Antiangiogenic activity of 4 – chloro phenyl carbothioamide derivatives in ex vivo and in vitro experimental study
Keywords:
Anti-angiogenesis, VEGF gene, human umbilical ventricular endothelial cell (HUVEC), colon cancer (HCT116)
Abstract
The present study sought to examine the potential antiangiogenic, antioxidant, and cytotoxic properties of a carbothioamide indole derivative and assess VEGF gene expression. The tested indole derivative's antiangiogenic efficacy was assessed using the ex-vivo rat aorta ring (RAR) assay. The DPPH test for scavenging activity was utilized to clarify the most likely cause of its antiangiogenic action. The MTT assay assessed the proliferation of the HUVEC cell line while the expression of the VEGF gene in the colon cancer (HCT116) cell line was analysed. The evaluated drug exhibited antiangiogenic efficacy with an IC50 value of 17.99µg/ml in the RAR assay. The drug successfully reduced the DPPH free radical in a concentration-dependent manner (IC50 = 100.3 µg/ml). The evaluated drug exhibited negligible to non-toxic effects on the HUVEC cell line, with an IC50 value of 733.6 μg/ml. It significantly downregulates the VEGF gene expression in HCT116 cells at 400 µg/ml. In conclusion, the 2-NHC compound exhibited significant antioxidant and anti-angiogenesis effects with minimum toxicity against normal human cells. 2-NHC appears to downregulate the VEGF gene expression in colon cancer cell lines.
References
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Al-Rubaye, I. M., Razzak Mahmood, A. A., Tahtamouni, L. H., AlSakhen, M. F., Kanaan, S. I., Saleh, K. M., & Yasin, S. R. (2024). In silico and in vitro evaluation of novel carbothioamide-based and heterocyclic derivatives of 4-(tert-butyl)-3-methoxybenzoic acid as EGFR tyrosine kinase allosteric site inhibitors. Results in Chemistry, 7, 101329. https://doi.org/https://doi.org/10.1016/j.rechem.2024.101329
Ali, Z. M., Kadhim, H. M., Hassan, O. M., Kubba, A., Hussein, Z. A., & Sahib, H. B. (2024). Antiangiogenic activity of 5-bromoindole carbothioamide derivative in ex vivo, in vivo, and in vitro experimental study [Article]. Pharmacia, 71, 1-9, Article e128589. https://doi.org/10.3897/PHARMACIA.71.E128589
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Brown, K. J., Maynes, S. F., Bezos, A., Maguire, D. J., Ford, M. D., & Parish, C. R. (1996). A novel in vitro assay for human angiogenesis. Lab Invest, 75(4), 539-555.
Cerezo, A. B., Hornedo-Ortega, R., Álvarez-Fernández, M. A., Troncoso, A. M., & García-Parrilla, M. C. (2017). Inhibition of VEGF-induced VEGFR-2 activation and HUVEC migration by melatonin and other bioactive indolic compounds. Nutrients, 9(3), 249.
Chadha, N., & Silakari, O. (2018). Chapter 8 - Indoles: As Multitarget Directed Ligands in Medicinal Chemistry. In O. Silakari (Ed.), Key Heterocycle Cores for Designing Multitargeting Molecules (pp. 285-321). Elsevier. https://doi.org/https://doi.org/10.1016/B978-0-08-102083-8.00008-X
Cheng, J., Yang, H. L., Gu, C. J., Liu, Y. K., Shao, J., Zhu, R., He, Y. Y., Zhu, X. Y., & Li, M. Q. (2019). Melatonin restricts the viability and angiogenesis of vascular endothelial cells by suppressing HIF-1α/ROS/VEGF. International journal of molecular medicine, 43(2), 945-955.
Chomczynski, P., & Sacchi, N. (1987). Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem, 162(1), 156-159. https://doi.org/10.1006/abio.1987.9999
D'Alessio, A., Moccia, F., Li, J. H., Micera, A., & Kyriakides, T. R. (2015). Angiogenesis and Vasculogenesis in Health and Disease. Biomed Res Int, 2015, 126582. https://doi.org/10.1155/2015/126582
Das, B., Dash, S. R., Patel, H., Sinha, S., Bhal, S., Paul, S., Das, C., Pradhan, R., Ahmed, I., & Goutam, K. (2023). Quinacrine inhibits HIF-1α/VEGF-A mediated angiogenesis by disrupting the interaction between cMET and ABCG2 in patient-derived breast cancer stem cells. Phytomedicine, 117, 154914.
