Design, synthesis and anticancer activity of 2-amidomethoxy-1,4-naphthoquinones and its conjugates with Biotin/polyamine.

In continuation with the previous work, a series of 5-hydroxy-2-amidomethoxy-1,4-naphthoquinones were prepared to establish the structure-activity relationship studies toward anticancer activity (IC50 in µM) against three cell lines; colo205 (colon adenocarcinoma), T47D (breast ductal carcinoma) and K562 (chronic myelogenous leukemia). Among the synthesized compounds, naphthoquinone amines, 5 (0.8; 0.6; 0.8), 14 (0.8; 0.6; 0.5) and the amine precursor, 4 (1.3; 0.3; 1.0) displayed potent anticancer activities. A tumor targeting drug delivery system was achieved by synthesizing the conjugate 6 (1.4; 0.5; 1.1) of naphthoquinone-amine 5 and Biotin which also proved its potency. Finally, to introduce polyamine conjugate, spermidine was attached with 2-amidomethoxy-1,4-naphthoquinone. The naphthoquinone-spermidine conjugate 27 (1.2; 1.7; 1.7) also retained the activity. Thus, potent naphthoquinone amines were explored and Biotin/polyamine conjugate was developed as tumor targeting drug delivery system.

Investigation of chemical reactivity of 2-alkoxy-1,4-naphthoquinones and their anticancer activity.

To establish the structure-activity relationship of 5-hydroxy-1,4-naphthoquinones toward anticancer activity, a series of its derivatives were prepared and tested for the activity (IC50 in µM) against three cell lines; colo205 (colon adenocarcinoma), T47D (breast ductal carcinoma) and K562 (chronic myelogenous leukemia). Among them 2 (IC50: 2.3; 2.0; 1.4 µM), 6 (IC50: 1.9; 2.2; 1.3 µM), 9 (IC50: 0.7; 1.7; 0.9 µM) and 10 (IC50:1.7; 1.0; 1.2 µM) showed moderate to excellent activity. Our perception toward the DNA substitution of alkoxy groups at the C2 position of these naphthoquinones for the anticancer activity led us to investigate their reactivity of substitution toward dimethylamine as a nucleophile. The ease of the substitution of alkoxy groups at the C2 position with dimethylamine is strongly accelerated by hydroxyl group at C5 position and is well correlated with the found anticancer activity results.