Design, synthesis, and biological evaluation of new challenging thalidomide analogs as potential anticancer immunomodulatory agents

El‐Zahabi, Mohamed Ayman; Sakr, Helmy; El‐Adl, Khaled; Zayed, Mohamed F.; Abdelraheem, Adel S.; Eissa, Sally I.; Elkady, Hazem; Eissa, Ibrahim H.

doi:10.1016/j.bioorg.2020.104218

Cited by 73 publications

(60 citation statements)

References 82 publications

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“…Furthermore, stirring of compound 17 with commercially available amines namely, ethylamine, n -butylamine, sec -butylamine, tert - butylamine, cyclopentylamine, cyclohexylamine, 4-aminoacetophenone, 3-chloroaniline, 4-chloroaniline, 2,5-dichloroaniline, 4-fluoroaniline, 2-hydroxyaniline, 4-hydroxyaniline, and 2-hydroxy-4-nitroaniline at room temperature in acetonitrile/TEA mixture afforded the corresponding intermediates 18a – n , respectively. On the other hand, to prepare the ester derivatives 20a – c, appropriate acid derivatives 19a – c namely, 2-chlorobenzoic acid, 3-chlorobenzoic, and 2-hydroxybenzoic acid were refluxed in methanol in the presence of sulphuric acid according to the reported procedures 42 , 53 , 54 . In addition, reflux of 20a – c with hydrazine hydrate afforded the corresponding acid hydrazides 21a – c 42 .…”

Section: Resultsmentioning

confidence: 99%

“…On the other hand, to prepare the ester derivatives 20a – c, appropriate acid derivatives 19a – c namely, 2-chlorobenzoic acid, 3-chlorobenzoic, and 2-hydroxybenzoic acid were refluxed in methanol in the presence of sulphuric acid according to the reported procedures 42 , 53 , 54 . In addition, reflux of 20a – c with hydrazine hydrate afforded the corresponding acid hydrazides 21a – c 42 . In the end, in acetonitrile and TEA mixture, compound 17 was stirred with the acid hydrazides 21a – c to produce the corresponding diamide derivatives 22a –c ( Scheme 2 ).…”

Section: Resultsmentioning

confidence: 99%

“…All the reagents, chemicals, and apparatus were presented in Supplementary data . Compounds 8 , 9 , 10 , 11 , 12 , 13 , 14 , 16 , 17 , 20a – c , and 21a – c were prepared in accordance with the reported procedures 41 , 42 , 44 , 49 , 50 , 52 .…”

Section: Methodsmentioning

confidence: 99%

“…Based on facts mentioned above and in the extension of our efforts to discover novel molecules with potential anticancer activity 5,[40][41][42][43][44][45][46][47][48] , we design and synthesise a new wave of bis([1, 2, 4]triazolo)[4,3-a:3 0 ,4 0 -c]quinoxaline derivatives having the basic crucial pharmacophoric features of VEGFR-2 inhibitors.…”

Section: Rationale Of Molecular Designmentioning

confidence: 99%

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Discovery of new VEGFR-2 inhibitors based on bis([1, 2, 4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives as anticancer agents and apoptosis inducers

Alsaif

Taghour

Alanazi

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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Herein, a new wave of bis([1, 2, 4]triazolo)[4,3- a :3',4'- c ]quinoxaline derivatives have been successfully designed and synthesised. The synthesised derivatives were biologically investigated for their cytotoxic activities against HepG2 and MCF-7. Also, the tested compounds were further examined in vitro for their VEGFR-2 inhibitory activity. The most promising derivative 23j was further investigated for its apoptotic behaviour in HepG2 cell lines using flow cytometric and western-plot analyses. Additional in-silico studies were performed to predict how the synthesised compounds can bind to VEGFR-2 and to determine the drug-likeness profiling of these derivatives. The results revealed that compounds 23a , 23i , 23j , 23l , and 23n displayed the highest antiproliferative activities against the two cell lines with IC 50 values ranging from 6.4 to 19.4 µM. Furthermore, compounds 23a , 23d , 23h , 23i , 23j , 23l , 23 m , and 23n showed the highest VEGFR-2 inhibitory activities with IC 50 values ranging from 3.7 to 11.8 nM, comparing to sorafenib (IC 50 = 3.12 nM). Moreover, compound 23j arrested the HepG2 cell growth at the G2/M phase and induced apoptosis by 40.12% compared to the control cells (7.07%). As well, such compound showed a significant increase in the level of caspase-3 (1.36-fold), caspase-9 (2.80-fold), and BAX (1.65-fold), and exhibited a significant decrease in Bcl-2 level (2.63-fold).

