MyMedR

Displaying all 5 publications

Abstract:

Sort:

Discovery of novel tris-1,2,3-triazole-based hybrids as VEGFR2 inhibitors with potent anti-proliferative and cytotoxicity through apoptosis induction

Alsehli M, Sheikh Ali AA, Nafie MS, Bardaweel S, Aljuhani A, Darwish KM, et al.

Bioorg Chem, 2025 Feb;155:108131.
PMID: 39798451 DOI: 10.1016/j.bioorg.2025.108131

The discovery of novel anti-cancer drugs motivated us to synthesize a new series of triple 1,2,3-triazole-based arm scaffolds featuring distinct un functionalized alkyl and/or aryl side chains with possible anti-cancer action using the click chemistry approach under both conventional and green microwave irradiation (MWI) methods. The Cu(I) catalyzed cycloaddition reaction of targeted tris-alkyne with un functionalized aliphatic and aromatic azides has been adopted as an efficient approach for synthesizing the desired click adducts. Microwave irradiation improved the synthetic processes, resulting in higher yields and faster reaction times. Spectroscopic techniques (FT-IR, 1H, 13C NMR andCHN analysis) were used for the elucidation of the resulting click structures. The newly synthesized tris-1,2,3-triazoles exhibited promising cytotoxicity, particularly compounds 26 and 28, with IC50 values of 22.18 µM and 20.3 µM against A549 and CaCo-2 cells, respectively. While they had IC50 values of 23.06 µM and 21.91 µM against T-47D and CaCo-2 cells, respectively. Both compounds exhibited promising anti-proliferative activity through the wound healing assay. Additionally, both compounds induced total apoptotic cell death by 68.3 % and 58.5 %, respectively, compared to untreated cells (7.7 %). Furthermore, they induced necrotic cell death by 1.4 % and 10.5 %, respectively, compared to 0.1 % in the untreated cells. For the molecular target, compounds 26 and 28 exhibited potent VEGFR2 inhibition with IC50 values of 35.5 nM and 27.8 nM, respectively, and this was highlighted through the molecular docking findings. Tris-1,2,3-triazoles (26 and 28) exhibited promising cytotoxicity and anti-proliferative against T-47D breast cancer cells through apoptosis and VEGFR2 inhibition using both enzyme kit and western blotting protein expression assays. Molecular docking study highlighted the binding affinity of tested compounds towards the VEGFR2 protein. Accordingly, tris-1,2,3-triazoles (26 and 28) can be further developed as more potent anti-cancer agents.

Matched MeSH terms: Protein Kinase Inhibitors/chemical synthesis
Development and investigation of thiazolidinedione and pyrazoline compounds as antiangiogenic weapons targeting VEGFR-2

Upadhyay N, Tilekar K, Safuan S, Kumar AP, Schweipert M, Meyer-Almes FJ, et al.

Future Med Chem, 2021 11;13(22):1963-1986.
PMID: 34581188 DOI: 10.4155/fmc-2021-0139

Background: Angiogenesis deregulation is often linked to cancer and is thus an essential target. Materials & methods: Twenty-nine compounds were developed as VEGFR-2 inhibitors. Compounds were evaluated to determine their antiangiogenic activity. Results: B1, PB11 and PB16 showed HUVEC's IC50 scores in the submicromolar range. B1, B2 and PB16 reduced cellular migration and capillary tube formation of HUVECs. VEGFR-2 inhibitory activity was found in the nanomolar range: 200 nM of B1, 500 nM of B2 and 600 nM of PB16. B1 and PB16 suppressed the formation of new capillaries on growing CAMs. B1 and PB16 occupied the ATP site and allosteric pocket of VEGFR-2 in docking studies. Conclusion: These compounds can target VEGFR-2 and are endowed with in vitro and in vivo antiangiogenic activity.

Matched MeSH terms: Protein Kinase Inhibitors/chemical synthesis
Fulltext Novel Phenolic Compounds as Potential Dual EGFR and COX-2 Inhibitors: Design, Semisynthesis, in vitro Biological Evaluation and in silico Insights

Abdelgawad MA, Musa A, Almalki AH, Alzarea SI, Mostafa EM, Hegazy MM, et al.

