Derivatives of (11E)-10-oxo-11-octadecen-13-olide (1) and its seco-acid 2 were synthesized from linoleic acid for purpose of elucidation of their cytotoxic activity. Linoleic acid was converted to (13S, 9Z, 11E)-13-hydroxy-9,11-dienoic acid (4) by soybean lipoxygenase-catalyzed oxidation followed by treatment with NaBH_4. The hydroxy acid 4 was cyclized by the Yamaguchi method and by the Mitsunobu method, to give 14-membered lactones S-5 and R-5, respectively, which reacted with oxygen and triethylsilane in the presence of Co(tdcpp) as a catalyst followed by acetylation-decomposition of the intermediary hydroperoxide to produce S-1 and R-1. Lipase-catalyzed hydrolysis of R-1 gave hydroxyketo acid R-2. The reduction-oxygenation of dienoic ester 7, prepared from 4 by treating with diazomethane and then t-butyldimethylsilyl chloride, afforded oxo derivative 8, which was deprotected to give hydroxyketo acid S-2. The other derivatives related to 1 and 2 were also synthesized by the similar manner described above. On the other hand, (E)-4-hydroxy-2-nonenal (HNE) and (E)-4-hydroxy-2-hexenal (HHE), cytotoxic aldehydes produced during lipid peroxidation in biological system, were synthesized in one step from commercially available 2,4-alkadienals by the Co(tdcpp)-catalyzed reduction-oxygenation. The deuterium-labeled HNE and HHE were prepared by use of triethyldeuterosilane and 2-propan(old) instead of triethylsilane and 2-propanol on the reduction-oxygenation of 2,4-alkadienals. The IC_<50> values of the fatty acid derivatives were determined against P388 mouse leukemia cells. The macrolide 1 showed the strongest cytotoxicity among the derivatives, however, no difference in the cytotoxicity was found between the optically active and racemic forms of 1. The cytotoxicity of the macrolides was enhanced, respectively, in comparison with that of the corresponding seco-acids. The enone moiety of 1 and 2 is assumed to be important for enhancing the cytotoxic action.
