Abstract
In recent decades, many physiological and pharmacological functions of vitamin K other than its role as the cofactor of γ-glutamyl carboxylase (GGCX) have been identified, and consequently, many vitamin K derivatives and related congeners, including putative metabolites, have been designed and synthesized. Their biological activities include antitumor activity, anti-inflammatory activity, neuroprotective effects, neural differentiation-inducing activity, and modulating potency toward the nuclear steroid and xenobiotic receptor (SXR). These activities make vitamin K and its derivatives attractive candidates for drug discovery. In this chapter, an overview of recent advances in the medicinal chemistry of vitamin K, focusing especially on SXR modulation, neural differentiation, and antitumor activities, was provided.
Keywords
- metabolites
- synthetic analogs; neural differentiation
- nuclear receptor
- steroid and xenobiotic receptor
- antitumor
- phthalazine-1
- 4-dione
1. Introduction
Vitamin K is the term used to describe derivatives of naphthoquinones

Figure 1.
Structures of vitamin K homologs.
2. Structure–activity relationship of vitamin K analogs for transcriptional activity through nuclear receptor SXR
There are two kinds of natural vitamin K homologs, phylloquinone (PK) (
Following describes several vitamin K derivatives synthesized for structure–activity relationship studies of SXR agonists. Focusing on the double bonds and methyl groups in the side chain of MK-4, compounds

Figure 2.
Structure of vitamin K analogs
Since the isoprene structure of the side chain of menaquinones is important for the activity, vitamin K derivatives

Figure 3.
Vitamin K analogs 15–24.
Then, in order to investigate how the transcriptional activity changes depending on the polarity of the side chain, vitamin K analogs introduced hydrophilic or hydrophobic functional groups at the end of the side chain; namely, compounds
3. Neuronal differentiation-inducing activity of vitamin K and its analogs
MK-4 is present at relatively high concentrations in the brain, though its physiological role remains unclear. As one of the biological action in the brain, it has been reported that it protects neurons against oxidative stress [14, 24, 25, 26]. It is also known that neural stem cells differentiate into neuronal progenitors and glial progenitors, and then, neuronal progenitors differentiate into neurons, while glial progenitors differentiate into astrocytes and oligodendrocytes [27]. Recently, it has been found that menaquinones selectively induce the differentiation of neural progenitors into neurons, although their potency was not high [28]. This activity differed depending on the repeat structure of the isoprene side chain of the menaquinones. Therefore, if this activity can be increased by derivatization of vitamin K, it might be possible to regulate differentiation using safe and small molecule inducers of neural differentiation. Thus, new vitamin K derivatives that would induce differentiation of neural stem cells into neurons were explored.
Considering the lipophilic environment of the brain, vitamin K analogs bearing various hydrophobic functional groups such as benzene or naphthalene in the side chain were designed and synthesized (Figure 4). The compounds were evaluated for neuronal differentiation-inducing activity toward stem cells derived from mouse fetal cerebrum. After the compounds were added to the cells and the cells were cultured, the expression levels of Map2 and Gfap, which are expressed specifically in neurons and astrocytes, were quantified by real-time PCR. Interestingly, most synthesized compounds showed a significant increase in the induction of neuronal differentiation compared with the control. In particular, derivative

