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Unveiling the Potential of BenzylethyleneAryl-Urea Scaffolds for the Design of New Onco Immunomodulating Agents
Raquel Gil-Edo1, Santiago Royo2, Miguel Carda1
1Inorganic and Organic Chemistry Department, University Jaume I, 12071 Castellón, Spain.
Abstract:
This work focuses on the development of thirteen benzylethylenearyl ureas and one carbamate. After the synthesis and purification of the compounds, we studied their antiproliferative action on cell lines, such as HEK-293, and cancer ones, such as HT-29, MCF-7 or A-549, on the immune Jurkat T-cells and endothelial cells HMEC-1. Compounds C.1, C.3, C.12 and C.14 were selected for further biological studies to establish their potential as immunomodulating agents. Some of the derivatives exhibited significant inhibitory effects on both targets: PD-L1 and VEGFR-2 in the HT-29 cell line, showing that urea C.12 is active against both targets. Some compounds could inhibit more than 50% of cancer cell proliferation compared to non-treated ones when assessed in co-cultures using HT-29 and THP-1 cells. In addition, they significantly reduced CD11b expression, which is a promising target for immune modulation in anticancer immunotherapies.
Insights
Researchers developed novel benzylethylenearyl ureas and carbamates, identifying compounds C.1, C.3, C.12, and C.14 as potential immunomodulators. These compounds show promise in inhibiting cancer cell proliferation and reducing CD11b expression for anticancer immunotherapies.
Area of Science:
- Medicinal Chemistry
- Immunology
- Cancer Biology
Background:
- Development of novel therapeutic agents is crucial for advancing cancer treatment.
- Targeting immune modulation pathways offers a promising strategy for anticancer immunotherapies.
- Existing treatments face challenges, necessitating exploration of new chemical entities.
Purpose of the Study:
- To synthesize and characterize novel benzylethylenearyl ureas and carbamates.
- To evaluate the antiproliferative and immunomodulatory potential of these compounds.
- To identify lead compounds for further development as anticancer agents.
Main Methods:
- Synthesis and purification of thirteen benzylethylenearyl ureas and one carbamate.
- Antiproliferative assays on various cell lines including cancer (HT-29, MCF-7, A-549), normal (HEK-293), immune (Jurkat T-cells), and endothelial (HMEC-1) cells.
- Inhibition assays targeting PD-L1 and VEGFR-2.
- Co-culture experiments with cancer and immune cells to assess proliferation inhibition and CD11b expression.
Main Results:
- Compounds C.1, C.3, C.12, and C.14 were selected for further studies.
- Urea C.12 demonstrated activity against both PD-L1 and VEGFR-2 targets in HT-29 cells.
- Several compounds inhibited over 50% of cancer cell proliferation in co-cultures.
- Significant reduction in CD11b expression was observed, indicating immunomodulatory effects.
Conclusions:
- The synthesized benzylethylenearyl ureas and carbamates show significant antiproliferative and immunomodulatory activities.
- Compound C.12 is a promising candidate targeting both PD-L1 and VEGFR-2.
- These compounds represent potential novel agents for anticancer immunotherapies by modulating immune responses and inhibiting cancer cell growth.
