6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio) hexanol: a promising new anticancer compound

Abstract

The 7-nitro-2,1,3-nitrobenzoxadiazole (NBD) derivatives are a series of compounds containing the NBD scaffold that are not glutathione (GSH) peptidomimetics, and result in a strong inhibition of glutathione S-transferases (GSTs). Growing evidences highlight their pivotal roles and outstanding anticancer activity in different tumor models. In particular, 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio) hexanol (NBDHEX) is extensively studied, which is a very efficient inhibitor of GSTP1-1. It triggers apoptosis in several tumor cell lines and this cytotoxic activity is observed at micro and submicromolar concentrations. Importantly, studies have shown that NBDHEX acts as an anticancer drug by inhibiting GSTs catalytic activity, avoiding inconvenience of the inhibitor extrusion from the cell by specific pumps and disrupting the interaction between the GSTP1-1 and key signaling effectors. Additionally, some researchers also have discovered that NBDHEX can act as late-phase autophagy inhibitor, which opens new opportunities to fully exploit its therapeutic potential. In this review, we summarize the advantages, anticancer mechanisms, and analogs of this compound, which will establish the basis on the usage of NBDHEX in clinical applications in future.

Keywords: GSTP1-1 (Glutathione S-transferase Pi); JNK (c-Jun N-Terminal Kinase); NBDHEX (6- (7-nitro-2,1,3-benzoxadiazol-4-ylthio) hexanol); anticancer.

Figure 1. Structures of NBDHEX and its analogs

Figure 2. Proposed action mechanism of NBDHEX

NBDHEX causes the dissociation of both the GSTP1-1–TRAF2 and the GSTP1-1–JNK complexes and triggers the activation of the MAPK signaling pathway. It induces apoptosis and cell cycle arrest via the phospho-activation of JNK and p38 and their downstream targets including c-Jun, ATF2, and p53. Besides, JNK can participate in impairing autophagy. In addition, the possibility that NBDHEX directly activates p38 through the imbalance of the intracellular redox state cannot be excluded, in which case, cells died by necrosis.