Article
Biochemistry & Molecular Biology
Donald Poirier, Rene Maltais, Jacques A. Rousseau, Jenny Roy, Serge Phoenix, Francisco Cortes-Benitez, Roger Lecomte
Summary: A compound that inhibits 17 beta-HSD3 activity and accumulates in prostate tumor tissues has been discovered. This finding opens up the possibility of targeted molecular radiotherapy or radioimaging diagnosis using radiolabelled versions of the compound.
BIOORGANIC CHEMISTRY
(2022)
Article
Pharmacology & Pharmacy
Cristina Gomez, Zerin Alimajstorovic, Nantia Othonos, Denise V. Winter, Sarah White, Gareth G. Lavery, Jeremy W. Tomlinson, Alexandra J. Sinclair, Alex Odermatt
Summary: This study compares the abilities of GUDCA/G7oxoLCA ratio and urinary (5α-THF+THF)/THE ratio to detect pharmacological 11 beta-HSD1 inhibition in humans. Results suggest that GUDCA/G7oxoLCA ratio is a more reliable biomarker for 11 beta-HSD1 inhibition.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Endocrinology & Metabolism
Yun Hu, Ying Wang, Ting-ting Cai, Lu Liu, Dong-mei Li, Jian-hua Ma, Bo Ding
Summary: Short-term intensive insulin therapy can increase serum testosterone levels in men with newly diagnosed type 2 diabetes, possibly due to enhanced conversion of DHEA to testosterone.
FRONTIERS IN ENDOCRINOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Francisco Cortes-Benitez, Jenny Roy, Martin Perreault, Rene Maltais, Donald Poirier
Summary: The new synthesized androsterone derivative showed improved inhibitory activity in rat testes microsomal fraction but not in whole cells. Additionally, structural modification increased metabolic stability and demonstrated significant cytotoxicity against various cancer cell lines. Furthermore, both the lead compound and the derivative showed better binding energy than NADP+ at the cofactor-binding site according to molecular dynamics simulations.
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Shenping Liu, Ruth F. Sommese, Nicole L. Nedoma, Lucy Mae Stevens, Jason K. Dutra, Liying Zhang, David J. Edmonds, Yang Wang, Michelle Garnsey, Michelle F. Clasquin
Summary: This study reports the crystal structures of HSD17B13 in complex with its cofactor and inhibitors, providing insights into its role in anchoring lipid droplet-associated proteins and disrupting function. These structures offer potential ideas for structure-based design of inhibitors for liver disease treatment.
NATURE COMMUNICATIONS
(2023)
Article
Chemistry, Medicinal
Ondrej Benek, Michaela Vaskova, Marketa Miskerikova, Monika Schmidt, Rudolf Andrys, Aneta Rotterova, Adam Skarka, Jana Hatlapatkova, Jana Zdarova Karasova, Matej Medvecky, Lukas Hroch, Lucie Vinklarova, Zdenek Fisar, Jana Hroudova, Jiri Handl, Jan Capek, Tomas Rousar, Tereza Kobrlova, Rafael Dolezal, Ondrej Soukup, Laura Aitken, Frank Gunn-Moore, Kamil Musilek
Summary: In this study, new benzothiazolylurea-based inhibitors were developed for 17 beta-HSD10, a potential drug target for Alzheimer's disease and hormone-dependent cancer. The most potent compounds within this class were identified, showing submicromolar inhibitory activity and cell penetrability. These compounds also showed no off-target effects, cytotoxicity, or neurotoxicity. Compound 9, one of the most potent inhibitors, was found to be bioavailable and able to penetrate the blood-brain barrier.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Catarina Goncalves, Josianne Carrico, Margarida Bastos, Manuel C. Lemos
Summary: In this study, a child raised as a female was found to have compound heterozygous mutations in the HSD17B3 gene, which blocked the synthesis of testosterone and resulted in a Disorder of Sex Development. A total of 70 different HSD17B3 mutations have been reported so far, and these findings may be useful for the clinical management and genetic diagnosis of this disorder.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Urology & Nephrology
Josyf C. Mychaleckyj, Erkka Valo, Takaharu Ichimura, Tarunveer S. Ahluwalia, Christian Dina, Rachel G. Miller, Ivan G. Shabalin, Beata Gyorgy, JingJing Cao, Suna Onengut-Gumuscu, Eiichiro Satake, Adam M. Smiles, Jani K. Haukka, David-Alexandre Tregouet, Tina Costacou, Kristina O'Neil, Andrew D. Paterson, Carol Forsblom, Hillary A. Keenan, Marcus G. Pezzolesi, Marlon Pragnell, Andrzej Galecki, Stephen S. Rich, Niina Sandholm, Ronald Klein, Barbara E. Klein, Katalin Susztak, Trevor J. Orchard, Ron Korstanje, George L. King, Samy Hadjadj, Peter Rossing, Joseph V. Bonventre, Per-Henrik Groop, James H. Warram, Andrzej S. Krolewski
Summary: Rare protein coding variants in the HSD17B14 gene were found to have a protective effect against the onset of ESKD in individuals with type 1 diabetes. However, gene and protein expression were attenuated in diabetic proximal tubules and mouse kidney injury models.
