1,4-Naphthoquinones are widely distributed in nature and many clinically important antitumor drugs containing a quinone moiety, such as anthracyclines, mitoxantrones and saintopin, show excellent anticancer activity. In this study, 2- or 6-substituted 5,8-dimethoxy-1,4-naphthoquinone (DMNQ) and 5,8-dihydroxy-1,4-naphthoquinone (DHNQ) derivatives were synthesized, and their cytotoxic activity against L1210 and P388 cancer cells was examined. Their antitumor activity was also assessed in mice bearing S-180 cells in the peritoneal cavity. In comparison with the DMNQ derivatives, the DHNQ derivatives exhibited more potent bioactivities than the DMNQ derivatives against both L1210 and P388 cells in vitro and S-180 cells in vivo. The ED50 values of the DHNQ derivatives against P388 cells were in the range of 0.18-1.81 microg/mL whereas those of the DMNQ derivatives were in the range of 0.26-40.41 microg/mL. The T/C (%) values of the DHNQ derivatives, 8, 17, 18, 19, and 20, were found to be comparable to or even better than that of adriamycin. It was also observed that the 2-substituted derivatives (8, 19, 20) showed better antitumor activity than the 6-substituted derivatives (7, 17, 18) in the mice bearing S-180 cells in the peritoneal cavity.

UV absorption spectroscopy and fluorescence spectroscopy were used in this study as the main tools to characterize the acylation reactions of 1,5-naphthylenediamine (NDA) with either n-propionic acid or benzoyl chloride to simulate polymerization for polyamides. IR spectroscopy was used to provide independent qualitative support for the acylation reactions. During acylation reactions, UV absorption spectra show blue shifts, while fluorescence emission spectra exhibit an initial red shift with a progressive reduction in intensity. With the use of the spectral parameters of NDA and two acylation products (monoamide and diamide), the kinetics of the acylation, which proceed in two stages, were analyzed. The rate constant of the conversion of NDA to monoamide is found to be faster (3-7 times) than that corresponding to the conversion of monoamide to diamide. This trend is confirmed by both UV absorption spectra and fluorescence spectra. The activation energies for the first-and second-stage reactions are about 20 kcal/mol, respectively. The reaction of NDA with benzoyl chloride is found to produce the same spectral results as the reaction with n-propionic acid. A calibration curve was established to correlate the extent of the acylation with the fluorescence intensity.

A series of nine new compounds bridged by acyl groups at the 5,8-dihydroxyl group of DHNQ were synthesized and their cytotoxic activity against L1210 and P388 cancer cells was examined. Their antitumor action in mice bearing S-180 cells in the peritoneal cavity was also assessed. Increasing the size of the acyl group (compounds 7-9) up to propyl increased the antitumor activity (T/C value), whereas the cytotoxicity of these compounds was comparable against L1210 (lymphocytic leukemia) and P388 (lymphoid neoplasm) cancer cells. Further increasing in the chain length (compounds 11-15) decreased the potency. Thus, acyl group chains of three carbon atoms is optimal for antitumor activity. The most potent compound of this series was 2-[N-methyl-N-(4-methyl-1,3-benzothiazol-2-yl)aminomethyl]-5,8-dipropylcarbonyloxy-1,4-naphthoquinone (compound 9) with a T/C (%) value of 354.

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