Publications by authors named "Hiroyuki Kagechika"

176 Publications

Pharmacophore-guided repurposing of fibrates and retinoids as GPR40 allosteric ligands with activity on insulin release.

J Enzyme Inhib Med Chem 2021 Dec;36(1):377-383

Department of Biotechnology, Chemistry and Pharmacy (Department of Excellence 2018-2022), University of Siena, Siena, Italy.

A classical drug repurposing approach was applied to find new putative GPR40 allosteric binders. A two-step computational protocol was set up, based on an initial pharmacophoric-based virtual screening of the DrugBank database of known drugs, followed by docking simulations to confirm the interactions between the prioritised compounds and GPR40. The best-ranked entries showed binding poses comparable to that of TAK-875, a known allosteric agonist of GPR40. Three of them (tazarotenic acid, bezafibrate, and efaproxiral) affect insulin secretion in pancreatic INS-1 832/13 β-cells with EC in the nanomolar concentration (5.73, 14.2, and 13.5 nM, respectively). Given the involvement of GPR40 in type 2 diabetes, the new GPR40 modulators represent a promising tool for therapeutic intervention towards this disease. The ability to affect GPR40 was further assessed in human breast cancer MCF-7 cells in which this receptor positively regulates growth activities (EC values were 5.6, 21, and 14 nM, respectively).
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http://dx.doi.org/10.1080/14756366.2020.1864629DOI Listing
December 2021

Construction of Aromatic Multilayered Structures Based on the Conformational Properties of N,N'-Dimethylated Squaramide.

Chempluschem 2021 Jan;86(1):198-205

Department of Chemistry, Faculty of Science, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo, 112-8610, Japan.

Squaramide is a highly rigid four-membered ring system bearing two carbonyl and two amino groups, and its derivatives have found applications in many fields. We synthesized several N,N'-dimethylated oligosquaramides linked via phenyl groups, and investigated their structures in the crystalline state and in solution. Compounds 1, 2 (bissquaramides), and 13 (trissquaramide) exist as folded structures in the crystalline state, in which the aromatic rings are located in a face-to-face position. In their multilayered structures, the benzene rings are more nearly parallel and are closer to each other, compared with those in N,N'-dimethylated oligoureas. Individual molecules of meta-connected compounds 2 and 13 show a helical structure with all-R or all-S axis chirality, but afford only racemic crystals. The NMR spectra indicated that these compounds retain well-ordered folded structures in solution. The unique steric and electronic properties of N,N'-dimethylated squaramide can provide access to novel functional aromatic multilayered and helical foldamers.
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http://dx.doi.org/10.1002/cplu.202000678DOI Listing
January 2021

Lithocholic Acid Derivatives as Potent Vitamin D Receptor Agonists.

J Med Chem 2021 01 28;64(1):516-526. Epub 2020 Dec 28.

Department of Chemistry, Faculty of Science, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Bunkyo, Tokyo 112-8610, Japan.

Lithocholic acid () was identified as a second endogenous ligand of vitamin D receptor (VDR), though its activity is very weak. In this study, we designed novel lithocholic acid derivatives based on the crystal structure of VDR-ligand-binding domain (LBD) bound to . Among the synthesized compounds, bearing a 2-hydroxy-2-methylprop-1-yl group instead of the 3-hydroxy group at the 3α-position of showed dramatically increased activity in HL-60 cell differentiation assay, being at least 10 000 times more potent than lithocholic acid () and 3 times more potent than 1α,25-dihydroxyvitamin D (). Although the binding affinities of and its epimer were less than that of , their transactivation activities were greater than that of . X-ray structure analyses of VDR LBD bound to or showed that the binding positions of these compounds in the ligand-binding pocket are similar to that of .
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http://dx.doi.org/10.1021/acs.jmedchem.0c01420DOI Listing
January 2021

6-Arylcoumarin as a Scaffold of Photofunctional Molecules with OFF-ON-OFF Type Regulation.

J Org Chem 2021 Feb 27;86(3):2264-2270. Epub 2020 Dec 27.

Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.

Coumarin has been utilized as a core structure of photofunctional molecules, such as fluorescent sensors and photoremovable protecting groups. Here, we show that the 6-arylcoumarin moiety can provide OFF-ON-OFF type regulatory functionality for such compounds. To illustrate its utility, we synthesized a coumarin derivative bearing two phenolic hydroxy groups at 7-position and on 6-aryl group as a fluorescent sensor showing an OFF-ON-OFF change in fluorescence intensity in response to an increase in pH from a strongly acidic condition. Further, we show that the efficiency of photoreaction of other derivatives with the same hydroxyl groups is switched from "OFF" at pH 3 and 6 to "ON" at pH 9 and then to OFF at pH 12, enabling their application as switchable photoremovable protective groups. These features arise from sequential deprotonation of two hydroxyl groups: the monoanionic form is responsible for the photoinduced fluorescence and photoreaction.
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http://dx.doi.org/10.1021/acs.joc.0c02419DOI Listing
February 2021

WNK regulates Wnt signalling and β-Catenin levels by interfering with the interaction between β-Catenin and GID.

