2-Phenoxy-1,4-naphthoquinones: From a Multitarget Antitrypanosomal to a Potential Antitumor Profile

Abstract

A small library of 2-phenoxy-1,4-naphthoquinone and 2-phenoxy-1,4-anthraquinone derivatives was initially developed to optimize the antitrypanosomatid profile of the multitarget hit compound B6 (1). The whole series was evaluated against the three most important human trypanosomatid pathogens (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania donovani), and two compounds (14 and 21) showed good activity, despite a concomitant mammalian cytotoxicity. Furthermore, a subset also inhibited the glycolytic TbGAPDH enzyme in vitro. In light of these results and aware of the antitumor properties of quinones, the anticancer potential of some selected derivatives was investigated. Intriguingly, the tested compounds displayed antitumor activity, while being less toxic against noncancerous cells. The observed cytotoxic potency was ascribed to a multitarget mechanism of action accounting for hGAPDH inhibition and mitochondrial toxicity. Overall, the development of further derivatives, able to finely modulate multiple pathways of cancer or parasite cell metabolism, might lead to more effective treatments against these devastating diseases.

Discovery of Sustainable Drugs for Neglected Tropical Diseases: Cashew Nut Shell Liquid (CNSL)‐Based Hybrids Target Mitochondrial Function and ATP Production in Trypanosoma brucei

“…[f] Diminazene aceturate. [g] The EC 50 value of 4 is 9.84±3.25 against human dermal fibroblasts (HDF) …”

“…The synthesis of 8 – 22 was performed as illustrated in Scheme . We exploited a previously developed one‐pot reaction to combine phenols 5 – 7 and 2‐bromo‐1,4‐naphtoquinones 23 – 27 ,. Phenols 5 – 7 were first treated with K 2 CO 3 at room temperature in DMF, and then the proper 2‐bromo‐1,4‐naphtoquinone ( 23 – 27 ) was added, to rapidly (2–3 h) afford final compounds 8 – 22 .…”

“…Based on the reported activity of starting compound 4 , which displays an IC 50 of 7.25 μ m against GAPDH, we first tested inhibition of this enzyme by 8 – 22 , at a fixed concentration of 10 μ m , following a previously reported protocol . However, none of the compounds displayed significant inhibition of GAPDH activity (<15 % decrease observed, data not shown).…”

Targeting mitochondria in cancer therapy could provide a basis for the selective anti-cancer activity

“…The cytotoxic effects of quinones have been attributed to several mechanisms: (i) DNA damage mediated via inhibition of DNA topoisomerase-II [31]; (ii) production of ROS via NADH/NADPH dehydrogenase-mediated formation of semiquinone radical that can reduce oxygen to produce super oxide [16]; (iii) inhibition of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) [17], (iv) inhibition of GSR [8, 17, 32], (v) alkylation of cellular nucleophiles such as GSH, DNA, RNA and proteins, and (vi) inhibition of mitochondrial function [17, 21]. To elucidate the type of compound activity which is responsible for its cytotoxic effects in cancer cells and which is tolerated in normal cells, we performed various in vitro and cell-based activity assays (Table 4).…”

Sustainable Multi-Target Drugs for Neglected Tropical Diseases Caused by Trypanosomatids: Dream or Reality?

“…In this context, we have reported on the hit compound 2-phenoxy-1,4-naphthoquinone (B6), with a remarkable activity against Trypanosoma brucei rhodesiense in a phenotypic assay (IC50 = 80 nM) and a promising selectivity index [2]. Particularly, B6 showed a multitarget mechanism of action, including radical production and covalent inhibition of Trypanosoma brucei glyceraldehyde 3-phosphate dehydrogenase (TbGAPDH) enzyme [3].As a further step, we recently explored the possibility to discover new MTDLs based on inexpensive resources. Particularly, we were attracted by the opportunity of using food waste products as sustainable starting materials.…”