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Exploring BenzylethoxyAryl Urea Scaffolds for Multitarget Immunomodulation Therapies.

ABSTRACT: Thirteen benzylethoxyaryl ureas have been synthesized and biologically evaluated as multitarget inhibitors of VEGFR-2 and PD-L1 proteins to overcome resistance phenomena offered by cancer. The antiproliferative activity of these molecules on several tumor cell lines (HT-29 and A549), on the endothelial cell line HMEC-1, on immune cells (Jurkat T) and on the non-tumor cell line HEK-293 has been determined. Selective indexes (SI) have been also determined and compounds bearing p-substituted phenyl urea unit together with a diaryl carbamate exhibited high SI values. Further studies on these selected compounds to determine their potential as small molecule immune potentiators (SMIPs) and as antitumor agents have been performed. From these studies, we have concluded that the designed ureas have good tumor antiangiogenic properties, exhibit good inhibition of CD11b expression, and regulate pathways involved in CD8 T-cell activity. These properties suggest that these compounds could be potentially useful in the development of new cancer immune treatments.

SUBMITTER: Gil-Edo R

PROVIDER: S-EPMC10218498 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Exploring BenzylethoxyAryl Urea Scaffolds for Multitarget Immunomodulation Therapies.

Gil-Edo Raquel R Hernández-Ribelles German G Royo Santiago S Thawait Natasha N Serrels Alan A Carda Miguel M Falomir Eva E

International journal of molecular sciences 20230511 10

Thirteen benzylethoxyaryl ureas have been synthesized and biologically evaluated as multitarget inhibitors of VEGFR-2 and PD-L1 proteins to overcome resistance phenomena offered by cancer. The antiproliferative activity of these molecules on several tumor cell lines (HT-29 and A549), on the endothelial cell line HMEC-1, on immune cells (Jurkat T) and on the non-tumor cell line HEK-293 has been determined. Selective indexes (SI) have been also determined and compounds bearing <i>p</i>-substituted ...[more]

PMID: 37239929

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Project description:Rationale: Mineral particles have been widely used in bone tissue engineering scaffolds due to their osteoconductive and osteoinductive properties. Despite their benefits, mineral particles can induce undesirable inflammation and subsequent bone resorption. Aspirin (Asp) is an inexpensive and widely used anti-inflammatory drug. The goal of this study is to assess the synergistic effect of Asp and optimized mineral particle coating in macroporous scaffolds to accelerate endogenous bone regeneration and reduce bone resorption in a critical-sized bone defect model. Methods: Four commonly used mineral particles with varying composition (hydroxyapatite v.s. tricalcium phosphate) and size (nano v.s. micro) were used. Mineral particles were coated onto gelatin microribbon (µRB) scaffolds. Macrophages (Mφ) were cultured on gelatin µRB scaffolds containing various particles, and Mφ polarization was assessed using PCR and ELISA. The effect of conditioned medium from Mφ on mesenchymal stem cell (MSC) osteogenesis was also evaluated in vitro. Scaffolds containing optimized mineral particles were then combined with varying dosages of Asp to assess the effect in inducing endogenous bone regeneration using a critical-sized cranial bone defect model. In vivo characterization and in vitro cell studies were performed to elucidate the effect of tuning Asp dosage on Mφ polarization, osteoclast (OC) activity, and MSC osteogenesis. Results: Micro-sized tricalcium phosphate (mTCP) particles were identified as optimal in promoting M2 Mφ polarization and rescuing MSC-based bone formation in the presence of conditioned medium from Mφ. When implanted in vivo, incorporating Asp with mTCP-coated µRB scaffolds significantly accelerated endogenous bone formation in a dose-dependent manner. Impressively, mTCP-coated µRB scaffolds containing 20 µg Asp led to almost complete bone healing of a critical-sized cranial bone defect as early as week 2 with no subsequent bone resorption. Asp enhanced M2 Mφ polarization, decreased OC activity, and promoted MSC osteogenesis in a dosage-dependent manner in vivo. These results were further validated using in vitro cell studies. Conclusions: Here, we demonstrate Asp and mineral particle-coated microribbon scaffold provides a promising therapy for repairing critical-sized cranial bone defects via immunomodulation. The leading formulation supports rapid endogenous bone regeneration without the need for exogenous cells or growth factors, making it attractive for translation. Our results also highlight the importance of optimizing mineral particles and Asp dosage to achieve robust bone healing while avoiding bone resorption by targeting Mφ and OCs.

