Limits...
A novel orally active water-soluble inhibitor of human glutathione transferase exerts a potent and selective antitumor activity against human melanoma xenografts.

De Luca A, Rotili D, Carpanese D, Lenoci A, Calderan L, Scimeca M, Mai A, Bonanno E, Rosato A, Geroni C, Quintieri L, Caccuri AM - Oncotarget (2015)

Bottom Line: Interestingly, the cellular response to MC3181 was cell-type-specific; the compound triggered a JNK-dependent apoptosis in the BRAF-V600E-mutated A375 cells, while it induced morphological changes together with an increase in melanogenesis in BRAF wild-type SK23-MEL cells.MC3181 exhibited a remarkable therapeutic activity against BRAF-V600E-mutant xenografts, both after intravenous and oral administration.Outstandingly, no treatment-related signs of toxicity were observed both in healthy and tumor-bearing mice after single and repeated administrations.

View Article: PubMed Central - PubMed

Affiliation: The NAST Centre for Nanoscience & Nanotechnology & Innovative Instrumentation, University of Tor Vergata, 00133 Rome, Italy.

ABSTRACT
We designed and synthesized two novel nitrobenzoxadiazole (NBD) analogues of the anticancer agent 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexan-1-ol (NBDHEX). The new compounds, namely MC3165 and MC3181, bear one and two oxygen atoms within the hydroxy-containing alkyl chain at the C4 position of the NBD scaffold, respectively. This insertion did not alter the chemical reactivity with reduced glutathione, while it conferred a remarkable increase in water solubility. MC3181 was more selective than NBDHEX towards the target protein, glutathione transferase P1-1, and highly effective in vitro against a panel of human melanoma cell lines, with IC50 in the submicromolar-low micromolar range. Interestingly, the cellular response to MC3181 was cell-type-specific; the compound triggered a JNK-dependent apoptosis in the BRAF-V600E-mutated A375 cells, while it induced morphological changes together with an increase in melanogenesis in BRAF wild-type SK23-MEL cells. MC3181 exhibited a remarkable therapeutic activity against BRAF-V600E-mutant xenografts, both after intravenous and oral administration. Outstandingly, no treatment-related signs of toxicity were observed both in healthy and tumor-bearing mice after single and repeated administrations. Taken together, these results indicate that MC3181 may represent a potential novel therapeutic opportunity for BRAF-mutated human melanoma, while being safe and water-soluble and thus overcoming all the critical aspects of NBDHEX in vivo.

No MeSH data available.


Related in: MedlinePlus

Structures and preparation of the NBDHEX derivatives MC3165 andMC3181(A) Chemical structures of NBDHEX, MC3165 and MC3181.(B) Scheme of MC3165 and MC3181 preparation. Thecompounds were obtained by a nucleophilic displacement reaction betweenthe commercial4-chloro-7-nitrobenzo[c][1,2,5]oxadiazole and the2-(2-mercaptoethoxy)ethanol and the2-(2-(2-mercaptoethoxy)ethoxy)ethanol, respectively. Reagents andconditions: a) Thiourea, H2O, N2, reflux, 18h; b)NaOH 5N, N2, reflux, 3h; c)4-chloro-7-nitrobenzo[c][1,2,5]oxadiazole,EtOH:H2O (0.3:1), pyridine, r.t., 4h.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4414177&req=5

Figure 1: Structures and preparation of the NBDHEX derivatives MC3165 andMC3181(A) Chemical structures of NBDHEX, MC3165 and MC3181.(B) Scheme of MC3165 and MC3181 preparation. Thecompounds were obtained by a nucleophilic displacement reaction betweenthe commercial4-chloro-7-nitrobenzo[c][1,2,5]oxadiazole and the2-(2-mercaptoethoxy)ethanol and the2-(2-(2-mercaptoethoxy)ethoxy)ethanol, respectively. Reagents andconditions: a) Thiourea, H2O, N2, reflux, 18h; b)NaOH 5N, N2, reflux, 3h; c)4-chloro-7-nitrobenzo[c][1,2,5]oxadiazole,EtOH:H2O (0.3:1), pyridine, r.t., 4h.

Mentions: As described in Fig. 1, MC3165 and MC3181were obtained by a nucleophilic displacement reaction between the commercial4-chloro-7-nitrobenzo[c] [1,2,5]oxadiazole and the2-(2-mercaptoethoxy)ethanol and the 2-(2-(2-mercaptoethoxy)ethoxy)ethanol,respectively. The mercapto alcohols were prepared from the commerciallyavailable 2-(2-chloroethoxy)ethanol and 2-(2-(2-chloroethoxy)ethoxy)ethanolthrough a reaction with thiourea in refluxing water under an inert atmosphere,followed by the basic hydrolysis of the hydrochloride intermediates under refluxconditions. The 2-(2-mercaptoethoxy)ethanol and the2-(2-(2-mercaptoethoxy)ethoxy)ethanol were finally reacted with the4-chloro-7-nitrobenzo[c][1,2,5]oxadiazole in anethanol:water (1:3) mixture, in the presence of pyridine at room temperature,providing the desired compounds, MC3165 and MC3181.


