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Fulltext Catalytic response and molecular simulation studies in the development of synthetic routes in trimeric triaryl pyridinium type ionic liquids

Tamilarasan R, Subramani A, Sasikumar G, Ganapathi P, Karthikeyan S, Ponnusamy S, et al.

Sci Rep, 2023 Mar 17;13(1):4453.
PMID: 36932171 DOI: 10.1038/s41598-023-31476-0

Under conventional and silica-supported Muffle furnace methods, water-soluble substituted trimeric triaryl pyridinium cations with various inorganic counter anions are synthesized. The solvent-free synthesis method is superior to the conventional method in terms of non-toxicity, quicker reaction times, ease of workup, and higher yields. Trimeric substituted pyridinium salts acted as excellent catalytic responses for the preparation of Gem-bisamide derivatives compared with available literature. To evaluate the molecular docking, benzyl/4-nitrobenzyl substituted triaryl pyridinium salt compounds with VEGFR-2 kinase were used with H-bonds, π-π stacking, salt bridges, and hydrophobic contacts. The results showed that the VEGFR-2 kinase protein had the most potent inhibitory activity. Intriguingly, the compound [NBTAPy]PF6- had a strongly binds to VEGFR-2 kinase and controlled its activity in cancer treatment and prevention.

Matched MeSH terms: Vascular Endothelial Growth Factor Receptor-2/metabolism
Expression of Vascular Endothelial Growth Factor and Its Receptors in Thyroid Nodular Hyperplasia and Papillary Thyroid Carcinoma: A Tertiary Health Care Centre Based Study

Mohamad Pakarul Razy NH, Wan Abdul Rahman WF, Win TT

Asian Pac J Cancer Prev, 2019 Jan 25;20(1):277-282.
PMID: 30678450

Introduction: Vascular endothelial growth factor (VEGF) is an angiogenic factor that plays an important role in
thyroid cancer. VEGF is known to have high affinity to VEGF receptors such as VEGFR-1 (Flt-1) and VEGFR-2 (KDR).
Papillary thyroid carcinoma (PTC) is the most common thyroid cancer and studies showed the increasing incidence of
PTC arising in nodular hyperplasia. Targeted therapy on these growth factors and receptors are used in management
of both differentiated and undifferentiated thyroid carcinoma. This study aims to determine the expression of VEGF
and VEGF receptors (VEGFR) in thyroid nodular hyperplasia and PTC. Methods: A cross-sectional study based on
paraffinized archival tissue blocks of 113 nodular hyperplasias and 67 PTC from the thyroidectomy specimens in
the year of 2003 to 2014. The tissue sections were then stained by immunohistochemistry for VEGF, VEGFR-1 and
VEGFR-2. The lymph node involvement and extrathyroid extension also were determined. Results: The mean age of
PTC patients was 44.7±15.8 years and nodular hyperplasia were 42.2±13.6 years. There was a statistical difference
of VEGFR-1 (p=0.028) and VEGFR-2 (p=0.003) expression between nodular hyperplasia and PTC. However, no
significant difference of VEGF expression (p=0.576) between both diseases. Co-expression of VEGF and VEGFR-1
was significant in both nodular hyperplasia (p=0.016) and PTC (p=0.03), meanwhile no relevant relationship for VEGF
and VEGFR-2 expression (p>0.05). No significant association (p>0.05) between lymph node status and extrathyroid
extension with age groups, gender, VEGF and VEGFR expression. Conclusions: VEGF, VEGFR-1 and VEGFR-2
showed overexpression in both nodular hyperplasia and PTC. The expression of VEGFR-1 and VEGFR-2 are more
significant in PTC with relevant co-expression of VEGF and VEGFR-1. Therefore, the inhibition of VEGFR offers a
promising prospect for tumour management in thyroid carcinoma.

Matched MeSH terms: Vascular Endothelial Growth Factor Receptor-2/metabolism
Ethyl cinnamate suppresses tumor growth through anti-angiogenesis by attenuating VEGFR2 signal pathway in colorectal cancer

Wang S, Yang J, Kuang X, Li H, Du H, Wu Y, et al.