Commun Biol 2020 Nov 12;3(1):666. Epub 2020 Nov 12.

Department of Molecular Cell Biology, Medical Research Institute (MRI), Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, 113-8510, Japan.

β-Catenin is an important component of the Wnt signalling pathway. As dysregulation or mutation of this pathway causes many diseases, including cancer, the β-Catenin level is carefully regulated by the destruction complex in the Wnt signalling pathway. However, the mechanisms underlying the regulation of β-Catenin ubiquitination and degradation remain unclear. Here, we find that WNK (With No Lysine [K]) kinase is a potential regulator of the Wnt signalling pathway. We show that WNK protects the interaction between β-Catenin and the Glucose-Induced degradation Deficient (GID) complex, which includes an E3 ubiquitin ligase targeting β-Catenin, and that WNK regulates the β-Catenin level. Furthermore, we show that WNK inhibitors induced β-Catenin degradation and that one of these inhibitors suppressed xenograft tumour development in mice. These results suggest that WNK is a previously unrecognized regulator of β-Catenin and a therapeutic target of cancer.
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http://dx.doi.org/10.1038/s42003-020-01386-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665214PMC
November 2020

Activation of β2-adrenergic receptor signals suppresses mesenchymal phenotypes of oral squamous cell carcinoma cells.

Cancer Sci 2021 Jan 18;112(1):155-167. Epub 2020 Nov 18.

Department of Biochemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

Metastasis is a primary reason related to the mortality of oral squamous cell carcinoma (OSCC) patients. A program called epithelial-mesenchymal transition (EMT) has been shown to play a critical role in promoting metastasis in epithelium-derived carcinoma. During EMT, epithelial cancer cells acquire motile mesenchymal phenotypes and detach from primary tumors. Recent lines of evidence have suggested that EMT confers cancer cells with tumor-initiating ability. Therefore, selective targeting of EMT would lead to the development of effective therapeutic agents. In this study, using a chemical biology approach, we identified isoxsuprine, a β2-adrenergic receptor (β2-AR) agonist as a low-molecular-weight compound that interferes with the acquisition of mesenchymal phenotypes of oral cancer cells. Treatment of multiple types of oral cancer cells with isoxsuprine led to the downregulation of mesenchymal cell markers that was accompanied by reduced cell motility. Similar inhibitory effects were also observed for isoprenaline, a non-selective β-adrenergic receptor (β-AR) agonist. In addition, inhibition of cell migration upon treatment with isoxsuprine was reverted by a non-selective β-AR antagonist, propranolol, and the CRISPR/Cas9 system-mediated deletion of the β2-AR gene, suggesting that the effects exerted by isoxsuprine involved signals mediated by β2-AR. In addition, in a subcutaneous xenograft model of oral cancer cells, the administration of isoxsuprine effectively suppressed primary tumor growth, suggesting β2-AR signals to be a promising cancer therapeutic target for treatment of OSCC.
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http://dx.doi.org/10.1111/cas.14670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780019PMC
January 2021

Development of Androgen-Antagonistic Coumarinamides with a Unique Aromatic Folded Pharmacophore.

Int J Mol Sci 2020 Aug 4;21(15). Epub 2020 Aug 4.

Department of Chemistry, Faculty of Science, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan.

First-generation nonsteroidal androgen receptor (AR) antagonists, such as flutamide () and bicalutamide (), are effective for most prostate cancer patients, but resistance often appears after several years due to the mutation of AR. Second-generation AR antagonists are effective against some of these castration-resistant prostate cancers, but their structural variety is still limited. In this study, we designed and synthesized 4-methyl-7-(-alkyl-arylcarboxamido)coumarins as AR antagonist candidates and evaluated their growth-inhibitory activity toward androgen-dependent SC-3 cells. Coumarinamides with a secondary amide bond did not show inhibitory activity, but their -methylated derivatives exhibited AR-antagonistic activity. Especially, and were more potent than the lead compound , which was comparable to hydroxyflutamide (). Conformational analysis showed that the inactive coumarinamides with a secondary amide bond have an extended structure with a -amide bond, while the active -methylated coumarinamides have a folded structure with a -amide bond, in which the two aromatic rings are placed face-to-face. Docking study suggested that this folded structure is important for binding to AR. Selected coumarinamide derivatives showed AR-antagonistic activity toward LNCaP cells with T877A AR, and they had weak progesterone receptor (PR)-antagonistic activity. The folded coumarinamide structure appears to be a unique pharmacophore, different from those of conventional AR antagonists.
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http://dx.doi.org/10.3390/ijms21155584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432827PMC
August 2020

Chemical Screening of Nuclear Receptor Modulators.

Int J Mol Sci 2020 Jul 31;21(15). Epub 2020 Jul 31.

Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.