Drug Des Devel Ther, 2021;15:2325-2337.
PMID: 34103896 DOI: 10.2147/DDDT.S310820

Introduction: Epidermal growth factor receptor (EGFR) inhibition is an imperative therapeutic approach targeting various types of cancer including colorectal, lung, breast, and pancreatic cancer types. Moreover, cyclooxygenase-2 (COX-2) is frequently overexpressed in different types of cancers and has a role in the promotion of malignancy, apoptosis inhibition, and metastasis of tumor cells. Combination therapy has been emerged to improve the therapeutic benefit against cancer and curb intrinsic and acquired resistance.
Methods: Three semi-synthetic series of compounds (C1-4, P1-4, and G1-4) were prepared and evaluated biologically as potential dual epidermal growth factor receptor (EGFR) and COX-2 inhibitors. The main phenolic constituents of Amaranthus spinosus L. (p-coumaric, caffeic and gallic) acids have been isolated and subsequently subjected to diazo coupling with various amines to get novel three chemical scaffolds with potential anticancer activities.
Results: Compounds C4 and G4 showed superior inhibitory activity against EGFR (IC50: 0.9 and 0.5 µM, respectively) and displayed good COX-2 inhibition (IC50: 4.35 and 2.47 µM, respectively). Moreover, the final compounds were further evaluated for their cytotoxic activity against human colon cancer (HT-29), pancreatic cancer (PaCa-2), human malignant melanoma (A375), lung cancer (H-460), and pancreatic ductal cancer (Panc-1) cell lines. Interestingly, compounds C4 and G4 exhibited the highest cytotoxic activity with average IC50 values of 1.5 µM and 2.8 µM against H-460 and Panc-1, respectively. The virtual docking study was conducted to gain proper understandings of the plausible-binding modes of target compounds within EGFR and COX-2 binding sites.
Discussion: The NMR of prepared compounds showed characteristic peaks that confirmed the structure of the target compounds. The synthesized benzoxazolyl scaffold containing compounds showed inhibitory activities for both COXs and EGFR which are consistent with the virtual docking study.

Matched MeSH terms: Protein Kinase Inhibitors/chemical synthesis
A novel chromone-based as a potential inhibitor of ULK1 that modulates autophagy and induces apoptosis in colon cancer

Shamsudin NF, Leong SW, Koeberle A, Suriya U, Rungrotmongkol T, Chia SL, et al.

Future Med Chem, 2024 Aug 02;16(15):1499-1517.
PMID: 38949858 DOI: 10.1080/17568919.2024.2363668

Aim: Chromones are promising for anticancer drug development.Methods & results: 12 chromone-based compounds were synthesized and tested against cancer cell lines. Compound 8 showed the highest cytotoxicity (LC50 3.2 μM) against colorectal cancer cells, surpassing 5-fluorouracil (LC50 4.2 μM). It suppressed colony formation, induced cell cycle arrest and triggered apoptotic cell death, confirmed by staining and apoptosis markers. Cell death was accompanied by enhanced reactive oxygen species formation and modulation of the autophagic machinery (autophagy marker light chain 3B (LC3B); adenosine monophosphate-activated protein kinase (AMPK); protein kinase B (PKB); UNC-51-like kinase (ULK)-1; and ULK2). Molecular docking and dynamic simulations revealed that compound 8 directly binds to ULK1.Conclusion: Compound 8 is a promising lead for autophagy-modulating anti-colon cancer drugs.

Matched MeSH terms: Protein Kinase Inhibitors/chemical synthesis
Double-edged Swords: Diaryl pyrazoline thiazolidinediones synchronously targeting cancer epigenetics and angiogenesis

Upadhyay N, Tilekar K, Safuan S, Kumar AP, Schweipert M, Meyer-Almes FJ, et al.

Bioorg Chem, 2021 11;116:105350.
PMID: 34547645 DOI: 10.1016/j.bioorg.2021.105350

In the present study, two novel series of compounds incorporating naphthyl and pyridyl linker were synthesized and biological assays revealed 5-((6-(2-(5-(2-chlorophenyl)-3-(4-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-oxoethoxy) naphthalene-2-yl)methylene)thiazolidine-2,4-dione (14b) as the most potent dual inhibitors of vascular endothelial growth factors receptor-2 (VEGFR-2) and histone deacetylase 4 (HDAC4). Compounds 13b, 14b, 17f, and 21f were found to stabilize HDAC4; where, pyridyl linker swords were endowed with higher stabilization effects than naphthyl linker. Also, 13b and 14b showed best inhibitory activity on VEGFR-2 as compared to others. Compound 14b was most potent as evident by in-vitro and in-vivo biological assessments. It displayed anti-angiogenic potential by inhibiting endothelial cell proliferation, migration, tube formation and also suppressed new capillary formation in the growing chick chorioallantoic membranes (CAMs). It showed selectivity and potency towards HDAC4 as compared to other HDAC isoforms. Compound 14b (25 mg/kg, i.p.) also indicated exceptional antitumor efficacy on in-vivo animal xenograft model of human colorectal adenocarcinoma (HT-29). The mechanism of action of 14b was also confirmed by western blot.

Matched MeSH terms: Protein Kinase Inhibitors/chemical synthesis