Synthesis and evaluation of antitumor activity of 2- and 6-[(1,3-benzothiazol-2-yl)aminomethyl]-5,8-dimethoxy-1,4- naphthoquinone derivatives

2- or 6-Substituted BZT-N derivatives were synthesized, and their cytotoxic activity against cancer L1210 and SNU-1 cells was examined. The antitumor action was also assessed in mice bearing S-180 cells in peritoneal cavity. In a comparison, it was found that 6-substituted BZT-N derivatives exhibited higher potencies in both bioactivities than 2-substituted BZT-N derivatives against L1210 cells in in vitro and S-180 in vitro tests exception of compound 36. Interestingly, it was observed that 2-substituted compound 36, which has methyl group at R₁ position, exhibited a better antitumor activity than 6-substituted compounds against L1210 and SNU-1 in vitro. The ED₅₀ value of 2-substituted compound 36 against L1210 was found to be comparable to the ED₅₀ value of adriamycin and was even better against the solid cancer cell line SNU-1. It was also observed that 2-substituted compound 36 showed better antitumor activity in mice bearing S-180 cells in the peritoneal cavity. The T/C (%) value of 2-substituted compound 36 was similar to that of adriamycin. Quantitative structure-activity relationship (QSAR) tests reveal that the experimental ED50 values against SNU-1 closely correlate with both the calculated HOMO energies (E_HOMO) and the measured ¹H-NMR chemical shift of 3-H (δ_H). The results suggests that a compound having higher E_HOMO and δ_H values usually should have a lower ED₅₀ (SNU-1) value.