Arsenical <i>C</i>‐Glucoside Derivatives with Promising Antitumor Activity

D’Orazio, Giuseppe; Parisi, Gelsomina; Policano, Claudia; Mechelli, Rosella; Codacci-Pisanelli, Giovanni; Pitaro, Michele; Ristori, Giovanni; Salvetti, Marco; Nicotra, Francesco; Ferla, Barbara La

doi:10.1002/ejoc.201500529

Eur J Org Chem

2015

DOI: 10.1002/ejoc.201500529

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Arsenical C‐Glucoside Derivatives with Promising Antitumor Activity

Giuseppe D’Orazio

Gelsomina Parisi²,

Claudia Policano³

et al.

Abstract: C‐Glucoside derivatives covalently linked to the arsenic atom in different oxidation states have been synthesized by avoiding protection‐deprotection steps. While compound 1, bearing an AsV atom, did not show any significant biological activity, compound 2, in which the glucose moiety is linked to the arsenic atom as dithioarsenical (AsIII), showed promising antiproliferative activity on a cell line of neuroblastoma (SK‐N‐BE).

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Cited by 3 publications

References 14 publications

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Anti-Inflammatory Effects of SGLT1 Synthetic Ligand in In Vitro and In Vivo Models of Lung Diseases

Rumio,

Dusio,

Cardani

et al. 2024

Immuno

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Background. Several research findings suggest that sodium–glucose co-transporter 1 (SGLT1) is implicated in the progression and control of infections and inflammation processes at the pulmonary level. Moreover, our previous works indicate an engagement of SGLT1 in inhibiting the inflammatory response induced in intestinal epithelial cells by TLR agonists. In this study, we report the anti-inflammatory effects observed in the lung upon engagement of the transporter, and upon the use of glucose and BLF501, a synthetic SGLT1 ligand, for the treatment of animal models of lung inflammation, including a model of allergic asthma. Methods. In vitro experiments were carried out on human pneumocytes stimulated with LPS from Pseudomonas aeruginosa and co-treated with glucose or BLF501, and the production of IL-8 was determined. The anti-inflammatory effect associated with SGLT1 engagement was then assessed in in vivo models of LPS-induced lung injury, as well as in a murine model of ovalbumin (OVA)-induced asthma, treating mice with aerosolized LPS and the synthetic ligand. After the treatments, lung samples were collected and analyzed for morphological alterations by histological examination and immunohistochemical analysis; serum and BALF samples were collected for the determination of several pro- and anti-inflammatory markers. Results. In vitro experiments on human pneumocytes treated with LPS showed significant inhibition of IL-8 production. The results of two in vivo experimental models, mice exposed to aerosolized LPS and OVA-induced asthma, revealed that the engagement of glucose transport protein 1 (SGLT1) induced a significant anti-inflammatory effect in the lungs. In the first model, the acute respiratory distress induced in mice was abrogated by co-treatment with the ligand, with almost complete recovery of the lung morphology and physiology. Similar results were observed in the OVA-induced model of allergic asthma, both with aerosolized and oral BLF501, suggesting an engagement of SGLT1 expressed both in intestinal and alveolar cells. Conclusions. Our results confirmed the engagement of SGLT1 in lung inflammation processes and suggested that BLF501, a non-metabolizable synthetic ligand of the co-transporter, might represent a drug candidate for therapeutic intervention against lung inflammation states.

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Anti-Inflammatory Effects of SGLT1 Synthetic Ligand in In Vitro and In Vivo Models of Lung Diseases

Rumio,

Dusio,

Cardani

et al. 2024

Immuno

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Synthesis of a Small Library of Glycoderivative Putative Ligands of SGLT1 and Preliminary Biological Evaluation

D’Orazio,

La Ferla

2024

Molecules

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Sodium–glucose co-transporter 1 (SGLT1) is primarily expressed on the membrane of enterocytes, a type of epithelial cell found in the intestines, where it mediates the unidirectional absorption of glucose and galactose. Beyond its well-established role in nutrient absorption, SGLT1 also plays a protective role in maintaining the integrity of the intestinal barrier. Specifically, the natural ligand of SGLT1 (d-glucose) and a synthetic C-glucoside developed by our group can induce a protective anti-inflammatory effect on the intestinal epithelium. In this paper, we report the creation of a small library of C-glycoside, putative ligands for SGLT1, to gain further insights into its unclear mechanism of action. Preliminary biological experiments performed on an in vitro model of doxorubicin-induced mucositis, a severe intestinal inflammatory condition, indicate that the aromatic moiety present in all the compounds of the library is crucial for biological activity, while the sugar component appears to have less influence. These findings will be exploited to develop new, more potent anti-inflammatory compounds and to better understand and rationalize the protective mechanism of action.

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Synthesis of Novel Arsonolipids and Development of Novel Arsonoliposome Types

et al. 2022

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Arsonolipids represent a class of arsenic-containing compounds with interesting biological properties either as monomers or as nanostructure forming components, such as arsonoliposomes that possess selective anticancer activity as proven by in vitro and in vivo studies. In this work, we describe, for the first time, the synthesis of novel arsono-containing lipids where the alkyl groups are connected through stable ether bonds. It is expected that this class of arsonolipids, compared with the corresponding ester linked, will have higher chemical stability. To accomplish this task, a new methodology of general application was developed, where a small arsono compound, 2-hydroxyethylarsonic acid, when protected with thiophenol, can be used in an efficient and simple way as a building block for the synthesis of arsono-containing lipids as well as other arsono-containing biomolecules. Thus, besides the above-mentioned arsonolipid, an arsono cholesterol derivative was also obtained. Both ether arsonolipid and arsono cholesterol were able to form liposomes having similar physicochemical properties and integrity to conventional arsonoliposomes. Furthermore, a preliminary in vitro anticancer potential assessment of the novel ether arsonolipid containing liposomes against human prostate cancer (PC-3) and Lewis lung carcinoma (LLC) cells showed significant activity (dose- and time-dependent), which was similar to that of the conventional arsonoliposomes (studied before). Given the fact that novel arsonolipids may be more stable compared to the ones used in conventional arsonoliposomes, the current results justify further exploitation of the novel compounds by in vitro and in vivo studies.

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Arsenical C‐Glucoside Derivatives with Promising Antitumor Activity

Cited by 3 publications

References 14 publications

Anti-Inflammatory Effects of SGLT1 Synthetic Ligand in In Vitro and In Vivo Models of Lung Diseases

Anti-Inflammatory Effects of SGLT1 Synthetic Ligand in In Vitro and In Vivo Models of Lung Diseases

Synthesis of a Small Library of Glycoderivative Putative Ligands of SGLT1 and Preliminary Biological Evaluation

Synthesis of Novel Arsonolipids and Development of Novel Arsonoliposome Types

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