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Tetrazole derivatives as potent immunomodulatory agents in tumor microenvironment
Alberto Pla-López1, Miguel Carda1, Eva Falomir1
1Inorganic and Organic Chemistry Department, University Jaume I, E-12071 Castellón, Spain.
Abstract:
Twenty-seven compounds bearing a tetrazole ring as a central unit have been designed, synthetized and biologically evaluated. Studies have been performed in order to compare the effect of tetrazole derivatives bearing amine electron-donor or nitro electron-acceptor groups. The antiproliferative activity has been determined in monoculture studies on tumor cell lines HT-29, A-549, MCF-7 and on non-tumor cell line HEK-293 as well as in co-culture studies (HT-29/THP-1). All the compounds have been studied as PD-L1 (Programmed Death Ligand 1), VEGFR-2 (Vascular Endothelial Growth Factor 2), CD-47 (Cluster of Differentiation 47) and c-Myc inhibitors. The effect on TNF-α secretion has also been determined. Bromoderivatives 23, 24 and chloroderivatives 26, 27 have demonstrated an apoptotic effect on HT-29 cancer cells. Compounds bearing an amine group have shown very promising effects as TME immunomodulatory agents.
Insights
Tetrazole derivatives were synthesized and tested for anticancer properties. Amine-containing compounds show promise as tumor microenvironment immunomodulators, while specific bromo and chloro derivatives induced apoptosis in HT-29 cancer cells.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Immunology
Background:
- Tetrazole scaffolds are recognized for their diverse biological activities.
- Modulating the tumor microenvironment (TME) is a key strategy in cancer therapy.
- Targeting Programmed Death Ligand 1 (PD-L1), Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2), Cluster of Differentiation 47 (CD-47), and c-Myc are critical in cancer treatment.
Purpose of the Study:
- To design, synthesize, and evaluate novel tetrazole derivatives for anticancer potential.
- To compare the effects of electron-donating (amine) versus electron-accepting (nitro) groups on tetrazole derivatives.
- To investigate the inhibitory effects of these compounds on PD-L1, VEGFR-2, CD-47, c-Myc, and TNF-α secretion.
Main Methods:
- Synthesis of 27 tetrazole-containing compounds.
- Antiproliferative activity assessed via monoculture (HT-29, A-549, MCF-7, HEK-293) and co-culture (HT-29/THP-1) assays.
- Inhibition profiling against PD-L1, VEGFR-2, CD-47, and c-Myc.
- Evaluation of tumor necrosis factor-alpha (TNF-α) secretion.
Main Results:
- Bromoderivatives (23, 24) and chloroderivatives (26, 27) induced apoptosis in HT-29 cancer cells.
- Compounds with amine groups exhibited significant immunomodulatory effects within the TME.
- Several compounds demonstrated inhibitory activity against PD-L1, VEGFR-2, CD-47, and c-Myc.
Conclusions:
- Tetrazole derivatives, particularly those with amine substituents, represent a promising class of TME immunomodulatory agents.
- Specific halogenated tetrazoles possess direct cytotoxic effects, inducing apoptosis in cancer cells.
- The designed tetrazole compounds offer potential as multi-targeted anticancer therapeutics.
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01:27Tumor Immunotherapy
02:17The Tumor Microenvironment