In the present work, novel 16 indole-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 cell lines. Generally, the opened analogs of glutarimide ring exhibited higher activities than the closed ones. Compounds 21a-b and 11d,g showed strong potencies against all tested cell lines with IC
50
values ranging from 8.27 to 25.20 µM comparable to that of thalidomide (IC
50
values ranging from 32.12 to 76.91 µM). The most active compounds were further evaluated for their in vitro immunomodulatory activities via estimation of human tumor necrosis factor alpha (TNF-α), human caspase-8 (CASP8), human vascular endothelial growth factor (VEGF), and nuclear factor kappa-B P65 (NF-κB P65) in HCT-116 cells. Thalidomide was used as a positive control. Compounds 11g, 21a and 21b showed remarkable significant reduction in TNF-α. Furthermore, compounds 11g, 21a and 21b showed significant elevation in CASP8 levels. Compounds 11g and 21a significantly inhibited VEGF. In addition, derivatives 11d, 11g and 21a showed significant decrease in level of NF-κB p65. Moreover, our derivatives exhibited good in silico docking and ADMET profile.
Communicated by Ramaswamy H. Sarma
•Sixteen thalidomide analogs based on quinazoline rings 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 assay of TNF-α and IL-6, effects on human caspase 3 levels, COX-I and COX-II inhibition testing were carried out for 4c, 5 g, and 7.•The most promising candidate, 4c, was examined for its cell cycle effect and apoptosis assay in comparison to thalidomide on the most sensitive cell line, MCF-7.
A new series of thalidomide analogs were synthesized and evaluated against HepG-2, HCT-116, PC3, and MCF-7. With IC50 values ranging from 2.41 to 14.78 μM, compounds 4c, 5g, and 7 demonstrated substantial potencies against all examined cell lines in comparison to thalidomide (IC50 = 32.12 - 76.91 μM)). The most active compounds were further evaluated for their in vitro immunomodulatory activities via IL6, TNF-α and human caspase-3 in MCF-7 cells using thalidomide as a positive control. Compounds 5g and 4c showed significant reductions in IL6 (80.65 %) and TNF-α (76.14 %), compared to thalidomide (45.11 % and 41.39, respectively). Furthermore, compound 4c exhibited a significant elevation in caspase-3 level (409.33 pg/mL) compared to thalidomide (349.55 pg/mL). In addition, the most active compounds were examined for their COX-I, COX-II, VEGFR inhibitory activities. Compound 5g was the most active member against COX-I (0.80 μM), compound 4c was the most active member against COX-II (0.80 μM), and compound 4c was the most active member against VEGFR (253 nM). Furthermore, the flowcytometry analyses revealed that compound 4c can arrest the cell line at Pre-G1 phase and induce a significant apoptotic effect (75.75 %) compared to control cells (2.62 %) and thalidomide (65.34 %). Our derivatives were subjected to molecular modeling to assess their binding to Cereblon and also dynamic simulations.
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•Design, synthesis and evaluation of new VEGFR-2 tyrosine kinase inhibitors.•Compound 36 was more potent than pazopanib in in vitro VEGFR-2 inhibitory assay.•Hepatocellular carcinoma ...is the most sensitive to compound 36.•Compound 36 made H.B. with the essential residues Glu885, Asp1046 and Cys919.•SAR was clearly established for quinazolin-4-one derivatives as VEGFR-2 inhibitors.
Globally cancer is the second leading cause of death. So that this work is an attempt to develop new effective anti-cancer agents. In line with pharmacophoric features of VEGFR-2 kinase inhibitors, new nineteen quinazolin-4-one derivatives were designed, synthesized and biologically evaluated for their potential anticancer activity. All target compounds were evaluated in vitro for VEGFR-2 tyrosine kinase inhibition. Then, nine compounds of best results were further investigated by in vitro assay against three human cancer cell lines, namely HepG2, PC3 and MCF. N’-{2-(3-Ethyl-6-nitro-4-oxo-3,4-dihydroquinazoline-2-yl)thioacetyl}benzohydrazide (36) was found to be the most potent candidate as it showed IC50 = 4.6 ± 0.06 µM against VEGFR-2 kinase. It also exhibited IC50 = 17.23 ± 1.5, 26.10 ± 2.2 and 30.85 ± 2.3 µg/mL against HepG2, PC3 and MCF, respectively. At the same time it showed IC50 = 145.93 ± 1.1 µg/mL against the normal human lung fibroblasts cell line (WI-38), indicating good selectivity index. Further investigation into HepG2 cell cycle showed the ability of compound 36 to induce apoptosis and arrest cell growth at G2/M phase. Moreover, docking studies demonstrated the ability of compound 36 to bind VEGFR-2 in a correct manner making three essential hydrogen bonds with the key residues Glu885, Asp1046 and Cys919. In sum, this work suggests that compound 36 can serve as a lead for development of effective anticancer agents targeting VEGFR-2.