Nuclear receptors are ligand-inducible transcriptional factors that control multiple biological phenomena, including proliferation, differentiation, reproduction, metabolism, and the maintenance of homeostasis. Members of the nuclear receptor superfamily have marked structural and functional similarities, and their domain functionalities and regulatory mechanisms have been well studied. Various modulators of nuclear receptors, including agonists and antagonists, have been developed as tools for elucidating nuclear receptor functions and also as drug candidates or lead compounds. Many assay systems are currently available to evaluate the modulation of nuclear receptor functions, and are useful as screening tools in the discovery and development of new modulators. In this review, we cover the chemical screening methods for nuclear receptor modulators, focusing on assay methods and chemical libraries for screening. We include some recent examples of the discovery of nuclear receptor modulators.
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http://dx.doi.org/10.3390/ijms21155512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432305PMC
July 2020

Structural development of N-(4-phenoxyphenyl)benzamide derivatives as novel SPAK inhibitors blocking WNK kinase signaling.

Bioorg Med Chem Lett 2020 09 13;30(17):127408. Epub 2020 Jul 13.

Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan. Electronic address:

We report here structural development of N-(4-phenoxyphenyl)benzamide derivatives as novel SPAK (STE20/SPS1-related proline/alanine-rich kinase) inhibitors. Abnormal activation of the signal cascade of with-no-lysine kinase (WNK) with OSR1 (oxidative stress-responsive kinase 1)/SPAK and NCC (NaCl cotransporter) results in characteristic salt-sensitive hypertension, and therefore inhibitors of the WNK-OSR1/SPAK-NCC cascade are candidates for antihypertensive drugs. Based on the structure of lead compound 2, we examined the SAR of N-(4-phenoxyphenyl)benzamide derivatives, and developed compound 20l as a potent SPAK inhibitor. Compounds 20l is a promising candidate for a new class of antihypertensive drugs.
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http://dx.doi.org/10.1016/j.bmcl.2020.127408DOI Listing
September 2020

Characterization of a novel compound that promotes myogenesis via Akt and transcriptional co-activator with PDZ-binding motif (TAZ) in mouse C2C12 cells.

PLoS One 2020 8;15(4):e0231265. Epub 2020 Apr 8.

Department of Medical Biochemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

Transcriptional co-activator with PDZ-binding motif (TAZ) plays versatile roles in the regulation of cell proliferation and differentiation. TAZ activity changes in response to the cellular environment such as mechanic and nutritional stimuli, osmolarity, and hypoxia. To understand the physiological roles of TAZ, chemical compounds that activate TAZ in cells are useful as experimental reagents. Kaempferol, TM-25659, and ethacridine are reported as TAZ activators. However, as each TAZ activator has a distinct property in cellular functions, additional TAZ activators are awaiting. We screened for TAZ activators and previously reported IB008738 as a TAZ activator that promotes myogenesis in C2C12 cells. In this study, we have characterized IBS004735 that was obtained in the same screening. IBS004735 also promotes myogenesis in C2C12 cells, but is not similar to IBS008738 in the structure. IBS004735 activates TAZ via Akt and has no effect on TAZ phosphorylation, which is the well-described key modification to regulate TAZ activity. Thus, we introduce IBS004735 as a novel TAZ activator that regulates TAZ in a yet unidentified mechanism.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231265PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141682PMC
July 2020

Prostaglandin E and its receptor EP2 trigger signaling that contributes to YAP-mediated cell competition.

Genes Cells 2020 Mar 7;25(3):197-214. Epub 2020 Feb 7.

Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

Cell competition is a biological process by which unfit cells are eliminated from "cell society." We previously showed that cultured mammalian epithelial Madin-Darby canine kidney (MDCK) cells expressing constitutively active YAP were eliminated by apical extrusion when surrounded by "normal" MDCK cells. However, the molecular mechanism underlying the elimination of active YAP-expressing cells was unknown. Here, we used high-throughput chemical compound screening to identify cyclooxygenase-2 (COX-2) as a key molecule triggering cell competition. Our work shows that COX-2-mediated PGE secretion engages its receptor EP2 on abnormal and nearby normal cells. This engagement of EP2 triggers downstream signaling via an adenylyl cyclase-cyclic AMP-PKA pathway that, in the presence of active YAP, induces E-cadherin internalization leading to apical extrusion. Thus, COX-2-induced PGE appears a warning signal to both abnormal and surrounding normal cells to drive cell competition.
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http://dx.doi.org/10.1111/gtc.12750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078805PMC
March 2020

A Polarity-Sensitive Fluorescent Amino Acid and its Incorporation into Peptides for the Ratiometric Detection of Biomolecular Interactions.

Chempluschem 2019 11 13;84(11):1716-1719. Epub 2019 Oct 13.

Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan.

