Synthesis and characterisation of a new benzamide-containing nitrobenzoxadiazole as a GSTP1-1 inhibitor endowed with high stability to metabolic hydrolysis.

Synthesis and characterisation of a new benzamide-containing nitrobenzoxadiazole as a GSTP1-1 inhibitor endowed with high stability to metabolic hydrolysis.

Publication date: Dec 01, 2019

The antitumor agent 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexan-1-ol (1) is a potent inhibitor of GSTP1-1, a glutathione S-transferase capable of inhibiting apoptosis by binding to JNK1 and TRAF2. We recently demonstrated that, unlike its parent compound, the benzoyl ester of 1 (compound 3) exhibits negligible reactivity towards GSH, and has a different mode of interaction with GSTP1-1. Unfortunately, 3 is susceptible to rapid metabolic hydrolysis. In an effort to improve the metabolic stability of 3, its ester group has been replaced by an amide, leading to N-(6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexyl)benzamide (4). Unlike 3, compound 4 was stable to human liver microsomal carboxylesterases, but retained the ability to disrupt the interaction between GSTP1-1 and TRAF2 regardless of GSH levels. Moreover, 4 exhibited both a higher stability in the presence of GSH and a greater cytotoxicity towards cultured A375 melanoma cells, in comparison with 1 and its analog 2. These findings suggest that 4 deserves further preclinical testing.

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Paolo, Di, Fulci, C., Rotili, D., Sciarretta, F., Lucidi, A., Morozzo Della Rocca, B., De Luca, A., Rosato, A., Quintieri, L., and Caccuri, A.M. Synthesis and characterisation of a new benzamide-containing nitrobenzoxadiazole as a GSTP1-1 inhibitor endowed with high stability to metabolic hydrolysis. 24977. 2019 J Enzyme Inhib Med Chem (34):1.

Concepts Keywords
Amide Glutathione
Analog GSTP1
Apoptosis Metabolism
Benzamide Antioxidants
Benzoyl Branches of biology
Cytotoxicity A375 melanoma
Ester Tumor
Ester Compound Apoptosis
Glutathione Drug Screening
Hydrolysis Drug metabolism
Inhibitor
Liver
Melanoma
Metabolic Stability
Microsomal
TRAF2
Transferase

Semantics

Type Source Name
drug DRUGBANK Glutathione
pathway KEGG Apoptosis
disease MESH melanoma
pathway KEGG Melanoma
disease MESH Tumor

Original Article

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