Medicinal Chemistry of Vitamin K Derivatives and Metabolites

Vitamin K acts as a cofactor for γ‐glutamyl carboxylase. Recently, various biological activities of vitamin K have been reported. Anti‐proliferative activities of vitamin K, especially in vitamin K3, are well known. In addition, various physiological and pharmacological functions of vitamin K2, such as transcription modulators as nuclear steroid and xenobiotic receptor (SXR) ligands and anti‐inflammatory effects, have been revealed in the past decade. Characterization of vitamin K metabolites is also important for clinical application of vitamin K and its derivatives. In this chapter, recent progress on the medicinal chemistry of vitamin K derivatives and metabolites is discussed

Recent Advances in the Medicinal Chemistry of Vitamin K Derivatives: An Overview (2000–2021)

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

An N-cyanoamide derivative of lithocholic acid co-operates with lysophosphatidic acid to promote human osteoblast (MG63) differentiation

Less-calcaemic vitamin D receptor (VDR) agonists have the potential to promote osteoblast maturation in a bone regenerative setting. The emergence of lithocholic acid (LCA) as a bona fide VDR agonist holds promise as an adjunct for arthroplasty following reports that it was less calcaemic than calcitriol (1,25D). However, LCA and some earlier derivatives, e.g., LCA acetate, had to be used at much higher concentrations than 1,25D to elicit comparable effects on osteoblasts. However, recent developments have led to the generation of far more potent LCA derivatives that even outperform the efficacy of 1,25D. These new compounds include the cyanoamide derivative, Dcha-150 (also known as AY2-79). In light of this significant development, we sought to ascertain the ability of Dcha-150 to promote human osteoblast maturation by monitoring alkaline phosphatase (ALP) and osteocalcin (OC) expression. The treatment of MG63 cells with Dcha-150 led to the production of OC. When Dcha-150 was co-administered with lysophosphatidic acid (LPA) or an LPA analogue, a synergistic increase in ALP activity occurred, with Dcha-150 showing greater potency compared to 1,25D. We also provide evidence that this synergy is likely attributed to the actions of myocardin-related transcription factor (MRTF)–serum response factor (SRF) gene transcription following LPA-receptor-induced cytoskeletal reorganisation

The ATRA-dependent overexpression of the glutamate transporter EAAC1 requires RARβ induction

AbstractThe mechanisms underlying trafficking and membrane targeting of EAAC1, the rodent counterpart of the human EAAT3 carrier for anionic amino acids, are well characterized. In contrast, much less is known on the regulation of Slc1a1, the gene that encodes for the transporter. We have recently found that all-trans retinoic acid (ATRA) stimulates EAAC1 expression and anionic amino acid transport in C6 rat glioma cells. We report here that the ATRA effect on EAAC1 activity was inhibited by the specific RAR antagonist LE540 and mimicked by Am80, a RAR agonist, but not by the RXR agonist HX630. Moreover, the ATRA-dependent induction of Slc1a1 mRNA required the synthesis of a protein intermediate and was not associated with changes in the messenger half-life. ATRA treatment induced the expression of both Rarb mRNA and RARβ protein several hours before the induction of Slc1a1, while the mRNA for RFX1, a transcription factor recently involved in Slc1a1 transcription, was unchanged. In addition, Rarb silencing markedly inhibited the ATRA-dependent increase of both Rarb and Slc1a1 mRNAs. We conclude that in C6 glioma cells the induction of Slc1a1 by ATRA requires the synthesis of RARβ, suggesting that the receptor is involved in the regulation of the transporter gene

Modulating biocatalytic activity towards sterically bulky substrates in CO2-expanded bio-based liquids by tuning physicochemical properties

The study of CO2-expanded liquids using a green component such as a bio-based solvent has been recently raised as a new concept for an alternative solvent, and yet been largely unexplored in literature for neither fundamental nor application studies. On the other hand, structural bulkiness of substrates remains one of the main limitations to promote enzymes as an efficient versatile catalytic tool for organic synthesis, especially biocatalysis in non-conventional solvents. Herein, we report a detailed investigation of CO2-expanded bio-based liquids as reaction media for improved biocatalysis of sterically hindered compounds. We have found that CO2 acts as a crucial trigger for various lipases to catalyse transesterification of challenging bulky alcohols in CO2-expanded 2-methyltetrahydrofuran (MeTHF). Furthermore, this study determines physicochemical and transport properties of CO2-expanded MeTHF for the first time, which were then utilized for modulating biocatalytic activity. It was found that lipase activity increased with the accordingly decrease of the dipolarity of CO2-expanded MeTHF, which is tunable by altering the concentration of CO2 in the solvent system

Retinoid X receptor α attenuates host antiviral response by suppressing type I interferon.