J Ethnopharmacol, 2024 May 23;326:117913.
PMID: 38360380 DOI: 10.1016/j.jep.2024.117913

ETHNOPHARMACOLOGICAL RELEVANCE: Kaempferia galanga Linn. is an aromatic medicinal herb with extensively applied in India, China, Malaysia and other South Asia countries for thousands of years. It has been mentioned to treat abdominal tumors. Ethyl cinnamate (EC), one of the main chemical constituents of the rhizome of K. galanga, exhibited nematocidal, sedative and vasorelaxant activities. However, its anti-angiogenic activity, and anti-tumor effect have not been investigated.
AIM OF THE STUDY: To investigate the anti-angiogenic mechanism of EC and its anti-tumor effect by suppressing angiogenesis.
MATERIALS AND METHODS: The in vitro anti-angiogenic effect was evaluated using HUVECs model induced by VEGF and zebrafish model in vivo. The influence of the EC on phosphorylation of VEGFR2 and its downstream signaling pathways were evaluated by western blotting assay. Molecule docking technology was conducted to explore the interaction between EC and VEGFR2. SPR assay was used for detecting the binding affinity between EC and VEGFR2. To further investigate the molecular mechanism of EC on anti-angiogenesis, VEGFR2 knockdown in HUVECs and examined the influence of the EC. Anti-tumor activity of EC was evaluated using colony formation assay and apoptosis assay. The inhibitory effect of EC on tumor growth was explored using HT29 colon cancer xenograft model.
RESULTS: EC obviously inhibited proliferation, migration, invasion and tube formation of VEGF-induced HUVECs. EC also induced apoptosis of HUVECs. Moreover, it inhibited the development of vessel formation in zebrafish. Further investigations demonstrated that EC could suppress the phosphorylation of VEGFR2, and its downstream signaling pathways were altered in VEGF-induced HUVECs. EC formed a hydrogen bond to bind with the ATP binding site of the VEGFR2, and EC-VEGFR2 interaction was shown in SPR assay. The suppressive effect of EC on angiogenesis was abrogated after VEGFR2 knockdown in HUVECs. EC inhibited the colon cancer cells colony formation and induced apoptosis. In addition, EC suppressed tumor growth in colon cancer xenograft model, and no detectable hepatotoxicity and nephrotoxicity. In addition, it inhibited the phosphorylation of VEGFR2, and its downstream signal pathways in tumor.
CONCLUSIONS: EC could inhibit tumor growth in colon cancer by suppressing angiogenesis via VEGFR2 signaling pathway, and suggested EC as a promising candidate for colon cancer treatment.

Matched MeSH terms: Vascular Endothelial Growth Factor Receptor-2/metabolism
Morphological and genetical changes of endothelial progenitor cells after in-vitro conversion into photoreceptors

Qiang S, Alsaeedi HA, Yuhong C, Yang H, Tong L, Kumar S, et al.

J. Photochem. Photobiol. B, Biol., 2018 Jun;183:127-132.
PMID: 29704860 DOI: 10.1016/j.jphotobiol.2018.04.003

BACKGROUND: Retinal degeneration is a condition ensued by various ocular disorders such as artery occlusion, diabetic retinopathy, retrolental fibroplasia and retinitis pigmentosa which cause abnormal loss of photoreceptor cells and lead to eventual vision impairment. No efficient treatment has yet been found, however, the use of stem cell therapy such as bone marrow and embryonic stem cells has opened a new treatment modality for retinal degenerative diseases. The major goal of this study is to analyze the potential of endothelial progenitor cells derived from bone marrow to differentiate into retinal neural cells for regenerative medicine purposes.
METHODS: In this study, endothelial progenitor cells were induced in-vitro with photoreceptor growth factor (taurine) for 21 days. Subsequently, the morphology and gene expression of CRX and RHO of the photoreceptors-induced EPCs were examined through immunostaining assay.
FINDINGS: The results indicated that the induced endothelial progenitor cells demonstrated positive gene expression of CRX and RHO. Our findings suggested that EPC cells may have a high advantage in cell replacement therapy for treating eye disease, in addition to other neural diseases, and may be a suitable cell source in regenerative medicine for eye disorders.

Matched MeSH terms: Vascular Endothelial Growth Factor Receptor-2/metabolism
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: Vascular Endothelial Growth Factor Receptor-2/metabolism
Cat's whiskers tea (Orthosiphon stamineus) extract inhibits growth of colon tumor in nude mice and angiogenesis in endothelial cells via suppressing VEGFR phosphorylation

Ahamed MB, Aisha AF, Nassar ZD, Siddiqui JM, Ismail Z, Omari SM, et al.