Dhuguru, J., & Skouta, R. (2020). Role of Indole Scaffolds as Pharmacophores in the Development of Anti-Lung Cancer Agents. Molecules, 25(7). https://doi.org/10.3390/molecules25071615
Dudley, A. C., & Griffioen, A. W. (2023). Pathological angiogenesis: mechanisms and therapeutic strategies. Angiogenesis, 26(3), 313-347.
El-Zahabi, M. A., Elkady, H., Sakr, H., Abdelraheem, A. S., Eissa, S. I., & El-Adl, K. (2023). Design, synthesis, anticancer evaluation, in silico docking and ADMET analysis of novel indole-based thalidomide analogs as promising immunomodulatory agents. Journal of Biomolecular Structure and Dynamics, 41(24), 15106-15123.
Fong, G. H. (2008). Mechanisms of adaptive angiogenesis to tissue hypoxia. Angiogenesis, 11(2), 121-140. https://doi.org/10.1007/s10456-008-9107-3
Hassan, O. M., Kubba, A., & Tahtamouni, L. H. (2023). Novel 5-bromoindole-2-carboxylic Acid Derivatives as EGFR Inhibitors: Synthesis, Docking Study, and Structure Activity Relationship. Anticancer Agents Med Chem, 23(11), 1336-1348. https://doi.org/10.2174/1871520623666230227153449
Hassan, O. M., Kubba, A., & Tahtamouni, L. H. (2023). Novel 5-bromoindole-2-carboxylic Acid Derivatives as EGFR Inhibitors: Synthesis, Docking Study, and Structure Activity Relationship. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents), 23(11), 1336-1348.
Heriz, M. H., Mahmood, A. A. R., Yasin, S. R., Saleh, K. M., AlSakhen, M. F., Kanaan, S. I., Himsawi, N., Saleh, A. M., & Tahtamouni, L. H. (2024). Synthesis, docking study, and antitumor evaluation of benzamides and oxadiazole derivatives of 3-phenoxybenzoic acid as VEGFR-2 inhibitors. Drug Dev Res, 85(3), e22186. https://doi.org/10.1002/ddr.22186
Hussein, Z. A., Al-Zubaidy, A. A., & Sahib, H. B. (2018). The anti-angiogenic activity of phoenix dactylifera seeds methanol extract in vivo study [Article]. Iranian Journal of Pharmaceutical Sciences, 14(2), 83-92. https://www.scopus.com/inward/record.uri?eid=2-s2.0-85061846214&partnerID=40&md5=3e17d81174f9cc54d6adc138b803e05b
Hussein, Z. A., Al-Zubaidy, A. A., & Sahib, H. B. (2018). The Anti-Angiogenic Activity of Phoenix Dactylifera Seeds Methanol Extract in Vivo Study: Phoenix dactylifera seeds Methanol Extract in vivo study. Iranian Journal of Pharmaceutical Sciences, 14(2), 83-92. https://doi.org/10.22037/ijps.v14.40665
Iacopetta, K., Collins-Praino, L. E., Buisman-Pijlman, F. T., Liu, J., Hutchinson, A. D., & Hutchinson, M. R. (2020). Are the protective benefits of vitamin D in neurodegenerative disease dependent on route of administration? A systematic review. Nutritional neuroscience, 23(4), 251-280.
Jagadeesan, S., & Karpagam, S. (2023). Novel series of N-acyl substituted indole based piperazine, thiazole and tetrazoles as potential antibacterial, antifungal, antioxidant and cytotoxic agents, and their docking investigation as potential Mcl-1 inhibitors. Journal of Molecular Structure, 1271, 134013.
Kadhim, H. M. (2016). Antiinflmmatory and antihyperlipidemic effect of adjuvant cinnamon in type 2 diabetic patients. Int. J. Pharm. Sci. Rev. Res, 41(1), 88-98.
Livak, K. J., & Schmittgen, T. D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods, 25(4), 402-408. https://doi.org/10.1006/meth.2001.1262
Manna, M. J., Abu-raghif, A., & Muhsin, H. Y. (2019). The effect of Niclosamide in acetic acid induce colitis: an experimental study. Prensa méd. argent, 105(5), 309-316.