Figure 4.
Vitamin K analogs: (a) an aromatic substituent was introduced at the 𝜔-terminal side chain. (b) A
Then, compounds
Thus, the introduction of a hydrophobic functional group at the end of the side chain can enhance the differentiation-inducing activity of vitamin K from neural stem cells to neurons. It is known that natural products such as neuropathiazol, epolactaene, and retinoic acid (retinoid) induce neuronal differentiation. All of these compounds have double bonds or phenyl groups in their side chains, similar to the active vitamin K derivatives synthesized in this study [31, 32, 33]. Based on these findings, it might be possible to obtain compounds that have more potent neuronal differentiation activity. At present, the mechanism by which vitamin K derivatives induce neuronal differentiation is unknown. If the proteins upon which vitamin K acts were identified, this would be helpful for rational design of more potent compounds.
As described above, the biological activity of vitamin K is greatly affected by differences in the side chain structure. In addition to vitamin K, many other fat-soluble vitamins, such as vitamins A, D, and E, also have alkyl side chains containing double bonds. This may suggest that there is an optimal side chain structure for each target biological activity, because the specific action of each vitamin differs depending on the alkyl side chain structure. Further investigation of the structure–activity relationships of the side chains and the naphthoquinone part is needed (Figure 4).
4. Antitumor activity of vitamin K derivatives
4.1 Menadione-based Cdc25 inhibitors
Antitumor activity is one of the most interesting features of vitamin K and its derivatives. Among synthetic compounds, a series of menadione-based alkylthio naphthoquinone derivatives including 2-hydroxyethylthio-3-methyl-1,4-naphthoquinone (Cpd 5; compound 5, NSC 672121:
In addition to the aryl moiety, modification of the sulfide side chain was also investigated. Garbay and coworkers developed carboxylic acid derivatives such as compounds
Because 1,4-naphthoquinone structure as well as quinolinedione structure is considered a promising scaffold for Cdc25 inhibitors, several naphthoquinone-based Cdc25 inhibitors other than Cpd 5 derivatives have been also reported as candidate antitumor agents. Quinolinedione derivatives NSC663284 (

Figure 5.
Structures of Cpd 5 and related derivatives bearing an alkylthio moiety.

Figure 6.
Examples of naphthoquinone- and quinolinedione-based Cdc25 inhibitors.
4.2 Anti-hepatocellular carcinoma activity of menaquinone derivatives
The inhibitory effect of menaquinones on tumor progression and the molecular mechanism involved have been intensively investigated [7, 49], and there is continuing interest in the use of menaquinones for the chemoprevention of hepatocellular carcinoma (HCC) due to their safety. Though several clinical studies have suggested a preventive effect of menaquinone against HCC recurrence [50, 51], the efficacy of menaquinones in suppressing HCC was not confirmed in a large-scale clinical study [52]. Therefore, further study of the anti-HCC activity of menaquinones and derivatives is needed. In order to investigate the anti-HCC activity of menaquinones, we focused on carboxylated derivatives, which include isolated and putative metabolites of menaquinones. In the case of MK-4, one of the most interesting vitamin K homologs because of its multifunctional properties, ω-carboxyl homologs of MK-4 (MK-4-ω-COOH:
Although several synthetic methods for oxidized vitamin K derivatives including K acid I (

Figure 7.
Putative catabolic pathway of MK-4 based on the identified metabolites.

Figure 8.
Structure of acyclic retinoid (ACR).
Then, the proliferation-inhibitory activity of ω-carboxyl menaquinone derivatives
Fujii and coworkers have also developed a different type of candidate anti-HCC agents based on the structure of menaquinones. Specifically, a series of compounds with a phthalazine-1,4-dione core, instead of 1,4-naphthoquinone in the parent menaquinones, and a prenyl substituent corresponding in length to that of MK-1 to MK-4 (

Figure 9.
Structure of menaquinone-based phthalazine-1,4-dione derivatives
5. Conclusion
Vitamin K derivatives are attractive lead compounds for drug discovery. In this chapter, three topics in the medicinal chemistry of vitamin K, namely, SXR modulation, neural differentiation, and antitumor effect, were covered. Structure–activity relationship study of menaquinone-based SXR ligands has provided detailed information on the SXR-ligand recognition profile, contributing to the further development of novel SXR modulators. Neuronal differentiation-inducing compounds would be useful as chemical tools to probe signaling pathways that control neuronal specification, and also as candidate therapeutic agents for the treatment of neural diseases. The antitumor activity of vitamin K and its derivatives is also of great interest. Various studies have revealed that Cdc25 is an important target of the antitumor effect of naphthoquinone derivatives, including Cpd 5 and related compounds, and caspase- and transglutaminase-dependent pathways are also potential targets of vitamin K-based anti-HCC agents. Further investigation of the mechanism of the anti-proliferative effect of menaquinone derivatives might lead to agents for the chemoprevention of HCC.
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