Hybrids of 1,4-Quinone with Quinoline Derivatives: Synthesis, Biological Activity, and Molecular Docking with DT-Diaphorase (NQO1)

Abstract

Hybrids 1,4-quinone with quinoline were obtained by connecting two active structures through an oxygen atom. This strategy allows to obtain new compounds with a high biological activity and suitable bioavailability. Newly synthesized compounds were characterized by various spectroscopic methods. The enzymatic assay used showed that these compounds were a suitable DT-diaphorase (NQO1) substrates as evidenced by increasing enzymatic conversion rates relative to that of streptonigrin. Hybrids were tested in vitro against a panel of human cell lines including melanoma, breast, and lung cancers. They showed also a high cytotoxic activity depending on the type of 1,4-quinone moiety and the applied tumor cell lines. It was found that cytotoxic activity of the studied hybrids was increasing against the cell lines with higher NQO1 protein level, such as breast (MCF-7 and T47D) and lung (A549) cancers. Selected hybrids were tested for the transcriptional activity of the gene encoding a proliferation marker (H3 histone), cell cycle regulators (p53 and p21) and the apoptosis pathway (BCL-2 and BAX). The molecular docking was used to examine the probable interaction between the hybrids and NQO1 protein.

Hybrids of 1,4-Naphthoquinone with Thymidine Derivatives: Synthesis, Anticancer Activity, and Molecular Docking Study

“…According to the literature, the 2,3-dichloro-1,4-naphthoquinone 1 is most often used as a substrate for synthesizing the 1,4-naphthoquinone derivatives [ 20 , 35 , 36 , 37 ]. The reaction between compound 1 and thymidine 4 or its derivatives 2 – 3 gives the monosubstituted derivatives 5 – 7 ( Scheme 1 ).…”

“…Modifying 1,4-naphthoquinone moiety at the C2 and C3 positions leads to obtaining a new compound with high biological activity. The pharmacokinetic research showed that the synthetic derivatives exhibit good solubility and bioavailability [ 18 , 19 , 20 , 21 , 22 ].…”

Lipophilicity and ADMET Analysis of Quinoline-1,4-quinone Hybrids

“…According to our previous research, the tested hybrids 1 – 24 induced the mitochondrial apoptotic pathway. Molecular mechanics studies showed that hybrids reduced the number of mRNA copies of gene encoding the BCL-2 protein [ 22 ]. These results inspired the study of interactions between the ligand and the BCL-2 protein using the AutoDock Vina program [ 35 ].…”

“…Synthesis and biological activity of the quinoline-1,4-quinone hybrids are described in the literature [ 22 ]. Their chemical structures are presented in Figure 2 .…”

“…The hybrids were highly active against a cancer cell line overexpressing the gene encoding the NQO1 protein. Investigation of the molecular mechanism of activity showed that the hybrids induced the mitochondrial apoptotic pathway by inhibiting the gene encoding the BCL-2 protein [ 22 ].…”