Mngwengwe, L., Lugongolo, M., Ombinda-Lemboumba, S., Ismail, Y., & Mthunzi-Kufa, P. (2024). The effect of low-level laser therapy on severe acute respiratory syndrome coronavirus-2 infected cells. Mechanisms of Photobiomodulation Therapy XVIII,
Nicosia, R. F. (2009). The aortic ring model of angiogenesis: a quarter century of search and discovery. J Cell Mol Med, 13(10), 4113-4136. https://doi.org/10.1111/j.1582-4934.2009.00891.x
Obaid, K. A., & Fawzi, H. A. (2024). Evaluation of empagliflozin efficacy as a promising anti-aging treatment in mice: In-vivo study [Article]. Pharmacia, 71, Article e116184. https://doi.org/10.3897/pharmacia.71.e116184
Payne, S., Neal, A., & De Val, S. (2024). Transcription factors regulating vasculogenesis and angiogenesis. Dev Dyn, 253(1), 28-58. https://doi.org/10.1002/dvdy.575
Petrioli, R., Miano, S. T., & Martellucci, I. (2022). Chapter 3 - Antiangiogenic agents in the treatment of colorectal, gastric, and gastroesophageal junction adenocarcinoma. In L. Morbidelli (Ed.), Antiangiogenic Drugs as Chemosensitizers in Cancer Therapy (Vol. 18, pp. 67-78). Academic Press. https://doi.org/https://doi.org/10.1016/B978-0-323-90190-1.00007-X
Raghif, A. R. A. (2016). The Anti-Angiogenic Activity of P-Hydroxy Chalcone. Int. J. Pharm. Sci. Rev. Res., 37(1), 117-121.
Saravanan, S., Vimalraj, S., Pavani, K., Nikarika, R., & Sumantran, V. N. (2020). Intussusceptive angiogenesis as a key therapeutic target for cancer therapy. Life Sci, 252, 117670.
Tokala, R., Sana, S., Lakshmi, U. J., Sankarana, P., Sigalapalli, D. K., Gadewal, N., Kode, J., & Shankaraiah, N. (2020). Design and synthesis of thiadiazolo-carboxamide bridged β-carboline-indole hybrids: DNA intercalative topo-IIα inhibition with promising antiproliferative activity. Bioorganic Chemistry, 105, 104357. https://doi.org/https://doi.org/10.1016/j.bioorg.2020.104357
Underwood, W., & Anthony, R. (2020). AVMA guidelines for the euthanasia of animals: 2020 edition. 2020-2021.
Unterleuthner, D., Neuhold, P., Schwarz, K., Janker, L., Neuditschko, B., Nivarthi, H., Crncec, I., Kramer, N., Unger, C., Hengstschläger, M., Eferl, R., Moriggl, R., Sommergruber, W., Gerner, C., & Dolznig, H. (2020). Cancer-associated fibroblast-derived WNT2 increases tumor angiogenesis in colon cancer. Angiogenesis, 23(2), 159-177. https://doi.org/10.1007/s10456-019-09688-8
Yao, Y., Huang, T., Wang, Y., Wang, L., Feng, S., Cheng, W., Yang, L., & Duan, Y. (2022). Angiogenesis and anti-leukaemia activity of novel indole derivatives as potent colchicine binding site inhibitors. Journal of Enzyme Inhibition and Medicinal Chemistry, 37(1), 652-665. https://doi.org/10.1080/14756366.2022.2032688
Yaseen, Y., Kubba, A., Shihab, W., & Tahtamouni, L. (2022). Synthesis, docking study, and structure-activity relationship of novel niflumic acid derivatives acting as anticancer agents by inhibiting VEGFR or EGFR tyrosine kinase activities. Pharmacia, 69. https://doi.org/10.3897/pharmacia.69.e86504
Published
2025-09-08
How to Cite
Ali, Z. M., KadhimH. ., HassanO. M., KubbaA., & Sahib, H. B. (2025). Antiangiogenic activity of 4 – chloro phenyl carbothioamide derivatives in ex vivo and in vitro experimental study. Indonesian Journal of Pharmacy. https://doi.org/10.22146/ijp.16909
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Section
Research Article
