenyloxycoumarin (
), has been isolated as well as β-sitosterol (
).
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•Twenty-four compounds of novel quinazolin-4(3H)-one derivatives were designed and synthesized.•Cytotoxic activities were evaluated against HepG-2, MCF-7 and HCT-116 cell lines.•In ...vitro anti VEGFR-2 and in vivo antitumor activities were evaluated.•Molecular docking studies were carried out.
Inhibiting VEGFR-2 has been set up as a therapeutic strategy for treatment of cancer. Accordingly, new quinazoline-based derivatives having the structural features of VEGFR-2 inhibitors were designed and synthesized. Anti-proliferative activities were evaluated against three human cancer cell lines (HepG-2, MCF-7 and HCT-116) using MTT assay method. Doxorubicin and sorafenib were used as positive controls. Compounds 26b, 29a, 29b and 30 showed excellent anti-cancer activities against all cell lines. Moreover, compound 31 was the most active with IC 50 values of 3.97 ± 0.2, 4.83 ± 0.2 and 4.58 ± 0.3 µM, respectively. The most active cytotoxic agents were further evaluated in vitro for their VEGFR-2 inhibitory activities, compound 31 showed a high activity against VEGFR-2 with an IC50 value of 2.5 ± 0.04 µM, almost equal to that of sorafenib (IC50 = 2.4 ± 0.05 µM). Further studies revealed the ability of this promising quinazoline derivative 31 to induce apoptosis and arrest cell cycle growth at G2/M phase. In vivo antitumor activities of the synthesized compounds revealed that compounds 30 and 31 possessed significant tumor growth inhibition effect. Molecular docking studies were also performed and finally we can say that VEGFR-2 inhibition confers the reported cytotoxic activities.
A new flavonoid, Jusanin, (
) has been isolated from the aerial parts of
. The chemical structure of Jusanin has been elucidated using 1D, 2D NMR, and HR-Ms spectroscopic methods to be ...5,2',4'-trihydroxy-6,7,5'-trimethoxyflavone. Being new in nature, the inhibition potential of
has been estimated against SARS-CoV-2 using different in silico techniques. Firstly, molecular similarity and fingerprint studies have been conducted for Jusanin against co-crystallized ligands of eight different SARS-CoV-2 essential proteins. The studies indicated the similarity between
and
, the co-crystallized ligand SARS-CoV-2 main protease (PDB ID: 6W63). To confirm the obtained results, a DFT study was carried out and indicated the similarity of (total energy, HOMO, LUMO, gap energy, and dipole moment) between
and
. Accordingly, molecular docking studies of
against the target enzyme have been achieved and showed that
bonded correctly in the protein's active site with a binding energy of -19.54 Kcal/mol. Additionally, in silico ADMET in addition to the toxicity evaluation of Jusanin against seven models have been preceded and indicated the general safety and the likeness of Jusanin to be a drug. Finally, molecular dynamics simulation studies were applied to investigate the dynamic behavior of the M
-Jusanin complex and confirmed the correct binding at 100 ns. In addition to 1, three other metabolites have been isolated and identified to be сapillartemisin A (
), methyl-3-S-hydroxyprenyl-cumarate (
), and β-sitosterol (
).
There is an urgent need to design new anticancer agents that can prevent cancer cell proliferation even with minimal side effects. Accordingly, two new series of 3-methylquinoxalin-2(1H)-one and ...3-methylquinoxaline-2-thiol derivatives were designed to act as VEGFR-2 inhibitors. The designed derivatives were synthesised and evaluated in vitro as cytotoxic agents against two human cancer cell lines namely, HepG-2 and MCF-7. Also, the synthesised derivatives were assessed for their VEGFR-2inhibitory effect. The most promising member 11e were further investigated to reach a valuable insight about its apoptotic effect through cell cycle and apoptosis analyses. Moreover, deep investigations were carried out for compound 11e using western-plot analyses to detect its effect against some apoptotic and apoptotic parameters including caspase-9, caspase-3, BAX, and Bcl-2. Many in silico investigations including docking, ADMET, toxicity studies were performed to predict binding affinity, pharmacokinetic, drug likeness, and toxicity of the synthesised compounds. The results revealed that compounds 11e, 11g, 12e, 12g, and 12k exhibited promising cytotoxic activities (IC
50
range is 2.1 − 9.8 µM), comparing to sorafenib (IC
50
= 3.4 and 2.2 µM against MCF-7 and HepG2, respectively). Moreover, 11b, 11f, 11g, 12e, 12f, 12g, and 12k showed the highest VEGFR-2 inhibitory activities (IC
50
range is 2.9 − 5.4 µM), comparing to sorafenib (IC
50
= 3.07 nM). Additionally, compound 11e had good potential to arrest the HepG2 cell growth at G2/M phase and to induce apoptosis by 49.14% compared to the control cells (9.71%). As well, such compound showed a significant increase in the level of caspase-3 (2.34-fold), caspase-9 (2.34-fold), and BAX (3.14-fold), and a significant decrease in Bcl-2 level (3.13-fold). For in silico studies, the synthesised compounds showed binding mode similar to that of the reference compound (sorafenib).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Guided by the structural optimization principle and the promising anticancer effect of the quinoxaline nucleus, a new series of novel HDAC inhibitors were designed and synthesized. The synthesized ...compounds were designed to bear the reported pharmacophoric features of the HDAC inhibitors in addition to an extra moiety to occupy the non-used vacant deep pocket of the HDAC receptor. The newly prepared compounds were evaluated for their
anti-proliferative activities against HepG-2 and HuH-7 liver cancer cell lines. The tested compounds showed promising anti-proliferative activities against both cell lines. The most active ten candidates (
,
,
,
,
,
,
,
,
, and
) were further evaluated for their effect on the gene expression levels of Bax as an apoptotic marker and Bcl-2 as an anti-apoptotic one. Moreover, they were evaluated for their ability to inhibit histone deacetylase (HDAC1, HDAC4, and HDAC6) activities. Compound
achieved the best cytotoxic activities on both HepG-2 and HuH-7 cell lines with IC
values of 1.53 and 3.06 µM, respectively, and also it showed the most inhibitory activities on HDAC1, HDAC4, and HDAC6 with IC
values of 1.76, 1.39, and 3.46 µM, respectively, compared to suberoylanilide hydroxamic acid (SAHA) as a reference drug (IC
= 0.86, 0.97, and 0.93 µM, respectively). Furthermore, it achieved a more characteristic arrest in the growth of cell population of HepG-2 at both G0/G1 and S phases with 1.23-, and 1.18-fold, respectively, compared to that of the control, as determined by cell cycle analysis. Also, compound
showed a marked elevation in the AnxV-FITC apoptotic HepG-2 cells percentage in both early and late phases increasing the total apoptosis percentage by 9.98-, and 10.81-fold, respectively, compared to the control. Furthermore, docking studies were carried out to identify the proposed binding mode of the synthesized compounds towards the prospective target (HDAC4).
ADMET and toxicity studies revealed that most of the synthesized compounds have accepted profiles of drug-likeness with low toxicity. Finally, an interesting SAR analysis was concluded to help the future design of more potent HDACIs in the future by medicinal chemists.
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