The retinoid X receptor α (RXRα), a key nuclear receptor in metabolic processes, is downregulated during host antiviral response. However, the roles of RXRα in host antiviral response are unknown. Here we show that RXRα overexpression or ligand activation increases host susceptibility to viral infections in vitro and in vivo, while Rxra-/- or antagonist treatment reduces infection by the same viruses. Consistent with these functional studies, ligand activation of RXR inhibits the expression of antiviral genes including type I interferon (IFN) and Rxra-/- macrophages produce more IFNβ than WT macrophages in response to polyI:C stimulation. Further results indicate that ligand activation of RXR suppresses the nuclear translocation of β-catenin, a co-activator of IFNβ enhanceosome. Thus, our studies have uncovered a novel RXR-dependent innate immune regulatory pathway, suggesting that the downregulation of RXR expression or RXR antagonist treatment benefits host antiviral response, whereas RXR agonist treatment may increase the risk of viral infections.We thank David Sanchez for his editorial advice and Harvey Roy Herschman for his helpful discussions. This work was funded by NIH RO1 AI078389, AI056154, AI47868, and AI069120 grants, the Tumor Immunology Training Grant (5T32CA009120), the grant from the Spanish Ministry of Economy and Competitiveness (SAF2012-31483) and the Medical Scientist Training Program.S

Neuritogenic activity of a genipin derivative in retinal ganglion cells is mediated by retinoic acid receptor β expression through nitric oxide/S-nitrosylation signaling

Genipin, a herbal iridoid, is known to have both neuroprotective and neuritogenic activity in neuronal cell lines. As it is structurally similar to tetrahydrobiopterin, its activity is believed to be nitric oxide (NO)-dependent. We previously proposed a novel neuroprotective activity of a genipin derivative, (1R)-isoPropyloxygenipin (IPRG001), whereby it reduces oxidative stress in RGC-5, a neuronal precursor cell line of retinal origin through protein S-nitrosylation. In the present study, we investigated another neuritogenic property of IPRG001 in RGC-5 cells and retinal explant culture where in we focused on the NO-cGMP-dependent and protein S-nitrosylation pathways. IPRG001 stimulated neurite outgrowth in RGC-5 cells and retinal explant culture through NO-dependent signaling, but not NO-dependent cGMP signaling. Neurite outgrowth with IPRG001 requires retinoic acid receptor β (RARβ) expression, which is suppressed by an RAR blocking agent and siRNA inhibition. Thereby, we hypothesized that RARβ expression is mediated by protein S-nitrosylation. S-nitrosylation of histone deacetylase 2 is a key mechanism in chromatin remodeling leading to transcriptional gene activation. We found a parallelism between S-nitrosylation of histone diacetylase 2 and the induction of RARβ expression with IPRG001 treatment. The both neuroprotective and neuritogenic activities of genipin could be a new target for the regeneration of retinal ganglion cells after glaucomatous conditions. © 2011 International Society for Neurochemistry

The Retinoic Acid Receptor Agonist Am80 Increases Mucosal Inflammation in an IL-6 Dependent Manner During Trichuris muris Infection

PURPOSE: Vitamin A metabolites, such as all-trans-retinoic acid (RA) that act through the nuclear receptor; retinoic acid receptor (RAR), have been shown to polarise T cells towards Th2, and to be important in resistance to helminth infections. Co-incidentally, people harbouring intestinal parasites are often supplemented with vitamin A, as both vitamin A deficiency and parasite infections often occur in the same regions of the globe. However, the impact of vitamin A supplementation on gut inflammation caused by intestinal parasites is not yet completely understood. METHODS: Here, we use Trichuris muris, a helminth parasite that buries into the large intestine of mice causing mucosal inflammation, as a model of both human Trichuriasis and IBD, treat with an RARα/β agonist (Am80) and quantify the ensuing pathological changes in the gut. RESULTS: Critically, we show, for the first time, that rather than playing an anti-inflammatory role, Am80 actually exacerbates helminth-driven inflammation, demonstrated by an increased colonic crypt length and a significant CD4(+) T cell infiltrate. Further, we established that the Am80-driven crypt hyperplasia and CD4(+) T cell infiltrate were dependent on IL-6, as both were absent in Am80-treated IL-6 knock-out mice. CONCLUSIONS: This study presents novel data showing a pro-inflammatory role of RAR ligands in T. muris infection, and implies an undesirable effect for the administration of vitamin A during chronic helminth infection. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10875-013-9936-8) contains supplementary material, which is available to authorized users

Retinoid X receptor gamma signaling accelerates CNS remyelination

The molecular basis of CNS myelin regeneration (remyelination) is poorly understood. We generated a comprehensive transcriptional profile of the separate stages of spontaneous remyelination that follow focal demyelination in the rat CNS and found that transcripts that encode the retinoid acid receptor RXR-γ were differentially expressed during remyelination. Cells of the oligodendrocyte lineage expressed RXR-γ in rat tissues that were undergoing remyelination and in active and remyelinated multiple sclerosis lesions. Knockdown of RXR-γ by RNA interference or RXR-specific antagonists severely inhibited oligodendrocyte differentiation in culture. In mice that lacked RXR-γ, adult oligodendrocyte precursor cells efficiently repopulated lesions after demyelination, but showed delayed differentiation into mature oligodendrocytes. Administration of the RXR agonist 9-cis-retinoic acid to demyelinated cerebellar slice cultures and to aged rats after demyelination caused an increase in remyelinated axons. Our results indicate that RXR-γ is a positive regulator of endogenous oligodendrocyte precursor cell differentiation and remyelination and might be a pharmacological target for regenerative therapy in the CNS