Antileukemic Properties and Structure-Activity Relationships of O- and SGlycosylated Derivatives of Juglone and Related 1,4-Naphthoquinones

Abstract

Glycosylated derivatives of physiologically active natural compound juglone and related 1,4-naphthoquinones are known as antifungal, immunomodulatory, and antitumor substances. However, their antileukemic properties and structure-activity relationships have been studied insufficiently. Antileukemic effects and structure-activity relationships (SAR) of the 50 1,4-naphthoquinone derivatives were examined using HL-60 human promyelocytic leukemia cells and MTS method of the study of cell viability. As was shown, the substances inhibited viability of HL-60 cells at the wide range of concentrations. SAR study revealed the structure peculiarities which lead to increase or decrease of the antileukemic activity of the compounds studied. In conclusion, O-or S-glycosylated derivatives of juglone and related 1,4-naphthoquinones have potential for development of the new antileukemic agents and should be further investigated.

Four‐dimensional quantitative structure‐activity analysis of 1,4‐naphthoquinone derivatives tested against HL‐60 human promyelocytic leukemia cells

“…Descriptor C13838 is reflecting the findings from SAR study and 2D‐QSAR model, regarding the positions 4 and 5 (R 3 ) of the 1,4‐naphthoquinone derivatives. Positive Coulomb descriptors, C8675, C19101, and C15944, as well as the negative ones (C6625, C10703, and C10730) are indicating the position and type of substituents in R 1 and R 2 that are favorable to the activity.…”

“…These charges are apparently related to the reduction/oxidation mechanisms of quinones that occur in cytochrome P450 enzymes, since carbon 1 is bound to one of the quinone oxygens involved in the production of superoxide radical anions (O 2 − · ) . In turn, the carbon 10 is located between the carbons 4 and 5, where carbon 4 is bound to a quinone oxygen and carbon 5 is bound to the hydroxyl group, whose importance to activity was already pointed out by Fedorov et al and by Zhao et al According to Zhao et al, important water molecules may be catalytically stabilized by the hydroxyl group at carbon 5. These water molecules participate in the proton transfer process at cytochrome P450 enzymes.…”

“…The effect of the glycosides on cell viability was determined by screening the compounds against HL‐60 human promyelocytic leukemia cells using MTS (5‐(3‐carboxymethoxyphenyl)‐2‐(4,5‐dimethylthiazolyl)‐3‐(4‐sulfophenyl) tetrazolium, inner sault) reduction into its formazan product, to obtain the inhibitory potency, IC 50 . They also performed a structure‐activity relationship (SAR) study for this series of compounds, which suggested that the juglone derivatives were among the most active compounds, emphasizing the importance of hydroxyl group at position 5 (basic structure in Table ) for the biological activity . More recently, using a subset of these derivatives, Costa and Ferreira conducted a two‐dimensional quantitative structure‐activity relationship (2D‐QSAR) analysis.…”

“…They also performed a structure-activity relationship (SAR) study for this series of compounds, which suggested that the juglone derivatives were among the most active compounds, emphasizing the importance of hydroxyl group at position 5 (basic structure in Table 1) for the biological activity. 11 More recently, using a subset of these derivatives, Costa and Ferreira 12 conducted a two-dimensional quantitative structure-activity relationship (2D-QSAR) analysis. From the 2D-QSAR model, 12 the biological activity increases when the charge over carbon 1 (C1) increases and total dipole moment and charge over carbon 10 (C10) diminish (Table 1).…”

Microbial transformation of β-lapachone to its glycosides by Cunninghamella elegans ATCC 10028b

“…Regarding naphthoquinone glycosylation, there are few reports on structure-activity relationships (SAR) and only one in which the study of antileukemic effects and SAR were performed. The evaluation of O-or S-glycosylated derivatives of juglone concluded that these compounds have potential for new antileukemic agents development (Fedorov et al, 2011).…”