Development of new anti-cancer drugs constructed with unsaturated alkyl chain

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Our research aim is development of candidates for new anti-cancer drugs based on unsaturated alkyl chain. In this study, we synthesized six kinds of “predictable" vitamin K metabolites. They were introduced vitamin K_2 (menaquinone-2, 3, and 4) molecule to ω-hydroxyl or ω-aldehyde group instead of ω-carboxylic acid becauw the metabolites including ω-carboxylic acid were unstable and unable to use for assay. The requisite analogues were synthesized by coupling the naphthoquinone derivative and side-chain moiety. For the synthesis of side-chain part, we chose geraniol, farnesol and geranylgeraniol as the starting material. While the naphthoquinone part was prepared from 1, 4-diacetoxy-2-methylnaphthoquimne. After coupling reaction, deprotection of protective group gave ω-hydroxyl derivative, and additional oxidative reaction yielded ω-aldehyde derivative. We focused on the apoptosis-inducing activity against HL-60 cells (human leukemia cells). Samples of 5 and 10 μM analogues were succes … More sively added to HL-60 cells. The apoptosis activity was determined with a flow cytemetry. The activity of most analogues increased in a dose-dependent manner. Menaquinone (MK)-3 particularly showed the most potent activity around 75% among vitamin K_2 homologues at 10 μM. On the other hand, the potency of MK-4 was approximately 15%, which equaled 20% of MK-3 at the same dose; however, MK-2 and ω-aldehyde analogues did not exhibit such activity. In terms of ω-oxygenated analogues, ω-oxygenated MK-3 decreased the potency compared to MK-3; however it still preserved about 50% potency of MK-3. Interestingly, only ω-oxygenated MK-4 increased the activity more than substrate MK-4 at 10 μM. Thus, the apoptosis-inducing activity of our analogues as well as natural vitamin K homologues exhibited cell selectivity against cancer cells. Our results indicated that metabolites of vitamin K might have potential as biologically active compounds and can provide useful information to develop new drugs based on vitamin K with modification of terminal alkyl group. Less