A fluorescent amino acid containing our recently developed 1,5-naphthyridin-2(1H)-one based- fluorophore, which is a structural component of the fluorescent natural compounds amarastelline A and nigakinone, has been developed. It has useful functions, that is, solvent-polarity-dependent change of fluorescence ratio at 370/480 nm and strong fluorescence in both aqueous solution and less polar organic solvents. To demonstrate its utility, it was incorporated into a C5 peptide with the aim of detecting the interaction of this peptide with calmodulin. As expected, the fluorescence ratio at 370/480 nm of the peptide was changed by the calmodulin only in the presence of Ca , thus indicating that the fluorescent peptide could sense the conformational change of calmodulin induced by Ca , followed by its interaction. These results also suggest that this fluorescent amino acid as well as its precursor, a succinimidyl ester, could be applicable for detecting various biomolecular interactions.
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http://dx.doi.org/10.1002/cplu.201900489DOI Listing
November 2019

Development of Helical Aromatic Amide Foldamers with a Diphenylacetylene Backbone.

J Org Chem 2020 02 17;85(4):2019-2039. Epub 2020 Jan 17.

Department of Chemistry and Biochemistry, Graduate School of Humanities and Sciences , Ochanomizu University , 2-1-1 Otsuka , Bunkyo-ku , Tokyo 112-8610 , Japan.

We designed and synthesized aromatic polyamides with a diphenylacetylene backbone, and , bearing ()-α- and ()-β-methyl-substituted triethyleneglycol (TEG) side chains, respectively, and examined their conformations in solution. Both polymers exhibit strong, solvent polarity-dependent circular dichroism spectra, which indicated that they take helical conformations in low-polarity solvents. The spectra were mirror images, depending on the chiral position of the side chains. Thus, the polyamide bearing ()-α-methyl-substituted TEG groups takes a left-handed helical conformation, while the polyamide with ()-β-methyl-substituted TEG groups takes a right-handed helical conformation. The difference in the screw sense of and would be caused by the steric interaction between the main chain and the side chain, as observed in poly(-benzamide) possessing ()-β-methyl-substituted TEG side chains () because the large cavity of the helical structure of would disturb the solvophobically induced helical folding. Detailed conformational analyses of the oligoamides with β-methyl-substituted TEG groups were conducted. Theoretical calculations indicated that the oligoamides with β-methyl-substituted TEG groups exist in a helical conformation with a cavity of 7 Å in diameter. The H NMR spectra of the oligomers revealed interactions with small anions such as chloride and acetate anions and with pyridinium cations.
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http://dx.doi.org/10.1021/acs.joc.9b02758DOI Listing
February 2020

Development of Boron-Cluster-Based Progesterone Receptor Antagonists Bearing a Pentafluorosulfanyl (SF) Group.

Chem Pharm Bull (Tokyo) 2019 ;67(12):1278-1283

Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU).

The progesterone receptor (PR) plays an important role in various physiological processes, especially in the female reproductive system, and abnormalities of PR function are associated with several diseases, including some types of cancer. Non-steroidal PR ligands are of interest as candidate drugs for treatment of PR-related diseases without the serious adverse effects that may be caused by steroidal ligands. For the development of non-steroidal PR ligands, both a hydrophobic backbone and a polar functional group corresponding to the 3-carbonyl group of progesterone, which interacts with Gln725 and Arg766 of the PR-ligand binding domain, are critically important. We previously showed that carborane is a useful hydrophobic pharmacophore for PR antagonists, and in this work, we introduced the pentafluorosulfanyl (SF) group as a novel polar functional group of carborane-based non-steroidal PR antagonists. All the synthesized SF-containing carborane derivatives exhibited PR-antagonistic activity at micromolar or submicromolar concentration. Among them, compounds 11 are potent progesterone antagonists with submicromolar IC values.
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http://dx.doi.org/10.1248/cpb.c19-00522DOI Listing
January 2020

Publisher Correction: A new regulatory mechanism for Raf kinase activation, retinoic acid-bound Crabp1.

Sci Rep 2019 Nov 14;9(1):17042. Epub 2019 Nov 14.

Department of Pharmacology, University of Minnesota, Minneapolis, MN, 55455, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-019-53692-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856344PMC
November 2019

A new regulatory mechanism for Raf kinase activation, retinoic acid-bound Crabp1.

Sci Rep 2019 07 29;9(1):10929. Epub 2019 Jul 29.

Department of Pharmacology, University of Minnesota, Minneapolis, MN, 55455, USA.

The rapidly accelerated fibrosarcoma (Raf) kinase is canonically activated by growth factors that regulate multiple cellular processes. In this kinase cascade Raf activation ultimately results in extracellular regulated kinase 1/2 (Erk1/2) activation, which requires Ras binding to the Ras binding domain (RBD) of Raf. We recently reported that all-trans retinoic acid (atRA) rapidly (within minutes) activates Erk1/2 to modulate cell cycle progression in stem cells, which is mediated by cellular retinoic acid binding protein 1 (Crabp1). But how atRA-bound Crabp1 regulated Erk1/2 activity remained unclear. We now report Raf kinase as the direct target of atRA-Crabp1. Molecularly, Crabp1 acts as a novel atRA-inducible scaffold protein for Raf/Mek/Erk in cells without growth factor stimulation. However, Crabp1 can also compete with Ras for direct interaction with the RBD of Raf, thereby negatively modulating growth factor-stimulated Raf activation, which can be enhanced by atRA binding to Crabp1. NMR heteronuclear single quantum coherence (HSQC) analyses reveal the 6-strand β-sheet face of Crabp1 as its Raf-interaction surface. We identify a new atRA-mimicking and Crabp1-selective compound, C3, that can also elicit such an activity. This study uncovers a new signal crosstalk between endocrine (atRA-Crabp1) and growth factor (Ras-Raf) pathways, providing evidence for atRA-Crabp1 as a novel modulator of cell growth. The study also suggests a new therapeutic strategy by employing Crabp1-selective compounds to dampen growth factor stimulation while circumventing RAR-mediated retinoid toxicity.
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http://dx.doi.org/10.1038/s41598-019-47354-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662813PMC
July 2019