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
(2021)
Review
Medicine, General & Internal
Daria Kupczyk, Renata Studzinska, Renata Kolodziejska, Szymon Baumgart, Martyna Modrzejewska, Alina Wozniak
Summary: This paper discusses the role of glucocorticoids in the human body, their relationship with obesity, metabolic syndrome, and cardiovascular complications, and emphasizes the importance of selective inhibition of 11 beta-HSD1 in the treatment of these diseases.
JOURNAL OF CLINICAL MEDICINE
(2022)
Article
Biochemistry & Molecular Biology
Meixi Wang, Jianrui Li, Hu Li, Biao Dong, Jing Jiang, Nannan Liu, Jiali Tan, Xuekai Wang, Lei Lei, Hongying Li, Han Sun, Mei Tang, Huiqiang Wang, Haiyan Yan, Yuhuan Li, Jiandong Jiang, Zonggen Peng
Summary: This study identified 17-beta-hydroxysteroid dehydrogenase type 13 (HSD17B13) as a potential target for the treatment of non-alcoholic fatty liver disease (NAFLD). The researchers found that HSD17B13 was highly expressed in the livers of NAFLD patients and its overexpression facilitated the progression of NAFLD. In mouse models, overexpressing HSD17B13 worsened liver steatosis and fibrosis, while down-regulating its expression showed therapeutic effects.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biotechnology & Applied Microbiology
Rui Tang, Xiaoxian Ren, Menglei Xia, Yanbing Shen, Linna Tu, Jianmei Luo, Qi Zhang, Yuying Wang, Peilin Ji, Min Wang
Summary: This study established a one-step biocatalytic carbonyl reduction strategy for the efficient biosynthesis of boldenone from phytosterol by bridging 17 beta-hydroxysteroid dehydrogenase with a cofactor regeneration strategy in Mycobacterium neoaurum. The yield of boldenone was significantly increased with the establishment of an intracellular cofactor regeneration strategy, reaching the highest reported yield for transformation from phytosterol in one step. This strategy has practical value for the production of many valuable steroidal products from natural inexpensive raw materials.
APPLIED AND ENVIRONMENTAL MICROBIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Hanwen Li, Sihan Hu, Runze Wu, Hongyou Zhou, Kai Zhang, Ke Li, Wenzheng Lin, Qin Shi, Hao Chen, Shan Lv
Summary: This study demonstrated that 11 beta-HSD1 plays a significant role in facilitating osteoclasts formation and maturation through the Hippo signaling pathway. Knock-in mice with high expression of 11 beta-HSD1 showed a significant decrease in bone volume, while specific knock-out in osteoclasts provided protection to the skeleton. In vitro experiments confirmed that high expression of 11 beta-HSD1 promoted osteoclast formation and maturation.
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Chloe G. Fenton, Ana Crastin, Claire S. Martin, Saicharan Suresh, Isabella Montagna, Bismah Hussain, Amy J. Naylor, Simon W. Jones, Morten S. Hansen, Caroline M. Gorvin, Maria Price, Andrew Filer, Mark S. Cooper, Gareth G. Lavery, Karim Raza, Rowan S. Hardy
Summary: This study reveals the critical role of 11 beta-HSD1 in inflammatory bone loss and its involvement in the anti-inflammatory effects of therapeutic glucocorticoids (GCs) in chronic inflammatory disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Hong Wang, Jianmin Sang, Zhongyao Ji, Yang Yu, Shaowei Wang, Yang Zhu, Huitao Li, Yiyan Wang, Qiqi Zhu, Renshan Ge
Summary: This study investigated the inhibitory effects of six BPA analogues on the glucocorticoid-metabolizing enzyme 11 beta-hydroxysteroid dehydrogenase 1 (11 beta-HSD1). The results showed that these compounds had stronger inhibitory effects on human 11 beta-HSD1 than on rat 11 beta-HSD1. Molecular docking studies predicted that bisphenol H and bisphenol G bound to the active site of human 11 beta-HSD1 and formed a hydrogen bond with catalytic residue Ser170. The inhibitory strength of BPA analogues on both human and rat enzymes depended on their lipophilicity, molecular weight, heavy atoms, molecular volume, and binding affinity.
Article
Oncology
Meghan R. Flanagan, David R. Doody, Jenna Voutsinas, Qian Wu, Kalyan Banda, Nima Sharifi, Christopher I. Li, Vijayakrishna K. Gadi
Summary: Inheritance of the HSD3B1 adrenal permissive genotype is associated with poor outcomes in postmenopausal ER+/HER2(-) breast cancer.
