Characterization of water-soluble esters of nitrobenzoxadiazole-based GSTP1-1 inhibitors for cancer treatment

[Display omitted] The 7-nitrobenzo[c][1,2,5]oxadiazole (NBD) derivative NBDHEX (compound 1) and its analogue MC3181 (compound 2) have been found to be potent inhibitors of tumor cell growth in vitro and therapeutically active and safe in mice bearing human melanoma xenografts. To enhance the aqueous...

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Bibliographic Details
Published in:Biochemical pharmacology 2020-08, Vol.178, p.114060-114060, Article 114060
Main Authors: Di Paolo, Veronica, Fulci, Chiara, Rotili, Dante, De Luca, Anastasia, Tomassi, Stefano, Serra, Massimo, Scimeca, Manuel, Geroni, Cristina, Quintieri, Luigi, Caccuri, Anna Maria
Format: Article
Language:English
Subjects:
4-Chloro-7-nitrobenzofurazan - chemistry
4-Chloro-7-nitrobenzofurazan - metabolism
4-Chloro-7-nitrobenzofurazan - therapeutic use
Animals
Antineoplastic Agents - chemistry
Antineoplastic Agents - metabolism
Antineoplastic Agents - therapeutic use
Cell Line, Tumor
Esters - chemistry
Esters - metabolism
Female
Glutathione S-Transferase pi - antagonists & inhibitors
Glutathione S-Transferase pi - metabolism
Glutathione Transferase - antagonists & inhibitors
Glutathione Transferase - metabolism
GSTP1-1
Humans
Male
MC3181
Melanoma xenografts
Metabolic stability
Mice
Mice, Nude
NBDHEX
Neoplasms - drug therapy
Neoplasms - metabolism
Phosphate esters
Solubility
Water - chemistry
Water - metabolism
Xenograft Model Antitumor Assays - methods
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Summary:[Display omitted] The 7-nitrobenzo[c][1,2,5]oxadiazole (NBD) derivative NBDHEX (compound 1) and its analogue MC3181 (compound 2) have been found to be potent inhibitors of tumor cell growth in vitro and therapeutically active and safe in mice bearing human melanoma xenografts. To enhance the aqueous solubility of these compounds, we synthesized the hemisuccinate of 1 (compound 3) and the phosphate monoesters of 1 and 2 (compound 4 and 5, respectively). These novel NBD derivatives displayed a solubility in the conventional phosphate-buffered saline up to 150-fold higher than that of 1, and up to 4-fold higher than that of 2. Notably, solubility of phosphates 4 and 5 in a potassium phosphate buffer at pH 7.4, was up to 500-fold higher than that of 1, and ~10-fold higher than that of 2. Compounds 3–5 retained high cytotoxicity towards cultured human melanoma and osteosarcoma cells and were cleaved in vitro by both human and murine hydrolases, thus releasing the corresponding parent compound (i.e., 1 or 2). Interestingly, esters 3–5 displayed high inhibitory activity towards the glutathione transferase (GST) isoform GSTP1-1 and showed a reactivity towards reduced glutathione comparable to that of the respective parent compound. Finally, both 4 and 5 were safe and effective when administered intravenously or orally as an aqueous solution to mice xenografted with A375 human melanoma tumors. Collectively, these results and the previously observed synergistic interaction between 1 and 2 and various approved anticancer drugs, suggest the possible utility of phosphates 4 and 5 as single agents and in combination regimens in cancers with unmet medical need, including melanoma.
ISSN:0006-2952
1873-2968
DOI:10.1016/j.bcp.2020.114060