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Rationale Of Molecular Designmentioning

confidence: 99%

See 2 more Smart Citations

Discovery of new VEGFR-2 inhibitors based on bis([1, 2, 4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives as anticancer agents and apoptosis inducers

Alsaif

Taghour

Alanazi

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…In view of the abovementioned findings and based on our continuous efforts to develop new anticancer agents,[ 70,34–39 ] especially VEGFR‐2 inhibitors, [ 12,13,40–44 ] the goal of our work was to synthesize new agents with the same essential pharmacophoric features of the reported and clinically used VEGFR‐2 inhibitors (e.g., sorafenib). The main core of our molecular design rationale comprised bioisosteric modification strategies of VEGFR‐2 inhibitors at four different positions (Figure 3).…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, docking, ADMET profile, and anticancer evaluations of novel thiazolidine‐2,4‐dione derivatives as VEGFR‐2 inhibitors

El‐Adl

Sakr

El‐Hddad

et al. 2021

Archiv der Pharmazie

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The anticancer activity of novel thiazolidine‐2,4‐diones was evaluated against HepG2, HCT‐116, and MCF‐7 cells. Among the tested cancer cell lines, HCT‐116 was the most sensitive one to the cytotoxic effect of the new derivatives. In particular, compounds 18, 11, and 10 were found to be the most potent derivatives among all the tested compounds against the HepG2, HCT‐116, and MCF‐7 cancer cell lines, with IC50 values ranging from 38.76 to 53.99 µM. The most active antiproliferative derivatives (7–14 and 15–19) were subjected to further biological studies to evaluate their inhibitory potentials against VEGFR‐2. The tested compounds displayed a good‐to‐medium inhibitory activity, with IC50 values ranging from 0.26 to 0.72 µM. Among them, compounds 18, 11, and 10 potently inhibited VEGFR‐2 at IC50 values in the range of 0.26–0.29 µM, which are nearly three times that of the sorafenib IC50 value (0.10 µM). Although our derivatives showed lower activities than the reference drug, they could be useful as a template for future design, optimization, adaptation, and investigation to produce more potent and selective VEGFR‐2 inhibitors with higher anticancer analogs. The ADMET profile showed that compounds 18, 11, and 10 do not violate any of Lipinski's rules and have a comparable intestinal absorptivity in humans. Also, the new derivatives could not inhibit cytochrome P3A4. Unlike sorafenib and doxorubicin, compounds 18, 11, and 10 are expected to have prolonged dosing intervals. Moreover, compounds 10 and 18 displayed a wide therapeutic index and higher selectivity against cancer cells as compared with their cytotoxicity against normal cells.

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Pyridine‐derived VEGFR‐2 inhibitors: Rational design, synthesis, anticancer evaluations, in silico ADMET profile, and molecular docking

Saleh

Abdel‐Rahman

Omar

et al. 2021

Archiv der Pharmazie

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Novel pyridine‐derived compounds (5–19) were designed and synthesized, and their anticancer activities were evaluated against HepG2 and MCF‐7 cells, targeting the VEGFR‐2 enzyme. Compounds 10, 9, 8, and 15 were found to be the most potent derivatives against the two cancer cell lines, HepG2 and MCF‐7, respectively, with IC50 = 4.25 and 6.08 µM, 4.68 and 11.06 µM, 4.34 and 10.29 µM, and 6.37 and 12.83 µM. Compound 10 displayed higher activity against HepG2 cells than sorafenib (IC50 = 9.18 and 5.47 µM, respectively) and doxorubicin (IC50 = 7.94 and 8.07 µM, respectively). It also showed higher activity than doxorubicin against MCF‐7 cells, but lower activity than sorafenib. Compounds 9, 8, and 15 displayed higher activities than sorafenib and doxorubicin against HepG2 cells but exhibited lower activities against MCF‐7 cells. Compound 10 potently inhibited VEGFR‐2 at an IC50 value of 0.12 µM, which is nearly equipotent to sorafenib (IC50 = 0.10 µM). Compounds 8 and 9 exhibited very good activity with the same IC50 value of 0.13 µM. The six most potent derivatives, 6, 9, 8, 10, 15, and 18, were tested for their cytotoxicity against normal Vero cells. Compounds 6, 8, 9, 10, 15, and 18 are, respectively, 1.13, 3.74, 4.18, 3.64, 2.81, and 2.00 times more toxic to HepG2 and 2.06, 1.58, 1.76, 2.54, 1.40, and 2.69 times more toxic to MCF‐7 breast cancer cells than in normal Vero cells.

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Design, synthesis, and biological evaluation of new challenging thalidomide analogs as potential anticancer immunomodulatory agents

Cited by 73 publications

References 82 publications

Discovery of new VEGFR-2 inhibitors based on bis([1, 2, 4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives as anticancer agents and apoptosis inducers

Discovery of new VEGFR-2 inhibitors based on bis([1, 2, 4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives as anticancer agents and apoptosis inducers

Design, synthesis, docking, ADMET profile, and anticancer evaluations of novel thiazolidine‐2,4‐dione derivatives as VEGFR‐2 inhibitors

Pyridine‐derived VEGFR‐2 inhibitors: Rational design, synthesis, anticancer evaluations, in silico ADMET profile, and molecular docking

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