Antitumor and antiviral activities of 4-substituted 1,2,3-triazolyl-2,3-dibenzyl-L-ascorbic acid derivatives

Abstract

Two series of 6-(1,2,3-triazolyl)-2,3-dibenzyl-l-ascorbic acid derivatives with the hydroxyethylene (8a-8u) and ethylidene linkers (10c-10p) were synthesized and evaluated for their antiproliferative activity against seven malignant tumor cell lines and antiviral activity against a broad range of viruses. Conformationally unrestricted spacer between the lactone and 1,2,3-triazole units in 8a-8u series had a profound effect on antitumor activity. Besides, the introduction of a long side chain at C-4 of 1,2,3-triazole that led to the synthesis of decyl-substituted 2,3-dibenzyl-l-ascorbic acid 8m accounted for a selective and potent antiproliferative activity on breast cancer MCF-7 cells cells in the nM range. Further analysis showed that compound 8m strongly enhanced expression of hypoxia inducible transcription factor 1 α (HIF-1α) and to some extent decreased expression of nitric oxide synthase 2 (NOS2) suggesting its role in regulating HIF-1α signalling pathway. The p-methoxyphenyl-substituted derivative 10g displayed specific anti-cytomegalovirus (CMV) potential, whereas aliphatic-substituted derivatives 8l and 8m had the most potent, yet relatively non-specific, anti-varicella-zoster (VZV) activity.

Keywords: 1,2,3-Triazole; Antitumoral; Antiviral activity; Butenolide; HIF-1; NOS2; Vitamin C.

Graphical abstract

Fig. 1

Purine and pyrimidine derivatives of l-ascorbic acid with antiproliferative and antiviral activities and 4-substituted 1,2,3-triazolyl-2,3-dibenzyl-l-ascorbic acid derivatives (8a−8u and 10c−10p).

Scheme 1

Reagents and conditions: i) acetyl chloride, acetone; ii) benzyl chloride, potassium carbonate (K₂CO)₃; iii) acetic acid, methanol; iv) tosyl chloride, pyridine, dichloromethane (CH₂Cl₂); v) sodium azide (NaN₃), dimethylformamide (DMF), water; vi) Cu, 1 M copper (II) sulphate (CuSO₄), tert-butanol, DMF, water, microwave reactor; vii) NaN₃, Cu, 1 M CuSO₄, DMF, water, microwave reactor; viii) NaN₃, acetonitrile; ix) copper (II) acetate (Cu(OAc)₂), methanol.

Fig. 2

Groupings of 35 synthesized compounds from 8a−8u and 10c−10p series according to their structural similarity (more blue/red-more similar/dissimilar compounds). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

PCA biplot visualization of synthesized compounds according to experimental IC₅₀ values (Table 1, Table 2). Coluoring denotes aromatic (red)/nonaromatic (blue) character of the R substituent (Scheme 1). More active compounds are grouped towards the left side of the plot. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 4

Insights into the structure–activity relationship of 4-substituted 1,2,3-triazolyl appended 2,3-dibenzyl-l-ascorbic acid derivatives (8a−8u and 10c−10p).

Fig. 5

Representative Western blots of predicted protein targets for compound 8m. Cellular levels of selected proteins before and after treatment of MCF-7 cells with compound 8m at IC₅₀ of 0.08 μM value for 24 and 48 h are presented. Approximate molecular weights (kDa) of primary antibodies are indicated. Relative protein expressions were determined by densitometric analysis of protein lines on the blots and normalized to the alpha-tubulin loading control. Data are presented as mean values ± SD. Statistically significant (p < 0.5) differences in the expression levels are marked with an asterisk; C = control cells.