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Medicinal Chemistry of Nuclear Receptors

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Role of Xenobiotics".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 12200

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Prof. Dr. Hiroyuki Kagechika

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Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
Interests: medicinal chemistry; chemical biology; organic chemistry

Special Issue Information

Dear Colleagues,

Nuclear receptors are ligand-inducible transcription factors, responsible for the action of hydrophobic signaling molecules, such as steroid hormones, thyroid hormones, vitamin A (retinolids), vitamin D, and some metabolic signals. These hydrophobic signaling molecules have significant physiological roles in growth, development, metabolism, immunity, and homeostasis, and dysregulation of nuclear receptors and their ligand functions closely involved in the pathogenesis of various diseases, such as cancer, cardiovascular diseases, autoimmune diseases, metabolic syndrome, and so on. Thus, specific modulators of multiple functions of nuclear receptors have been developed for the purpose of their clinical application, or used as the chemical probes for elucidation of nuclear receptor functions. In this Special Issue, we are pleased to invite original manuscripts focusing on the basic and applied research of medicinal chemistry targeting various nuclear receptors.

Prof. Dr. Hiroyuki Kagechika
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Steroid hormone receptor
thyroid hormone receptor
retinoid receptor
vitamin D receptor
metabolic signals
cancer
cardiovascular diseases
autoimmune diseases
metabolic syndrome

Published Papers (5 papers)

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Research

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12 pages, 1805 KiB

Open AccessArticle

Challenging Approach to the Development of Novel Estrogen Receptor Modulators Based on the Chemical Properties of Guaiazulene

by Kiminori Ohta, Asako Kaise, Takumi Ogawa and Yasuyuki Endo

Int. J. Mol. Sci. 2022, 23(3), 1113; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031113 - 20 Jan 2022

Viewed by 1534

Abstract

Tamoxifen, a therapeutic agent for breast cancer, has been associated with genetic polymorphisms in the metabolism of N,N-dialkylaminoethyl substituent, which plays an important role in the expression of selective estrogen receptor modulator (SERM) activity. To solve this problem, we developed a novel estrogen receptor (ER) modulator, Az-01, on the basis of the aromaticity, dipole moment, and isopropyl group of guaiazulene. Az-01 showed four-fold lower binding affinity for ER than E2 but had similar ER-binding affinity to that of 4-hydroxytamoxifen (4-HOtam). Unlike tamoxifen, Az-01 acted as a partial agonist with very weak estrogenic activity at high concentrations when used alone, and it showed potent anti-estrogenic activity in the presence of E2. The cell proliferation and inhibition activities of Az-01 were specific to ER-expressing MCF-7 cells, and no effect of Az-01 on other cell proliferation signals was observed. These findings are important for the development of new types of SERMs without the N,N-dialkylaminoethyl substituent as a privileged functional group for SERMs. Full article

(This article belongs to the Special Issue Medicinal Chemistry of Nuclear Receptors)

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41 pages, 9248 KiB

Open AccessArticle

Modeling, Synthesis, and Biological Evaluation of Potential Retinoid-X-Receptor (RXR) Selective Agonists: Analogs of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahyro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(4-isobutoxy-3-isopropylphenyl)amino)nicotinic Acid (NEt-4IB)

by Peter W. Jurutka, Orsola di Martino, Sabeeha Reshi, Sanchita Mallick, Zhela L. Sabir, Lech J. P. Staniszewski, Ankedo Warda, Emma L. Maiorella, Ani Minasian, Jesse Davidson, Samir J. Ibrahim, San Raban, Dena Haddad, Madleen Khamisi, Stephanie L. Suban, Bradley J. Dawson, Riley Candia, Joseph W. Ziller, Ming-Yue Lee, Chang Liu, Wei Liu, Pamela A. Marshall, John S. Welch and Carl E. Wagner Show full author list Hide full author list

Int. J. Mol. Sci. 2021, 22(22), 12371; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212371 - 16 Nov 2021

Cited by 2 | Viewed by 3194

Abstract

Five novel analogs of 6-(ethyl)(4-isobutoxy-3-isopropylphenyl)amino)nicotinic acid—or NEt-4IB—in addition to seven novel analogs of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene) were prepared and evaluated for selective retinoid-X-receptor (RXR) agonism alongside bexarotene (1), a FDA-approved drug for cutaneous T-cell lymphoma (CTCL). Bexarotene treatment elicits side-effects by provoking or disrupting other RXR-dependent pathways. Analogs were assessed by the modeling of binding to RXR and then evaluated in a human cell-based RXR-RXR mammalian-2-hybrid (M2H) system as well as a RXRE-controlled transcriptional system. The analogs were also tested in KMT2A-MLLT3 leukemia cells and the EC₅₀ and IC₅₀ values were determined for these compounds. Moreover, the analogs were assessed for activation of LXR in an LXRE system as drivers of ApoE expression and subsequent use as potential therapeutics in neurodegenerative disorders, and the results revealed that these compounds exerted a range of differential LXR-RXR activation and selectivity. Furthermore, several of the novel analogs in this study exhibited reduced RARE cross-signaling, implying RXR selectivity. These results demonstrate that modification of partial agonists such as NEt-4IB and potent rexinoids such as bexarotene can lead to compounds with improved RXR selectivity, decreased cross-signaling of other RXR-dependent nuclear receptors, increased LXRE-heterodimer selectivity, and enhanced anti-proliferative potential in leukemia cell lines compared to therapeutics such as 1. Full article

