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 similar to 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.

Di Paolo, V., Fulci, C., Rotili, D., De Luca, A., Tomassi, S., Serra, M., et al. (2020). Characterization of water-soluble esters of nitrobenzoxadiazole-based GSTP1-1 inhibitors for cancer treatment. BIOCHEMICAL PHARMACOLOGY, 178, 114060 [10.1016/j.bcp.2020.114060].

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

Fulci C.;De Luca A.;Scimeca M.;Caccuri A. M.
2020-01-01

Abstract

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 similar to 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.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/10
Settore CHIM/08
English
GSTP1-1
NBDHEX
MC3181
Phosphate esters
Metabolic stability
Melanoma xenografts
4-Chloro-7-nitrobenzofurazan
Animals
Antineoplastic Agents
Cell Line, Tumor
Esters
Female
Glutathione S-Transferase pi
Glutathione Transferase
Humans
Male
Mice
Mice, Nude
Neoplasms
Solubility
Water
Xenograft Model Antitumor Assays
Di Paolo, V., Fulci, C., Rotili, D., De Luca, A., Tomassi, S., Serra, M., et al. (2020). Characterization of water-soluble esters of nitrobenzoxadiazole-based GSTP1-1 inhibitors for cancer treatment. BIOCHEMICAL PHARMACOLOGY, 178, 114060 [10.1016/j.bcp.2020.114060].
Di Paolo, V; Fulci, C; Rotili, D; De Luca, A; Tomassi, S; Serra, M; Scimeca, M; Geroni, C; Quintieri, L; Caccuri, Am
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/284668
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