Project description:The cocrystallization landscape of benzamide and urea interacting with aliphatic and aromatic carboxylic acids was studied both experimentally and theoretically. Ten new cocrystals of benzamide were synthesized using an oriented samples approach via a fast dropped evaporation technique. Information about types of known bi-component cocrystals augmented with knowledge of simple binary eutectic mixtures was used for the analysis of virtual screening efficiency among 514 potential pairs involving aromatic carboxylic acids interacting with urea or benzamide. Quantification of intermolecular interaction was achieved by estimating the excess thermodynamic functions of binary liquid mixtures under supercooled conditions within a COSMO-RS framework. The smoothed histograms suggest that slightly more potential pairs of benzamide are characterized in the attractive region compared to urea. Finally, it is emphasized that prediction of cocrystals of urea is fairly direct, while it remains ambiguous for benzamide paired with carboxylic acids. The two known simple eutectics of urea are found within the first two quartiles defined by excess thermodynamic functions, and all known cocrystals are outside of this range belonging to the third or fourth quartile. On the contrary, such a simple separation of positive and negative cases of benzamide miscibility in the solid state is not observed. The difference in properties between urea and benzamide R2,2(8) heterosynthons is also documented by alterations of substituent effects. Intermolecular interactions of urea with para substituted benzoic acid analogues are stronger compared to those of benzamide. Also, the amount of charge transfer from amide to aromatic carboxylic acid and vice versa is more pronounced for urea. However, in both cases, the greater the electron withdrawing character of the substituent, the higher the binding energy, and the stronger the supermolecule polarization via the charge transfer mechanism.

Project description:Abstract: Controlled release of immunomodulatory cytokines like interleukin-4 (IL-4) from biomaterials can modulate host immune cell behavior to improve tissue integration, however options for modifying complex biomaterials remain limited. Bioconjugation strategies using biotin-avidin interactions offer a promising approach since biotin can be conjugated to proteins, biomaterials, and even cells, without compromising their function. Although it is known that conjugation of biotin to large biomolecules reduces its binding affinity for avidin and avidin variants, the potential to control release of biotinylated molecules via leveraging affinity interactions has not been thoroughly investigated. Moreover, the effects of biotin and avidin variants on innate immunity are poorly understood. Therefore, the goal of this study was to determine if biotin-avidin interactions could be manipulated to control the release of IL-4 from biomaterials and to investigate the subsequent effects on primary human macrophage phenotype. First, we characterized the effects of soluble biotin, avidin, and avidin variants, streptavidin and CaptAvidin, on the phenotype of primary human macrophages using RNA sequencing and found that CaptAvidin significantly influenced macrophage gene expression while other variants did not. Then, after evaluating how bioconjugation parameters influenced biotin density and avidin variant binding to porous gelatin scaffolds, we found that biotin-avidin affinity interactions influenced the spontaneous release of biotinylated IL-4 (bIL-4) from biotinylated and desthiobiotinylated scaffolds bound with either avidin or streptavidin for up to ten days in vitro. Finally, we measured the response of primary human macrophages (8 donors) cultured on modified scaffolds, finding an increase in IL-4 driven genes when bIL-4 was released via biotin-streptavidin affinity interactions compared to desorption-based release. These results highlight how biotin-avidin interactions can be leveraged for spontaneous release to achieve an immunomodulatory drug delivery system.

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Exploring BenzylethoxyAryl Urea Scaffolds for Multitarget Immunomodulation Therapies.

Publications

Exploring BenzylethoxyAryl Urea Scaffolds for Multitarget Immunomodulation Therapies.

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