A novel series of pyrimidine-5-carbonitrile derivatives bearing benzylidene and hydrazone moieties with different linkers (spacers) were designed and synthesized as possible inhibitors of the ...vascular endothelial growth factor receptor-2 (VEGFR-2). The newly synthesized compounds were evaluated
in vitro
for their cytotoxic activities against two human cancer cell lines namely colon cancer (HCT-116) and breast cancer (MCF-7) using sorafenib as a standard anticancer drug. Compounds
9d
,
11e
,
12b
, and
12d
showed higher cytotoxic activities than sorafenib with IC
50
values ranging from 1.14 to 10.33 μM. In particular, compound
11e
exhibited excellent activities against HCT-116 and MCF-7 with IC
50
values of 1.14 and 1.54 μM, respectively. Moreover, compound
11e
exhibited about 47.32-fold cytotoxic activity against normal human fibroblast (WI-38) cells, lower than the cytotoxicity against the cancer cells. Compounds
11e
and
12b
were the most potent VEGFR-2 inhibitors with IC
50
values of 0.61 and 0.53 μM, respectively, compared to sorafenib. Bedsides, compound
11e
arrested the HCT-116 cell growth at S and sub-G1 phases, induced a significant increase in the apoptotic cells, and caused remarkable decrease in the levels of TNF-α, IL-6, and caspase-3. Finally, the binding patterns of the target derivatives were investigated through the docking study against the proposed molecular target (VEGFR-2, PDB ID
1YWN
). The results of molecular docking studies showed similar binding modes to sorafenib against VEGFR-2. In addition, molecular dynamic simulations revealed the stability of compound
11e
in the active site for 100 ns.
A novel series of pyrimidine-5-carbonitrile derivatives bearing benzylidene and hydrazone moieties with different linkers (spacers) were designed and synthesized as possible inhibitors of the vascular endothelial growth factor receptor-2 (VEGFR-2).
Herin, new nicotinamide candidates were designed and synthesized as VEGFR-2 inhibitors.
antiproliferative activities were assessed against MCF-7, HepG-2 and HCT-116 cancer cell lines. The top ...cytotoxic members
,
,
, and
were estimated against their selected target (VEGFR-2). Further mechanistic tests were studied for the most potent cytotoxic candidate
, these studies revealed the ability of compound
to hinder the progression of HCT-116 cells at S and Pre-G1phases besides boosting early and late apoptosis. Also compound
was found to significantly decrease the levels immunomodulatory proteins TNF-α and IL-6 while showing a four-fold rise in an apoptotic marker caspase-3 when compared to control cells. The therapeutic index of the designed derivatives was evaluated by computational ADMET and toxicity calculations as well as their potentiality to occupy the VEGFR-2 active site was signposted by molecular docking assessments. Finally, molecular dynamic simulation studies of compound
-VEGFR-2 complex indicated the high steadiness of compound
in the VEGFR-2 active site. This study presents compound
as a lead candidate that can be optimized to get a strong VEGFR-2 inhibitor.Communicated by Ramaswamy H. Sarma.
Immunomodulatory medications like thalidomide and its analogs prevent the production of some proinflammatory cytokines linked to cancer. A new series of thalidomide analogs were designed and ...synthesized in order to develop potential antitumor immunomodulatory agents. The antiproliferative activities of the new candidates against a panel of three human cancer cell lines (HepG-2, PC3 and MCF-7) were assessed in comparison to thalidomide as a positive control. The obtained results showed the relative significant potency of
18f
(IC
50
= 11.91 ± 0.9, 9.27 ± 0.7, and 18.62 ± 1.5 μM) and
21b
(IC
50
= 10.48 ± 0.8, 22.56 ± 1.6, and 16.39 ± 1.4 μM) against the mentioned cell lines, respectively. These results were comparable to thalidomide (IC
50
= 11.26 ± 0.54, 14.58 ± 0.57, and 16.87 ± 0.7 μM, respectively). To see to what extent the biological properties of the new candidates are relative to those of thalidomide, the effects of
18f
and
21b
on the expression levels of TNF-α, CASP8, VEGF, and NF-κB P65 were evaluated. Significant reductions in the proinflammatory TNF-α, VEGF, and NF-κB P65 levels in HepG-2 cells were observed after exposure to compounds
18f
and
21b
. Furthermore, a sharp increase in CASP8 levels was detected. The obtained results revealed that
21b
is of greater significance than thalidomide in TNF-α and NF-κB P65 inhibition. The
in silico
ADMET and toxicity studies showed that most of tested candidates have a good profile of drug-likeness and low toxicity potential.
Novel thalidomide analogs as anticancer immunomodulatory agents.
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