ANNALS OF SURGICAL ONCOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Tatsuki Okumi, Atsunori Mori, Kentaro Okano
Summary: A regiocontrolled halogen dance reaction of 2,5-dibromopyrroles is reported using an N,N-dimethylsulfamoyl group to facilitate the interconversion of 2,3- and 2,4-dibromopyrrolyllithiums. This method was successfully applied to the formal synthesis of atorvastatin.
CHEMICAL COMMUNICATIONS
(2023)
Article
Chemistry, Multidisciplinary
Yushin Shibuya, Koki Susami, Hiroyuki Fukuoka, Seiha Yamaoka, Kentaro Okano, Atsunori Mori
Summary: Chiraphos acts as a highly effective ligand for nickel catalysts in cross-coupling polymerization reactions. The efficient nickel(II) catalyst promotes the cross-coupling polymerization of 2,5-differently substituted 1,4-dihalobenzene, particularly with a sterically congested substituent at the side chain, resulting in the formation of poly(1,4-phenylene). This catalyst exhibits high activity and enables control over the molecular weight and degree of polymerization.
Article
Chemistry, Applied
Masatoshi Yamada, Kazuki Azuma, Iori Takizawa, Yuki Ejima, Mitsuhisa Yamano, Kimio Satoh, Takayuki Doi, Hirofumi Ueda, Hidetoshi Tokuyama
Summary: A scalable asymmetric total synthesis of (-)-emetine, an important component in emetics, has been achieved. The synthesis involved 13 steps of highly efficient chemical reactions, including catalytic asymmetric allylation and industrial deoxygenation, eliminating the need for chromatographic purification. A high yield of (-)-emetine center dot 2HCl (12%) with over 93.2% HPLC purity was obtained, and the synthesis can be easily scaled up for larger production and currently used in natural ipecac syrup for clinical application.
ORGANIC PROCESS RESEARCH & DEVELOPMENT
(2023)
Article
Materials Science, Multidisciplinary
Sonoka Yamamoto, Ryutaro Yamashita, Chihiro Kubota, Kentaro Okano, Masatoshi Kitamura, Masahiro Funahashi, Syu-Cheng Ye, Yung-Tin Pan, Masaki Horie, Takuji Shintani, Hironori Murata, Hideto Matsuyama, Atsunori Mori
Summary: A thiophene-thiophene block copolymer with hydrophilic and hydrophobic side chains was synthesized. The block copolymer exhibited cylindrical microphase separation and the hydrophilic domain penetrated perpendicular to the substrate. The conductive properties of the thin film changed depending on its orientation to the substrate, with parallel orientation being conductive and perpendicular orientation being insulative. Electrochemical analysis showed that lithium ions transferred through the cylindrical domain composed of benzene sulfonic acid side chains.
JOURNAL OF MATERIALS CHEMISTRY C
(2023)
Article
Chemistry, Multidisciplinary
Hirofumi Ueda, Soichiro Sato, Kenta Noda, Hiroyuki Hakamata, Eunsang Kwon, Nagao Kobayashi, Hidetoshi Tokuyama
Summary: A biomimetic oxidative dimerization method for tryptophan derivatives was developed using oxygen as a bulk oxidant in aqueous media catalyzed by an iron octacarboxy phthalocyanine complex. The highly active iron catalyst enables aerobic enzyme-mimetic oxidation in a flask. This method provides a facile access to a broad range of dimerized peptides with unique scaffold, which can be used as a powerful tool for creating new small- and medium-sized molecules as drug candidates.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Ken-ichi Ojima, Hirofumi Ueda, Hidetoshi Tokuyama, M. Iyag
Summary: This study conducted synthetic studies on a dimeric indole alkaloid, cimicidu-phytine, by modifying the synthesis of (+)-haplophytine. The key aspects of this synthesis included the chemoselective deallylation of an N,O-diallyl derivative of a hydroxy aniline and the copper sulfate-mediated oxidative lactonization via oxidation of the amino moiety. A highly convergent strategy successfully synthesized the originally proposed cimiciduphytine, but it proved to be unstable under air and underwent cyclization to generate a bridged derivative.
BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN
(2023)
Article
Chemistry, Organic
Kentaro Okano, Yuya Okui, Atsunori Mori
Summary: A formal synthesis of dictyodendrin B was achieved by regiocontrolled functionalization of the alpha,beta-dibromopyrrole derivative, followed by reductive cyclization and further chemical transformation. The synthesis involved the construction of the characteristic tetracyclic pyrrolo[2,3c]carbazole skeleton and manipulation of the ester moiety.
