Design, synthesis, anticancer evaluation, and <i>in silico</i> ADMET analysis of novel thalidomide analogs as promising immunomodulatory agents

Kotb, Anas Ramadan; Abdallah, Abdallah E.; Elkady, Hazem; Eissa, Ibrahim H.; Taghour, Mohammed S; Bakhotmah, Dina A.; Abdelghany, Tarek M.; El‐Zahabi, Mohamed Ayman

doi:10.1039/d3ra00066d

Cited by 11 publications

(3 citation statements)

References 48 publications

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“…In another modification, we thought that if we change the methylene group between the NH 2 and the carbonyl group, we might get better binding results by adding a new hydrogen bonding site (Figure 4). In continuation of our efforts to obtain new immunomodulatory [35][36][37][38][39][40][41][42][43][44] and/or anticancer agents, [45][46][47][48][49][50][51] we designed and synthesized novel thalidomide analogs that were tested in vitro against the HepG-2, HCT-116, PC3, and MCF-7 cancer cell lines. By measuring the immunomodulatory effects of the synthesized compounds in HCT-116 cells against CASP8, TNF-α, VEGF, and NF-κB P65, we conducted additional research to better understand their immunomodulatory effect.…”

Section: Minimal Requirements For Basal Binding Moietiesmentioning

confidence: 99%

“…In continuation of our efforts to obtain new immunomodulatory [ 35–44 ] and/or anticancer agents, [ 45–51 ] we designed and synthesized novel thalidomide analogs that were tested in vitro against the HepG‐2, HCT‐116, PC3, and MCF‐7 cancer cell lines. By measuring the immunomodulatory effects of the synthesized compounds in HCT‐116 cells against CASP8, TNF‐α, VEGF, and NF‐κB P65, we conducted additional research to better understand their immunomodulatory effect.…”

Section: Introductionmentioning

confidence: 99%

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Novel promising benzoxazole/benzothiazole‐derived immunomodulatory agents: Design, synthesis, anticancer evaluation, and in silico ADMET analysis

Elkady

El‐Adl

Sakr

et al. 2023

Archiv der Pharmazie

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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.

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Section: Minimal Requirements For Basal Binding Moietiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel promising benzoxazole/benzothiazole‐derived immunomodulatory agents: Design, synthesis, anticancer evaluation, and in silico ADMET analysis

Elkady

El‐Adl

Sakr

et al. 2023

Archiv der Pharmazie

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“…It was found to be active against MM, diffuse large B-cell lymphoma (DLBCL), and solid tumors [26]. Other quinazoline derivatives showed TNF-α, IL-6, and IL1β inhibition [28][29][30], NF-κB inhibition [31], and immunomodulatory [32] and antiproliferative activities [5,18,[33][34][35][36], along with induction of apoptosis and elevation of caspase levels [37,38].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of New Potential Unusual Modified Anticancer Immunomodulators for Possible Non-Teratogenic Quinazoline-Based Thalidomide Analogs

Mabrouk

Abdallah

Mahdy

et al. 2023

IJMS

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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 IC50 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 IC50 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.

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Facile Directed Synthesis of (Z)‐1‐(Aryl(arylimino)methyl)piperidine‐2,6‐diones from C,N‐Diarylformamidines

et al. 2023

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A simple methodology has been developed for the synthesis of previously unstudied N‐substituted glutarimide derivatives ‐ (Z)‐1‐(aryl(arylimino)methyl)piperidine‐2,6‐diones 4 a–p obtained in one step from C,N‐diarylformamidines 1 a–p and glutaric anhydride 6 with product yields from 46 up to 88 % and chromatographic purity from 94 to 99 %. The structures of the obtained compounds were proved using NMR spectroscopy 1H, 13C, X‐ray diffraction analysis, mass spectroscopy, and elemental analysis. An in vivo study of the analgesic activity of a representative of series 4 a was carried out.

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Design, synthesis, anticancer evaluation, and in silico ADMET analysis of novel thalidomide analogs as promising immunomodulatory agents

Abstract: Novel thalidomide analogs as anticancer immunomodulatory agents.

Cited by 11 publications

References 48 publications

Novel promising benzoxazole/benzothiazole‐derived immunomodulatory agents: Design, synthesis, anticancer evaluation, and in silico ADMET analysis

Novel promising benzoxazole/benzothiazole‐derived immunomodulatory agents: Design, synthesis, anticancer evaluation, and in silico ADMET analysis

Design, Synthesis, and Biological Evaluation of New Potential Unusual Modified Anticancer Immunomodulators for Possible Non-Teratogenic Quinazoline-Based Thalidomide Analogs

Facile Directed Synthesis of (Z)‐1‐(Aryl(arylimino)methyl)piperidine‐2,6‐diones from C,N‐Diarylformamidines

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