(This article belongs to the Special Issue Medicinal Chemistry of Nuclear Receptors)

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19 pages, 4474 KiB

Open AccessArticle

Stereoselective Synthesis of 24-Fluoro-25-Hydroxyvitamin D₃ Analogues and Their Stability to hCYP24A1-Dependent Catabolism

by Fumihiro Kawagoe, Sayuri Mototani, Kaori Yasuda, Hiroki Mano, Toshiyuki Sakaki and Atsushi Kittaka

Int. J. Mol. Sci. 2021, 22(21), 11863; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111863 - 01 Nov 2021

Cited by 6 | Viewed by 1404

Abstract

Two 24-fluoro-25-hydroxyvitamin D₃ analogues (3,4) were synthesized in a convergent manner. The introduction of a stereocenter to the vitamin D₃ side-chain C24 position was achieved via Sharpless dihydroxylation, and a deoxyfluorination reaction was utilized for the fluorination step. Comparison between (24R)- and (24S)-24-fluoro-25-hydroxyvitamin D₃ revealed that the C24-R-configuration isomer 4 was more resistant to CYP24A1-dependent metabolism than its 24S-isomer 3. The new synthetic route of the CYP24A1 main metabolite (24R)-24,25-dihydroxyvitamin D₃ (6) and its 24S-isomer (5) was also studied using synthetic intermediates (30,31) in parallel. Full article

(This article belongs to the Special Issue Medicinal Chemistry of Nuclear Receptors)

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11 pages, 2843 KiB

Open AccessArticle

Peptide Stapling Improves the Sustainability of a Peptide-Based Chimeric Molecule That Induces Targeted Protein Degradation

by Hidetomo Yokoo, Nobumichi Ohoka, Mami Takyo, Takahito Ito, Keisuke Tsuchiya, Takashi Kurohara, Kiyoshi Fukuhara, Takao Inoue, Mikihiko Naito and Yosuke Demizu

Int. J. Mol. Sci. 2021, 22(16), 8772; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168772 - 16 Aug 2021

Cited by 11 | Viewed by 2678

Abstract

Peptide-based target protein degradation inducers called PROTACs/SNIPERs have low cell penetrability and poor intracellular stability as drawbacks. These shortcomings can be overcome by easily modifying these peptides by conjugation with cell penetrating peptides and side-chain stapling. In this study, we succeeded in developing the stapled peptide stPERML-R7, which is based on the estrogen receptor alpha (ERα)-binding peptide PERML and composed of natural amino acids. stPERML-R7, which includes a hepta-arginine motif and a hydrocarbon stapling moiety, showed increased α-helicity and similar binding affinity toward ERα when compared with those of the parent peptide PERML. Furthermore, we used stPERML-R7 to develop a peptide-based degrader LCL-stPERML-R7 targeting ERα by conjugating stPERML-R7 with a small molecule LCL161 (LCL) that recruits the E3 ligase IAPs to induce proteasomal degradation via ubiquitylation. The chimeric peptide LCL-stPERML-R7 induced sustained degradation of ERα and potently inhibited ERα-mediated transcription more effectively than the unstapled chimera LCL-PERML-R7. These results suggest that a stapled structure is effective in maintaining the intracellular activity of peptide-based degraders. Full article

(This article belongs to the Special Issue Medicinal Chemistry of Nuclear Receptors)

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Review

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38 pages, 37598 KiB

Open AccessReview

Structural Biology-Based Exploration of Subtype-Selective Agonists for Peroxisome Proliferator-Activated Receptors

by Hiroyuki Miyachi

Int. J. Mol. Sci. 2021, 22(17), 9223; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179223 - 26 Aug 2021

Cited by 10 | Viewed by 2389

Abstract

Progress in understanding peroxisome proliferator-activated receptor (PPAR) subtypes as nuclear receptors that have pleiotropic effects on biological responses has enabled the exploration of new subtype-selective PPAR ligands. Such ligands are useful chemical biology/pharmacological tools to investigate the functions of PPARs and are also candidate drugs for the treatment of PPAR-mediated diseases, such as metabolic syndrome, inflammation and cancer. This review summarizes our medicinal chemistry research of more than 20 years on the design, synthesis, and pharmacological evaluation of subtype-selective PPAR agonists, which has been based on two working hypotheses, the ligand superfamily concept and the helix 12 (H12) holding induction concept. X-ray crystallographic analyses of our agonists complexed with each PPAR subtype validate our working hypotheses. Full article

(This article belongs to the Special Issue Medicinal Chemistry of Nuclear Receptors)

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