Development of novel lithocholic acid derivatives as vitamin D receptor agonists.

Bioorg Med Chem 2019 08 3;27(16):3674-3681. Epub 2019 Jul 3.

Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan. Electronic address:

Lithocholic acid (2) was identified as the second endogenous ligand of vitamin D receptor (VDR), though its binding affinity to VDR and its vitamin D activity are very weak compared to those of the active metabolite of vitamin D, 1α,25-dihydroxyvitamin D (1). 3-Acylated lithocholic acids were reported to be slightly more potent than lithocholic acid (2) as VDR agonists. Here, aiming to develop more potent lithocholic acid derivatives, we synthesized several derivatives bearing a 3-sulfonate/carbonate or 3-amino/amide substituent, and examined their differentiation-inducing activity toward human promyelocytic leukemia HL-60 cells. Introduction of a nitrogen atom at the 3-position of lithocholic acid (2) decreased the activity, but compound 6 bearing a 3-methylsulfonate group showed more potent activity than lithocholic acid (2) or its acylated derivatives. The binding of 6 to VDR was confirmed by competitive binding assay and X-ray crystallographic analysis of the complex of VDR ligand-binding domain (LBD) with 6.
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http://dx.doi.org/10.1016/j.bmc.2019.07.003DOI Listing
August 2019

Structural development of a type-1 ryanodine receptor (RyR1) Ca-release channel inhibitor guided by endoplasmic reticulum Ca assay.

Eur J Med Chem 2019 Oct 29;179:837-848. Epub 2019 Jun 29.

Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), Tokyo, 101-0062, Japan. Electronic address:

Type-1 ryanodine receptor (RyR1) is a calcium-release channel localized on sarcoplasmic reticulum (SR) of the skeletal muscle, and mediates muscle contraction by releasing Ca from the SR. Genetic mutations of RyR1 are associated with skeletal muscle diseases such as malignant hyperthermia and central core diseases, in which over-activation of RyR1 causes leakage of Ca from the SR. We recently developed an efficient high-throughput screening system based on the measurement of Ca in endoplasmic reticulum, and used it to identify oxolinic acid (1) as a novel RyR1 channel inhibitor. Here, we designed and synthesized a series of quinolone derivatives based on 1 as a lead compound. Derivatives bearing a long alkyl chain at the nitrogen atom of the quinolone ring and having a suitable substituent at the 7-position of quinolone exhibited potent RyR1 channel-inhibitory activity. Among the synthesized compounds, 14h showed more potent activity than dantrolene, a known RyR1 inhibitor, and exhibited high RyR1 selectivity over RyR2 and RyR3. These compounds may be promising leads for clinically applicable RyR1 channel inhibitors.
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http://dx.doi.org/10.1016/j.ejmech.2019.06.076DOI Listing
October 2019

Design, Synthesis and Biological Evaluation of Novel Nonsteroidal Progesterone Receptor Antagonists Based on Phenylamino-1,3,5-triazine Scaffold.

Chem Pharm Bull (Tokyo) 2019 ;67(6):566-575

Institute for Quantitative Biosciences, The University of Tokyo.

We report here the development of phenylamino-1,3,5-triazine derivatives as novel nonsteroidal progesterone receptor (PR) antagonists. PR plays key roles in various physiological systems, including the female reproductive system, and PR antagonists are promising candidates for clinical treatment of multiple diseases. By using the phenylamino-1,3,5-triazine scaffold as a template structure, we designed and synthesized a series of 4-cyanophenylamino-1,3,5-triazine derivatives. The synthesized compounds exhibited PR antagonistic activity, and among them, compound 12n was the most potent (IC = 0.30 µM); it also showed significant binding affinity to the PR ligand-binding domain. Docking simulation supported the design rationale of the compounds. Our results suggest that the phenylamino-1,3,5-triazine scaffold is a versatile template for development of nonsteroidal PR antagonists and that the developed compounds are promising lead compounds for further structural development of nonsteroidal PR antagonists.
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http://dx.doi.org/10.1248/cpb.c19-00094DOI Listing
June 2019

Androgen receptor modulators: a review of recent patents and reports (2012-2018).

Expert Opin Ther Pat 2019 06 19;29(6):439-453. Epub 2019 May 19.

b Institute of Biomaterials and Bioengineering , Tokyo Medical and Dental University , Tokyo , Japan.

