Growth inhibitory effects of 3′-nitro-3-phenylamino nor-beta-lapachone against HL-60: A redox-dependent mechanism

Abstract

In this study, the cytotoxicity, genotoxicity and early ROS generation of 2,2-dimethyl-(3H)-3-(N-3'-nitrophenylamino)naphtho[1,2-b]furan-4,5-dione (QPhNO(2)) were investigated and compared with those of its precursor, nor-beta-lapachone (nor-beta), with the main goal of proposing a mechanism of antitumor action. The results were correlated with those obtained from electrochemical experiments held in protic (acetate buffer pH 4.5) and aprotic (DMF/TBABF(4)) media in the presence and absence of oxygen and with those from dsDNA biosensors and ssDNA in solution, which provided evidence of a positive interaction with DNA in the case of QPhNO(2). QPhNO(2) caused DNA fragmentation and mitochondrial depolarization and induced apoptosis/necrosis in HL-60 cells. Pre-treatment with N-acetyl-l-cysteine partially abolished the observed effects related to the QPhNO(2) treatment, including those involving apoptosis induction, indicating a partially redox-dependent mechanism. These findings point to the potential use of the combination of pharmacology and electrochemistry in medicinal chemistry.

Effects of a novel β–lapachone derivative on Trypanosoma cruzi : Parasite death involving apoptosis, autophagy and necrosis

“…This process may be caused by β-lapachone-mediated ROS production as oxidative stress was shown to trigger mitochondrial fission and mitophagy (Frank et al., 2012). Furthermore, Mitochondrial oxidative stress is involved in astrocyte necrotic cell death (Jacobson and Duchen, 2002) and a β-lapachone derivative was reported to produce apoptosis and necrosis simultaneously in HL-60 cells (Araújo et al., 2012). In addition, the secondary necrosis may comprise the natural outcome of apoptosis (Silva, 2010) and necrosis subsequently takes place following apoptosis in HeLa cells (Xie et al., 2013), epithelial cells incubated with Candida albicans (Villar and Zhao, 2010) and in the Cnidarian Hydractinia symbiolongicarpus (Buss et al., 2012) in a process that may be termed “secondary necrosis” (Silva et al., 2008).…”

“…Hence, mitophagy and mitochondrial loss of function may lead to metabolic deficit, possibly promoting parasite necrosis. β-lapachone and its derivatives were shown to trigger apoptosis and autophagy in both parasites (Docampo et al., 1978, Menna-Barreto et al., 2009a, Salomão et al., 2013) and tumor cells (Li et al., 1999, Li et al, 2003; Park et al., 2011, Di Rosso et al., 2013), involving the formation of ROS (Araújo et al., 2012, Salomão et al., 2013). …”

Electrochemical Properties of Substituted 2‐Methyl‐1,4‐Naphthoquinones: Redox Behavior Predictions

“…The current intensities of the second reduction step were found to be weaker with respect to that leading to the radical anion intermediate 1,4-NQC À (the Supporting Information, Table S4). This electrochemical behavior might result from either comproportionation reactions (E 1 1/2 ÀE 2 1/2 % 0.62-0.73 V and ln K Comp are ranging from 24 to 29) [76][77][78][79] or by fast and irreversible dimerization process [80] between the quinone dianion (1,4-NQ 2À ) and the naphthoquinone (1,4-NQ) to afford an electro-inactive dimeric species [84] 1,4-NQ 2…”

Redox Polypharmacology as an Emerging Strategy to Combat Malarial Parasites

“…The current intensities (Table S3) of the second reduction step ( i pc2 ) leading to 1,4‐NQ 2− were systematically found to be weaker with respect to the reduction step ( i pc1 ) leading to the monoradical anion 1,4‐NQ ⋅− . This electrochemical behavior may result from comproportionation reactions ( E 1 1/2 ‐ E 2 1/2 ∼0.65–0.74 V and ln K comp ranging from ∼23 to 26) and/or by fast and irreversible dimerization between 1,4‐NQ 2− and 1,4‐NQ to afford the electro‐inactive dimer (1,4‐NQ) 2 2− .…”