br Naphthoquinone scaffold a derivative

1,4-Naphthoquinone scaffold, a derivative of naphthalene bearing two carbonyl oxygen atoms, is the most stable and widely reported isoform of naphthoquinones. The pharmacological significance of 1,4-naphthoquinone nucleus is well established [6,7]. In particular, several natural and synthetic 1,4-naphthoquinone derivatives have been re-ported to be potential anticancer agents [7,8]. The most elucidated mechanism for naphthoquinone anticancer activity includes DNA to-poisomerase inhibition. Some synthesized compounds have been re-ported to exhibit cytotoxic activity via targeting Hsp90, STAT3 pathway and inhibition of proteasome. Moreover, naphthoquinones
impact involving ROS-related pathways such as PI3K-mTOR, Cdc25 phosphatase, NF-κB, EGFR, receptor tyrosine kinase (RTK), AMP-acti-vated protein kinase and mitogen-activated protein kinases (MAPK) [7,9]. ROS inducing effect and oxidant stress related pathways can prompt proteins, lipids, RNA and DNA damage or alter. Among com-pounds with naphthoquinone structure, quinone moiety is known to redox Actinomycin D as a precursor of ROS species which leads to oxidative stress, caused by the loss of the pro-oxidant/anti-oxidant equilibrium [10–12]. Structures of some natural and synthetic medicinal 1,4-naphthoquinone derivatives are depicted in Fig. 1.
1,2,3-Triazole based heterocycles are reported to possess various medicinal and biological potentials such as anticancer, antiviral, anti-microbial, herbicidal, anti-inflammatory cardiovascular and tyrosinase inhibitory activities [13–19]. Some unique properties like tendency to make hydrogen bonding, dipole-dipole and π stacking interactions of triazole compounds as well as their similarity to amide bonds in terms of distance and planarity [20,21], have improved the significance of 1,2,3-triazole scaffold in the field of medicinal chemistry as they in-tensively favor to bind with the biomolecular targets.
It has been reported in the literature that 1,4-naphthoquinone-
Corresponding author at: Department of Medicinal Chemistry, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran. E-mail addresses: [email protected], [email protected] (M. Khoshneviszadeh).
Fig. 1. Some natural and synthetic 1,4-naphthoquinone derivatives as anticancer agents.
triazole hybrids showed various biological activities, including anti-mycobacterial [22], anti-Trypanosoma cruzi [23], antileishmanial [24] and antimalarial [25].The first studies of 1,4-naphthoquinone-1,2,3-triazole hybrids considered to be anticancer agents was reported by Olivera Group. Among the tested derivatives, two compounds demon-strated good cytotoxic activities against K562 and HL-60 cells. It was stated that the cytotoxicity is mediated through apoptosis in HL-60 cells and cell cycle arrest in S-phase in K562 cell line [26,27]. da Silva Júnior Group screened several -lapachone, nor-a-lapachone and 1,4-naph-thoquinone containing 1,2,3-triazole moiety for their cytotoxic activ-ities against different cancer and normal cell lines. The obtained results indicated that some of them were considerably active with IC50 values below 2 μM [28,29]. Further studies to expand the trypanocidal and antitumor activities resulted in naphthoquinone-based 5-iodo-1,4-dis-ubstituted-,1,4- and 1,5-disubstituted-1,2,3-triazoles with improved cytotoxic activities against cancer cell lines. The most potent molecule showed IC50 in the range of 0.41–1.23 μM [30]. More recently, Mal-lavadhani and his co-workers investigated novel series of menadione linked to 1,2,3-triazole ring with promising cytotoxic activities against A-549, DU-145, Hela and MCF-7 cell lines. In particular, one of the most potent compounds showed greater potency than menadione as a parent molecule, and standard Tamoxifen against MCF-7 cell line [31]. A summary of aforementioned points on anticancer naphthoquinone-triazole hybrids is depicted in Scheme 1.