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Molecules 2018, 23(7), 1738; https://doi.org/10.3390/molecules23071738

Antitumor Effects and Delivery Profiles of Menahydroquinone-4 Prodrugs with Ionic or Nonionic Promoiety to Hepatocellular Carcinoma Cells

Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
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Academic Editor: William Robert Wilson
Received: 27 June 2018 / Revised: 14 July 2018 / Accepted: 15 July 2018 / Published: 16 July 2018
(This article belongs to the Special Issue Targeted Prodrugs 2018)
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Abstract

Hepatocellular carcinoma (HCC) shows poor prognosis owing to its very frequent recurrence even after curative treatment. Thus, an effective and safe long-term chemopreventive agent is strongly in demand. Menahydroquinone-4 (MKH) is an active form of menaquinone-4 (MK-4, vitamin K2) that is involved in the synthesis of vitamin K-dependent proteins in the liver. We hypothesized that efficient delivery of MKH might be critical to regulate HCC proliferation. The discovery of a suitable prodrug targeting HCC in terms of delivery and activation could reduce the clinical dose of MK-4 and maximize efficacy and safety. We previously showed that MKH dimethylglycinate (MKH-DMG) enables effective delivery of MKH into HCC cells and exhibits strong antitumor effects compared with MK-4. In this study, we prepared anionic MKH hemi-succinate (MKH-SUC) and non-ionic MKH acetate (MKH-ACT), in addition to cationic MKH-DMG, and evaluated MKH delivery profiles and antitumor effects in vitro. MKH-SUC showed the highest uptake and the most efficient release of MKH among the examined compounds and exhibited rapid and strong antitumor effects. These results indicate that MKH-SUC might have a good potential as an MKH delivery system for HCC that overcomes the limitations of MK-4 as a clinical chemopreventive agent. View Full-Text
Keywords: prodrug; menahydroquinone-4; menaquinone-4; drug delivery system; hepatocellular carcinoma prodrug; menahydroquinone-4; menaquinone-4; drug delivery system; hepatocellular carcinoma
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Setoguchi, S.; Watase, D.; Matsunaga, K.; Yamakawa, H.; Goto, S.; Terada, K.; Ohe, K.; Enjoji, M.; Karube, Y.; Takata, J. Antitumor Effects and Delivery Profiles of Menahydroquinone-4 Prodrugs with Ionic or Nonionic Promoiety to Hepatocellular Carcinoma Cells. Molecules 2018, 23, 1738.

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