Hybrid Molecules Containing Naphthoquinone and Quinolinedione Scaffolds as Antineoplastic Agents

Abstract

In recent decades, molecular hybridization has proven to be an efficient tool for obtaining new synthetic molecules to treat different diseases. Based on the core idea of covalently combining at least two pharmacophore fragments present in different drugs and/or bioactive molecules, the new hybrids have shown advantages when compared with the compounds of origin. Hybridization could be successfully applied to anticancer drug discovery, where efforts are underway to develop novel therapeutics which are safer and more effective than those currently in use. Molecules presenting naphthoquinone moieties are involved in redox processes and in other molecular mechanisms affecting cancer cells. Naphthoquinones have been shown to inhibit cancer cell growth and are considered privileged structures and useful templates in the design of hybrids. The present work aims at summarizing the current knowledge on antitumor hybrids built using 1,4- and 1,2-naphthoquinone (present in natural compounds as lawsone, napabucasin, plumbagin, lapachol, α-lapachone, and β -lapachone), and the related quinolone- and isoquinolinedione scaffolds reported in the literature up to 2021. In detail, the design and synthetic approaches adopted to produce the reported compounds are highlighted, the structural fragments considered in hybridization and their biological activities are described, and the structure–activity relationships and the computational analyses applied are underlined.

Synthesis of thia-Michael-Type Adducts between Naphthoquinones and N-Acetyl-L-Cysteine and Their Biological Activity

“…For example, they can find application in natural and synthetic dyes [ 4 , 5 ], and biopesticides and bioherbicides [ 6 , 7 ] and play important roles in many biochemical processes, being involved in cellular respiration [ 8 , 9 ], photosynthesis [ 10 ], and cellular defense [ 11 , 12 ]. In the pharmaceutical field, they are used as trypanocidal, anti-inflammatory [ 13 ], antithrombotic [ 14 , 15 ], antiviral [ 16 ], antifungal [ 17 ], and antitumor agents [ 18 ], but their clinical use as antineoplastic drugs [ 19 ] has been limited for a long time by their toxicity.…”

In Silico and In Vitro Study of Janus Kinases Inhibitors from Naphthoquinones

“…For example, the results of experiments and 3D-QSAR study suggest that naphtho [2,3-b]thiophene-4,9-dione analogs are promising in the development of new anti-colorectal cancer agents [ 20 ]. In vitro assays proved that the hybrid molecule of three component reaction of 2-hydroxy-1,4-naphthoquinone (lawsone), 4-hydroxycoumarin, and 3,4-dimethoxybenzaldehyde under solvent-free conditions could inhibit chronic myelogenous leukemia cell proliferation with the IC 50 value in a micromolar range [ 21 ].…”

Anticancer Properties of 3-Dietoxyphosphorylfuroquinoline-4,9-dione

“…Heterocyclic compounds play an important role in the development of anticancer agents [ 1 ] because the ability of heteroatoms to participate in hydrogen bonding with the target protein can improve the selectivity and potency of the molecules [ 2 ]. The scaffold of quinolinediones is often found in nature and used for the development of new, biologically active substances.…”