Introduction: Androgen receptor (AR) is one of the most promising targets of drug discovery because of its importance in male reproductive systems and homeostasis of bone and muscle. Various AR-modulating agents have been developed and used clinically to treat androgen-dependent disorders, including prostate cancer, and some new-generation antiandrogens have recently been approved. Intensive studies are underway to develop various AR-modulating compounds, including conventional antagonists, tissue-specific AR modulators (SARMs), degraders, and nonconventional AR-modulating compounds that target sites other than the ligand-binding domain (LBD), such as the N-terminal domain (NTD) or the DNA-binding domain (DBD).

Areas Covered: The authors provide an overview of AR-modulating agents from 2012 to 2018.

Expert Opinion: The LBD has been the primary target for AR modulation, and important AR-modulating agents, including SARMs and recently approved antiandrogens such as enzalutamide and apalutamide, have been developed as conventional LBD antagonists. Development of LBD-targeting antiandrogens to treat prostate cancer is a kind of cat-and-mouse game between clinical agents and AR mutations, and therefore next-generation antiandrogens are still required. Development of nonconventional AR-modulating agents targeting NTD and DBD, is likely to be a promising approach to develop multiple and synergistic strategies able to overcome any kind of androgen-dependent condition.
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http://dx.doi.org/10.1080/13543776.2019.1618831DOI Listing
June 2019

Two new alkaloids from Crinum asiaticum var. japonicum.

J Nat Med 2019 Jun 8;73(3):648-652. Epub 2019 Apr 8.

College of Humanities and Sciences, Nihon University, Sakurajosui, Setagaya-ku, Tokyo, 156-8550, Japan.

A new crinine-type alkaloid crijaponine A (1), a new galanthamine-type alkaloid crijaponine B (2), and 11 known alkaloids-ungeremine (3), lycorine (4), 2-O-acetyllycorine (5), 1, 2-O-diacetyllycorine (6), (-)-crinine (7), 11-hydroxyvittatine (8), hamayne (9), (+)-epibuphanisine (10), crinamine (11), yemenine A (12), and epinorgalanthamine (13)-were isolated from the rhizome and fruits of Crinum asiaticum var. japonicum. The structural elucidation of the isolated compounds was performed by spectroscopic methods including 2D NMR. The isolated compounds were evaluated for cytotoxicity against HeLa and HL-60 cells lines and were tested for acetylcholinesterase inhibition activity.
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http://dx.doi.org/10.1007/s11418-019-01304-9DOI Listing
June 2019

Class IIb HDAC Inhibition Enhances the Inhibitory Effect of Am80, a Synthetic Retinoid, in Prostate Cancer.

Biol Pharm Bull 2019 ;42(3):448-452

Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU).

Combination therapy is often an effective strategy to treat cancer. In this study, we examined the growth-inhibitory effects of Am80 (tamibarotene), a specific retinoic acid receptor (RAR) α/β agonist, in combination with a histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), or a DNA methyl transferase (DNMT) inhibitor, 5-aza-2'-deoxycytidine, on androgen receptor (AR)-positive and AR-negative prostate cancer cell lines (LNCaP and PC-3, respectively). We found that the combination therapy of SAHA and Am80 showed an enhanced growth-inhibitory effect on LNCaP cells. Further studies with various HDAC isotype-selective inhibitors showed that SAHA and KD5170 (a selective class I and II HDAC inhibitor) each increased the RARα protein level in LNCaP cells. Our results indicate that the target of the enhancing effect belongs to the Class IIb HDACs, especially HDAC6. Dual targeting of Class IIb HDAC and RARα may be a candidate therapeutic strategy for prostate cancer.
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http://dx.doi.org/10.1248/bpb.b18-00782DOI Listing
July 2019

A new LC-MS assay for the quantitative analysis of vitamin K metabolites in human urine.

J Lipid Res 2019 04 22;60(4):892-899. Epub 2019 Jan 22.

Departments of Medicinal Chemistry University of Washington, Seattle, WA 98195-7610.

Vitamin K (VK), in both its phylloquinone and menaquinone forms, has been hypothesized to undergo ω- and β-oxidation on its hydrophobic side chain in order to generate the observed urinary metabolites, K acid I and K acid II, which are excreted primarily as glucuronide conjugates. Synthetic standards of K acid I, K acid II, and a putative intermediate metabolite, menaquinone (MK)1 ω-COOH, were used to develop and optimize a new atmospheric pressure negative chemical ionization LC-MS/MS assay for the quantitation of these compounds in urine from untreated individuals and subjects treated with a high dose VK supplement. VK catabolites were extracted from urine, deconjugated, and converted to their methyl ester derivatives using previously reported methodology. The assay showed a high degree of sensitivity, with limits of detection below 10-50 fmol of metabolite per milliliter of urine, as well as an inter-assay precision of 8-12%. Metabolite standards provided unambiguous evidence for MK1 ω-COOH as a new human urinary metabolite of VK. This assay provides a minimally invasive, highly sensitive, and specific alternative for monitoring VK status in humans.
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http://dx.doi.org/10.1194/jlr.D087916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446701PMC
April 2019

Synthesis and Conformational Analysis of Alternately N-Alkylated Aromatic Amide Oligomers.

