Unraveling the vasculature network around the tumor with aryl urea derivatives

Significance 

Normal cells have mechanisms that enables them prevent excessive growth. An example is the process of apoptosis. Mutations in genes controlling those mechanisms give rise to excessive and uncontrolled growth of cells resulting in cancer formation. In addition, the cancer cells have developed additional mechanisms of evading control and ensuring their superiority over normal cells, hallmarks of cancer. The ability to form their own blood vessels by stimulating growth factors such as endothelial growth factor enables them to acquire nutrients and grow undeterred. It also participates in its spread, metastasis, via the bloodstream.

The treatment of cancer is achieved using radiotherapy and antineoplastic drugs. Other modalities include agents that block some of these hallmarks. For example, those agents that blocks angiogenesis which result in an inadequate supply of nutrients to cancer cells, slowed growth, ischemia, and death. A natural vascular disruptor agent is combretastatin which is isolated from a plant extract. Synthetic agents are also available. The inhibition of vascular endothelial growth factor can be achieved by anti-cancer drugs sunitinib (marketed as Sutent by Pfizer) and sorafenib (marketed as Nexavar by Bayer). They block intracellular signaling by VEGF. They are used in treating renal cell carcinoma.

In a recent research paper published in European Journal of Medicinal Chemistry, Jaume I University scientists: Laura Conesa-Milián, Professor Eva Falomir, Dr. Juan Murga, and Dr. Miguel Carda together with Dr. J. Alberto Marco at University of Valencia synthesized much improved molecules with antiangiogenic activity by installing AMCA-4(3’-Amino-Combretastatin) urea functionality.

They showed low micromolar concentrations of most urea compounds were sufficient to inhibit cellular proliferation. The inhibition of the cell cycle increased subG0 stage, and arrest of mitosis was achieved with all the urea compounds. On the other hand, they found out that sunitinib and sorafenib had no effect on cell division. Urea and AMCA-4 caused compression and fragmentation of nuclei and aggregation of tubulin. The inhibition of apoptosis was achieved in most of the urea compounds.

When the research team looked at the effect on angiogenesis, they used the classical endothelial tube formation. They found that ortho-bromo substituted urea 8 and ortho-chloro substituted urea 5 were highly active in preventing angiogenesis of tumor cells at a concentration of 0.1µm. When compared to sunitinib and sorafenib, these molecules had less inhibition of blood vessel formation. The interaction with the VEGFR-2 was also examined by the researchers with the outcome that the two compounds were also the most active. The down-regulation of the VEGF receptors was achieved in all the urea compounds at different levels. For instance, urea 8 and 5 caused the down-regulation to half. The highest inhibition of the activity of VEGFR tyrosine kinase was achieved by ortho-chloro substituted urea 5.

In conclusion, the Spanish scientists synthesized new urea derived molecules that can be utilized in killing cancer cells. The most active agents were ortho-bromo substituted urea 8 and ortho-chloro substituted urea 5. They inhibit cell division of the cancer cells, causes apoptosis resulting in their destruction, prevent the formation of new blood vessels, inhibit the tyrosine kinase signaling of VEGF receptors, and inhibit the proliferation of tumor cells. Their use may help in counteracting most of the hallmarks developed by malignant cells resulting in the destruction of malignant cells, slowed growth, and prevention of its spread via the circulation. Clinical advancement of these molecules will be important to realize their potential.

Unraveling the vasculature network around the tumor with aryl urea derivatives - Medicine Innovates
Effect of urea 8 at 1, 0.3, 0.1 and 0.03 µM concentration (from left to right).

About the author

Laura Conesa-Milián completed her bachelor’s degree in chemistry at Universitat Jaume I of Castelló de la Plana, Spain, in 2013. One year later, she obtained her Master’s degree in Applied and Pharmacological Chemistry, concretely in the modality of Medicinal Chemistry, and started to collaborate with the research group “Joining Medicine and Chemistry” at Universitat Jaume I. In 2015, Laura received a grant from the Spanish Ministry of Education in order to continue her investigation and develop the PhD in the mentioned group. As a doctoral student, her project has been based on the design, synthesis and biological evaluation of combretastatin analogues with antineoplastic properties, which has resulted in published papers and conference presentations. Along her academical training, Laura has also developed short stays in international research institutes such as Príncipe Felipe Research Center (Valencia), Biological Research Center (Madrid) and Rega Institute for Medical Research (Leuven).

Reference

Conesa-Milián, L., Falomir, E., Murga, J., Carda, M., & Marco, J. A. (2019). Synthesis and biological evaluation as antiangiogenic agents of ureas derived from 3′-aminocombretastatin A-4. European journal of medicinal chemistry, 162, 781-792.

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