Nutr Cancer, 2012;64(1):89-99.
PMID: 22136553 DOI: 10.1080/01635581.2012.630160

Cat's whiskers (Orthosiphon stamineus) is commonly used as Java tea to treat kidney stones including a variety of angiogenesis-dependent diseases such as tumorous edema, rheumatism, diabetic blindness, and obesity. In the present study, antitumor potential of standardized 50% ethanol extract of O. stamineus leaves (EOS) was evaluated against colorectal tumor in athymic mice and antiangiogenic efficacy of EOS was investigated in human umbilical vein endothelial cells (HUVEC). EOS at 100 mg/kg caused 47.62 ± 6.4% suppression in tumor growth, while at 200 mg/kg it caused 83.39 ± 4.1% tumor regression. Tumor histology revealed significant reduction in extent of vascularization. Enzyme-linked immunosorbent assay showed EOS (200 mg/kg) significantly reduced the vascular endothelial growth factor (VEGF) level in vitro (211 ± 0.26 pg/ml cell lysate) as well as in vivo (90.9 ± 2 pg/g tissue homogenate) when compared to the control (378 ± 5 and 135.5 ± 4 pg, respectively). However, EOS was found to be noncytotoxic to colon cancer and endothelial cells. In vitro, EOS significantly inhibited the migration and tube formation of human umbilical vein endothelial cells (HUVECs). EOS suppressed VEGF-induced phosphorylation of VEGF receptor-2 in HUVECs. High performance liquid chromatography (HPLC) analysis of EOS showed high rosmarinic acid contents, whereas phytochemical analysis revealed high protein and phenolic contents. These results demonstrated that the antitumor activity of EOS may be due to its VEGF-targeted antiangiogenicity.

Matched MeSH terms: Vascular Endothelial Growth Factor Receptor-2/metabolism
Fulltext Mutant p53 cooperates with the SWI/SNF chromatin remodeling complex to regulate VEGFR2 in breast cancer cells

Pfister NT, Fomin V, Regunath K, Zhou JY, Zhou W, Silwal-Pandit L, et al.

Genes Dev., 2015 Jun 15;29(12):1298-315.
PMID: 26080815 DOI: 10.1101/gad.263202.115

Mutant p53 impacts the expression of numerous genes at the level of transcription to mediate oncogenesis. We identified vascular endothelial growth factor receptor 2 (VEGFR2), the primary functional VEGF receptor that mediates endothelial cell vascularization, as a mutant p53 transcriptional target in multiple breast cancer cell lines. Up-regulation of VEGFR2 mediates the role of mutant p53 in increasing cellular growth in two-dimensional (2D) and three-dimensional (3D) culture conditions. Mutant p53 binds near the VEGFR2 promoter transcriptional start site and plays a role in maintaining an open conformation at that location. Relatedly, mutant p53 interacts with the SWI/SNF complex, which is required for remodeling the VEGFR2 promoter. By both querying individual genes regulated by mutant p53 and performing RNA sequencing, the results indicate that >40% of all mutant p53-regulated gene expression is mediated by SWI/SNF. We surmise that mutant p53 impacts transcription of VEGFR2 as well as myriad other genes by promoter remodeling through interaction with and likely regulation of the SWI/SNF chromatin remodeling complex. Therefore, not only might mutant p53-expressing tumors be susceptible to anti VEGF therapies, impacting SWI/SNF tumor suppressor function in mutant p53 tumors may also have therapeutic potential.

Matched MeSH terms: Vascular Endothelial Growth Factor Receptor-2/metabolism*
Fulltext Capilliposide B blocks VEGF-induced angiogenesis in vitro in primary human retinal microvascular endothelial cells

Han H, Yang Y, Wu Z, Liu B, Dong L, Deng H, et al.

Biomed Pharmacother, 2021 Jan;133:110999.
PMID: 33227710 DOI: 10.1016/j.biopha.2020.110999

Abnormal angiogenesis is associated with intraocular diseases such as proliferative diabetic retinopathy and neovascular age-related macular degeneration, and current therapies for these eye diseases are not satisfactory. The purpose of this study was to determine whether capilliposide B (CPS-B), a novel oleanane triterpenoid saponin derived from Lysimachia capillipes Hemsl, can inhibit vascular endothelial growth factor (VEGF)-induced angiogenesis signaling events and cellular responses in primary human retinal microvascular endothelial cells (HRECs). Our study revealed that the capilliposide B IC50 for HRECs was 8.5 μM at 72 h and that 1 μM capilliposide B specifically inhibited VEGF-induced activation of VEGFR2 and its downstream signaling enzymes Akt and Erk. In addition, we discovered that this chemical effectively blocked VEGF-stimulated proliferation, migration and tube formation of the HRECs, suggesting that capilliposide B is a promising prophylactic for angiogenesis-associated diseases such as proliferative diabetic retinopathy.

Matched MeSH terms: Vascular Endothelial Growth Factor Receptor-2/metabolism
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: Vascular Endothelial Growth Factor Receptor-2/metabolism