J Org Chem 2018 12 15;83(23):14338-14349. Epub 2018 Nov 15.

Department of Chemistry and Biochemistry, Graduate School of Humanities and Sciences , Ochanomizu University , 2-1-1 Otsuka , Bunkyo-ku, Tokyo 112-8610 , Japan.

Alternately N-alkylated aromatic amides such as 1-3 bearing various side chains were designed and synthesized as novel helical foldamers. The CD spectra of oligomers with chiral side chains showed a positive Cotton effect, which indicates that these oligomers take helical conformations in solution. The CD intensity gradually increased with increasing chain length, and pentamer 3d showed remarkably strong CD signals in chloroform. The absorption maxima of the UV spectra were increasingly red shifted with increasing chain length, in contrast to the case of poly( p- N-alkylbenzamide)s. Structure optimization of the oligomers based on the crystal structure of 1a as the monomer unit supported the formation of helical structure with a large cavity and also suggested intramolecular hydrogen bond formation between secondary amides. The results of calculation were consistent with the observed spectroscopic features.
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http://dx.doi.org/10.1021/acs.joc.8b02045DOI Listing
December 2018

Structure-activity relationship of novel (benzoylaminophenoxy)phenol derivatives as anti-prostate cancer agents.

Bioorg Med Chem 2018 10 6;26(18):5118-5127. Epub 2018 Sep 6.

Department of Chemistry, Faculty of Science, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan. Electronic address:

The androgen receptor (AR) is a ligand-inducible transcription factor belonging to the nuclear receptor superfamily, and is a target molecule for development of drugs to treat prostate cancer. However, AR antagonists in clinical use, such as flutamide (3a) and bicalutamide (4), encounter resistance after several years of hormone therapy, predominantly due to mutations of AR. Thus, although some new-generation AR antagonists have been developed, novel types of AR antagonists are still required to treat drug-resistant prostate cancer. We previously reported a novel (benzoylaminophenoxy)phenol derivative 10a, which is structurally distinct from conventional AR antagonists. Here, we systematically examined the structure-activity relationship of (benzoylaminophenoxy)phenol derivatives on the inhibitory activity on the prostate cancer cell proliferations. We found that the 4-[4-(benzoylamino)phenoxy]phenol backbone is important for anti-prostate cancer activity. Introduction of a small substituent at the 2 position of the central benzene ring (B ring) increases the activity. Among the synthesized compounds, 19a and 19b exhibited the most potent inhibitory activity toward dihydrotestosterone-induced proliferation of several androgen-dependent cell lines, SC-3 (wild-type AR), LNCaP (T877A AR), and 22Rv1 (H874Y AR), but interestingly also inhibited proliferation of AR-independent PC-3 cells. These compounds, which have a different pharmacophore from conventional AR antagonists, are promising drug candidates for the treatment of prostate cancer.
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http://dx.doi.org/10.1016/j.bmc.2018.09.008DOI Listing
October 2018

Prevention of acute liver injury by suppressing plasma kallikrein-dependent activation of latent TGF-β.

Biochem Biophys Res Commun 2018 10 12;504(4):857-864. Epub 2018 Sep 12.

Liver Cancer Prevention Research Unit, RIKEN Center for Integrative Medical Sciences, Saitama, Japan; Graduate School of Medical & Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address:

Acute liver injury (ALI) is highly lethal acute liver failure caused by different etiologies. Transforming growth factor β (TGF-β) is a multifunctional cytokine and a well-recognized inducer of apoptotic and necrotic cell death in hepatocytes. Latent TGF-β is activated partly through proteolytic cleavage by a serine protease plasma kallikrein (PLK) between the R58 and L59 residues of its propeptide region. Recently, we developed a specific monoclonal antibody to detect the N-terminal side LAP degradation products ending at residue R58 (R58 LAP-DPs) that reflect PLK-dependent TGF-β activation. This study aimed to explore the potential roles of PLK-dependent TGF-β activation in the pathogenesis of ALI. We established a mouse ALI model via the injection of anti-Fas antibodies (Jo2) and observed increases in the TGF-β1 mRNA level, Smad3 phosphorylation, TUNEL-positive apoptotic hepatocytes and R58-positive cells in the liver tissues of Jo2-treated mice. The R58 LAP-DPs were observed in/around F4/80-positive macrophages, while macrophage depletion with clodronate liposomes partly alleviated the Jo2-induced liver injury. Blocking PLK-dependent TGF-β activation using either the serine proteinase inhibitor FOY305 or the selective PLK inhibitor PKSI-527 or blocking the TGF-β receptor-mediated signaling pathway using SB431542 significantly prevented Jo2-induced hepatic apoptosis and mortality. Furthermore, similar phenomena were observed in the mouse model of ALI with the administration of acetaminophen (APAP). In summary, R58 LAP-DPs reflecting PLK-dependent TGF-β activation may serve as a biomarker for ALI, and targeting PLK-dependent TGF-β activation has potential as a therapeutic strategy for ALI.
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http://dx.doi.org/10.1016/j.bbrc.2018.09.026DOI Listing
October 2018

Recent Advances in Chemical Tools for the Regulation and Study of Protein Lysine Methyltransferases.