A novel orally active water-soluble inhibitor of human glutathione transferase exerts a potent and selective antitumor activity against human melanoma xenografts.

De Luca A, Rotili D, Carpanese D, Lenoci A, Calderan L, Scimeca M, Mai A, Bonanno E, Rosato A, Geroni C, Quintieri L, Caccuri AM - Oncotarget (2015)

Structures and preparation of the NBDHEX derivatives MC3165 andMC3181(A) Chemical structures of NBDHEX, MC3165 and MC3181.(B) Scheme of MC3165 and MC3181 preparation. Thecompounds were obtained by a nucleophilic displacement reaction betweenthe commercial4-chloro-7-nitrobenzo[c][1,2,5]oxadiazole and the2-(2-mercaptoethoxy)ethanol and the2-(2-(2-mercaptoethoxy)ethoxy)ethanol, respectively. Reagents andconditions: a) Thiourea, H2O, N2, reflux, 18h; b)NaOH 5N, N2, reflux, 3h; c)4-chloro-7-nitrobenzo[c][1,2,5]oxadiazole,EtOH:H2O (0.3:1), pyridine, r.t., 4h.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4414177&req=5

Figure 1: Structures and preparation of the NBDHEX derivatives MC3165 andMC3181(A) Chemical structures of NBDHEX, MC3165 and MC3181.(B) Scheme of MC3165 and MC3181 preparation. Thecompounds were obtained by a nucleophilic displacement reaction betweenthe commercial4-chloro-7-nitrobenzo[c][1,2,5]oxadiazole and the2-(2-mercaptoethoxy)ethanol and the2-(2-(2-mercaptoethoxy)ethoxy)ethanol, respectively. Reagents andconditions: a) Thiourea, H2O, N2, reflux, 18h; b)NaOH 5N, N2, reflux, 3h; c)4-chloro-7-nitrobenzo[c][1,2,5]oxadiazole,EtOH:H2O (0.3:1), pyridine, r.t., 4h.
Mentions: As described in Fig. 1, MC3165 and MC3181were obtained by a nucleophilic displacement reaction between the commercial4-chloro-7-nitrobenzo[c] [1,2,5]oxadiazole and the2-(2-mercaptoethoxy)ethanol and the 2-(2-(2-mercaptoethoxy)ethoxy)ethanol,respectively. The mercapto alcohols were prepared from the commerciallyavailable 2-(2-chloroethoxy)ethanol and 2-(2-(2-chloroethoxy)ethoxy)ethanolthrough a reaction with thiourea in refluxing water under an inert atmosphere,followed by the basic hydrolysis of the hydrochloride intermediates under refluxconditions. The 2-(2-mercaptoethoxy)ethanol and the2-(2-(2-mercaptoethoxy)ethoxy)ethanol were finally reacted with the4-chloro-7-nitrobenzo[c][1,2,5]oxadiazole in anethanol:water (1:3) mixture, in the presence of pyridine at room temperature,providing the desired compounds, MC3165 and MC3181.

Bottom Line: Interestingly, the cellular response to MC3181 was cell-type-specific; the compound triggered a JNK-dependent apoptosis in the BRAF-V600E-mutated A375 cells, while it induced morphological changes together with an increase in melanogenesis in BRAF wild-type SK23-MEL cells.MC3181 exhibited a remarkable therapeutic activity against BRAF-V600E-mutant xenografts, both after intravenous and oral administration.Outstandingly, no treatment-related signs of toxicity were observed both in healthy and tumor-bearing mice after single and repeated administrations.

View Article: PubMed Central - PubMed

Affiliation: The NAST Centre for Nanoscience & Nanotechnology & Innovative Instrumentation, University of Tor Vergata, 00133 Rome, Italy.

ABSTRACT
We designed and synthesized two novel nitrobenzoxadiazole (NBD) analogues of the anticancer agent 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexan-1-ol (NBDHEX). The new compounds, namely MC3165 and MC3181, bear one and two oxygen atoms within the hydroxy-containing alkyl chain at the C4 position of the NBD scaffold, respectively. This insertion did not alter the chemical reactivity with reduced glutathione, while it conferred a remarkable increase in water solubility. MC3181 was more selective than NBDHEX towards the target protein, glutathione transferase P1-1, and highly effective in vitro against a panel of human melanoma cell lines, with IC50 in the submicromolar-low micromolar range. Interestingly, the cellular response to MC3181 was cell-type-specific; the compound triggered a JNK-dependent apoptosis in the BRAF-V600E-mutated A375 cells, while it induced morphological changes together with an increase in melanogenesis in BRAF wild-type SK23-MEL cells. MC3181 exhibited a remarkable therapeutic activity against BRAF-V600E-mutant xenografts, both after intravenous and oral administration. Outstandingly, no treatment-related signs of toxicity were observed both in healthy and tumor-bearing mice after single and repeated administrations. Taken together, these results indicate that MC3181 may represent a potential novel therapeutic opportunity for BRAF-mutated human melanoma, while being safe and water-soluble and thus overcoming all the critical aspects of NBDHEX in vivo.

No MeSH data available.


Related in: MedlinePlus