Article
Chemistry, Organic
Yuxuan Feng, Taro Yukioka, Mei Matsuyama, Atsunori Mori, Kentaro Okano
Summary: A method for the regioselective functionalization of haloarenes through deprotonative lithiation is described. The haloaryllithiums generated were trapped with a zinc chloride diamine complex in a batch reactor, resulting in the formation of organozinc species without aryne formation. These species reacted with electrophiles to yield the corresponding products in yields of 38-98%. The method was successfully applied to the gram-scale, five-step total synthesis of carbazomycin A with an overall yield of 33%.
Article
Chemistry, Organic
Masahiro Hosoya, Atsunori Mori, Kentaro Okano
Summary: The regioselectivity for deprotonation of a pyridylthiophene can be controlled by changing the reaction conditions. In addition, the in situ transmetalation and halogen dance on the corresponding organometallic species can be controlled by additives, reaction temperature, and the above reaction conditions. As a result, this method enables the synthesis of four iodinated constitutional isomers from a single starting material, 2-(5-bromo-2-thienyl)pyridine.
Article
Chemistry, Organic
Seiha Yamaoka, Hiroyuki Fukuoka, Naoki Noda, Kentaro Okano, Masaki Horie, Atsunori Mori
Summary: A nickel thiocyanate complex was synthesized and used as a catalyst for various polymerization reactions and coupling reactions. The polymerization of 1,4-dihalobenzenes and 2-halo-3-hexylthiophenes resulted in the formation of poly-1,4-phenylenes and poly(3-hexylthiophene-2,5-diyl), respectively. The complex also catalyzed Suzuki-Miyaura couplings and Buchwald-Hartwig aminations, leading to the formation of biaryls and arylamines.
Article
Chemistry, Multidisciplinary
Kosuke Okada, Ken-ichi Ojima, Hirofumi Ueda, Hidetoshi Tokuyama
Summary: The synthesis of (+)-pleiocarpamine, (+)-voacalgine A and (+)-bipleiophylline was achieved in this study. The 10-step synthesis of (+)-pleiocarpamine features the construction of stereochemistry at the C16 position by radical cyclization and the synthesis of the highly strained cage-like structure via Pd-catalyzed intramolecular aromatic C-H functionalization. By modifying the biomimetic aerobic oxidative coupling of tryptophane derivatives catalyzed by FePc(CO2H)(8), the oxidative coupling of (+)-pleiocarpamine with pyrocatechuic acid produced (+)-voacalgine A. The total synthesis of (+)-bipleiophylline was completed by the second coupling of (+)-voacalgine A with (+)-pleiocarpamine or the one-pot couplings of 2 equiv of (+)-pleiocarpamine with pyrocatechuic acid.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Organic
Kengo Inoue, Atsunori Mori, Kentaro Okano
Summary: A two-step halogen transfer reaction of bromoarenes was reported. Bromoaryllithiums generated through deprotonative lithiation were converted into organozinc species by in situ zincation, followed by bromination to produce bromoarenes. It was also discovered that the bromo group could undergo regioselective translocation in the presence of ethylmagnesium chloride.
Article
Chemistry, Physical
Kohei Hosokawa, Kohei Tabuchi, Yuki Nakanishi, Kentaro Okano, Masaki Horie, Atsunori Mori
Summary: Multiple ring-closing metathesis of oligomeric bithiophene produced a vine-shaped oligomer with molecular asymmetry. Stereochemical studies revealed that the dimeric meso and racemic mixture converted to a meso-enriched product in the solid state, while the obtained meso compound reverted back to the meso and racemic mixture upon heating in chloroform solution. Heating the meso isomer in the solid state did not lead to isomerization.
MOLECULAR SYSTEMS DESIGN & ENGINEERING
(2023)
Article
Chemistry, Organic
Kengo Inoue, Atsunori Mori, Kentaro Okano
Summary: A two-step halogen transfer method for bromoarenes was reported. By utilizing deprotonative lithiation and in situ zincation, organozinc species were generated and then subjected to bromination to obtain di-, tri-, and tetrabromoarenes with high yields. Regioselective bromine-magnesium exchange followed by electrophilic trapping resulted in benzene, pyridine, quinoline, pyrimidine, and thiazole derivatives with bromo group translocation.
Article
Chemistry, Organic
Yuko Wakahara, Takahiro Noro, Juri Sakata, Hirofumi Ueda, Hidetoshi Tokuyama
Summary: This study investigates the construction of tetrahydroquinolines with a spirocyclic structure at the 4-position. A five-step sequence was developed, including the synthesis of benzocyclopentanone oxime, followed by the addition of aryl Grignard Reagent, intramolecular Friedel-Crafts acylation, condensation with hydroxylamine, and reductive ring expansion reaction. The method was successfully used to construct various tetrahydroquinolines with spirocyclic rings of different sizes and adamantane and indane structures at the 4-position.