Chem Rec 2018 Dec 6;18(12):1745-1759. Epub 2018 Aug 6.

Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo, 101-0062, Japan.

Protein lysine methyltransferases (PKMTs) are epigenetic regulators that modulate gene transcription and physiological functions by catalyzing the post-translational methylation of specific lysine residues of substrate proteins, such as histones. They are considered to be candidate drugs for the treatment of various diseases, including acute myeloid leukemia, and in the past decade, potent and selective inhibitors of individual PKMTs have been developed. Some are currently under clinical trial. In this review, we will focus on some breakthrough PKMT inhibitors, and discuss chemistry-based methods available for elucidation of the physiological functions of PKMTs and methylated proteins.
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http://dx.doi.org/10.1002/tcr.201800034DOI Listing
December 2018

Novel Nonsteroidal Progesterone Receptor (PR) Antagonists with a Phenanthridinone Skeleton.

ACS Med Chem Lett 2018 Jul 23;9(7):641-645. Epub 2018 Jun 23.

Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.

The progesterone receptor (PR) plays an important role in various physiological systems, including female reproduction and the central nervous system, and PR antagonists are thought to be effective not only as contraceptive agents and abortifacients but also in the treatment of various diseases, including hormone-dependent cancers and endometriosis. Here, we identified phenanthridin-6(5)-one derivatives as a new class of PR antagonists and investigated their structure-activity relationships. Among the synthesized compounds, , , and exhibited very potent PR antagonistic activity with high selectivity for PR over other nuclear receptors. These compounds are structurally distinct from other nonsteroidal PR antagonists, including cyanoaryl derivatives, and should be useful for further studies of the clinical utility of PR antagonists.
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http://dx.doi.org/10.1021/acsmedchemlett.8b00058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047039PMC
July 2018

Chemical compounds that suppress hypoxia-induced stress granule formation enhance cancer drug sensitivity of human cervical cancer HeLa cells.

J Biochem 2018 Nov;164(5):381-391

Department of Medical Biochemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

In eukaryotic cells, when exposed to certain types of stress including hypoxia, eIF2α is phosphorylated by several kinases including protein kinase R (PKR) and PKR-like endoplasmic reticulum kinase (PERK). Subsequently, protein translation is stopped and stress granules (SGs) are formed. Cancer cells form SGs under hypoxia. SGs accumulate apoptosis-related molecules and play anti-apoptotic roles. Thus, hypoxia-induced SG formation contributes to drug resistance in cancer cells. For this reason, inhibition of SG formation is expected to be beneficial in cancer therapy. To prove this concept, chemical reagents that inhibit SG formation are required as experimental tools. We searched for chemical compounds that suppress SG formation and identified that β-estradiol, progesterone, and stanolone (hereafter described as EPS) inhibit SG formation in human cervical cancer HeLa cells. As it turned out, EPS block PKR but not PERK, thus fail to suppress SG formation in most cancer cells, where SGs are formed via PERK. Nevertheless, in this study, we used HeLa cells as a model and demonstrated that EPS block hypoxia-induced SG formation in HeLa cells and consequently reduce drug resistance that HeLa cells acquire under hypoxia. Our findings support that inhibition of SG formation is a useful method to control cancers.
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http://dx.doi.org/10.1093/jb/mvy062DOI Listing
November 2018

Development of biotin-retinoid conjugates as chemical probes for analysis of retinoid function.

Bioorg Med Chem Lett 2018 08 6;28(14):2442-2445. Epub 2018 Jun 6.

Department of Functional Genomics and Cancer, Institute of Genetics and Molecular and Cellular Biology, (IGBMC), Centre National de la Recherche Scientifique UMR7104, Institut National de la Santé et de la Recherche Médicale U964, Université de Strasbourg, BP 10142, Illkirch Cedex 67404, France.

Herein, we report the rational design, synthesis and biological evaluation of conjugates consisting of the synthetic retinoid Am580 and biotin connected via a linker moiety. We found that the linking substructure between the retinoid part and the biotin part is critical for retaining the biological activity. Conjugate 4 with a shorter linker showed similar potency to endogenous retinoid ATRA (1) and the parent compound Am580 (2) for neural differentiation of mouse embryotic carcinoma P19 cells, and showed the same pattern of induction of gene expression. It is expected to be useful as a probe for investigations of retinoid function. The design rationale and structure-activity relationship of the linker moiety are expected to be helpful for developing biotin conjugates of other nuclear receptor ligands.
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http://dx.doi.org/10.1016/j.bmcl.2018.06.011DOI Listing
August 2018