Author: Hu, Qinghua ; Zhou, Mengze ; Mao, Tianqi ; Wang, Yaxuan ; Zhu, Yifan ; Tian, Sheng ; Zhang, Zhoudong ; Li, Huanqiu ; Li, Duxin ; Guo, Yueyue ; Li, Yehong ; Cheng, Xiangyu ; Wang, Hui

As a member of purinoceptors, the P2Y₆ receptor (P2Y₆R) plays a crucial role in modulating immune signals and has been considered as a potential therapeutic target for inflammatory diseases. On the basis of the speculated probable conformation and binding determinants of P2Y₆R, a hierarchical strategy that combines virtual screening, bioassays, and chemical optimization was presented. A potent P2Y₆R antagonist (compound 50) was identified to possess excellent antagonistic activity (IC₅₀ = 5.914 nM) and high selectivity. In addition, binding assays and chemical pull-down experiments confirmed that compound 50 was nicely bound to P2Y₆R. Notably, compound 50 could effectively ameliorate DSS-induced ulcerative colitis in mice through inhibiting the activation of NLRP3 inflammasome in colon tissues. Moreover, treatment with compound 50 reduced LPS-induced pulmonary edema and infiltration of inflammatory cells in mice. These findings suggest that compound 50 could serve as a specific P2Y₆R antagonist for treating inflammatory diseases and deserve further optimization studies.

02 May 2023·Pharmaceuticals (Basel, Switzerland)

Design, Synthesis and Biological Evaluation of Novel MDH Inhibitors Targeting Tumor Microenvironment.

Article

Author: Yang, Hyun-A ; Lee, Kyeong ; Godesi, Sreenivasulu ; Lee, Chang Hoon ; Han, Jeong-Ran ; Im, Joo-Young ; Won, Misun ; Lee, Joohan ; Ban, Hyun Seung ; Kwak, Dong-Ik ; Choi, Yongseok ; Kim, Minkyoung ; Nada, Hossam ; Kim, Jang-Keun

MDH1 and MDH2 enzymes play an important role in the survival of lung cancer. In this study, a novel series of dual MDH1/2 inhibitors for lung cancer was rationally designed and synthesized, and their SAR was carefully investigated. Among the tested compounds, compound 50 containing a piperidine ring displayed an improved growth inhibition of A549 and H460 lung cancer cell lines compared with LW1497. Compound 50 reduced the total ATP content in A549 cells in a dose-dependent manner; it also significantly suppressed the accumulation of hypoxia-inducible factor 1-alpha (HIF-1α) and the expression of HIF-1α target genes such as GLUT1 and pyruvate dehydrogenase kinase 1 (PDK1) in a dose-dependent manner. Furthermore, compound 50 inhibited HIF-1α-regulated CD73 expression under hypoxia in A549 lung cancer cells. Collectively, these results indicate that compound 50 may pave the way for the development of next-generation dual MDH1/2 inhibitors to target lung cancer.

01 May 2023·Steroids

Androgenic steroids in Over-the-Counter dietary Supplements: Analysis for association with adverse health effects

Article

Author: Aldous, Kenneth M ; Okoniewski, Richard ; Spink, David C ; Spink, Barbara C ; LeMaster, David M ; Tran, Buu N

From 2012 to 2013, approximately 16 New York residents reported vague, nonspecific adverse health effects which included fatigue, loss of scalp hair, and muscle aches. One patient was hospitalized for liver damage. An epidemiological investigation identified a common factor among these patients; the consumption of B-50 vitamin and multimineral supplements from the same supplier. To investigate whether these nutritional supplements might have been responsible for the adverse health effects observed, comprehensive chemical analyses of marketed lots of the supplements were performed. To determine presence of organic components and contaminants, organic extracts of samples were prepared and analyzed using gas chromatography-mass spectrometry (GC-MS), liquid chromatography-tandem mass spectrometry (LC-MS/MS), liquid chromatography high-resolution mass spectrometry (LC-HRMS), and nuclear magnetic resonance (NMR). These analyses revealed the presence of significant levels of methasterone (17β-hydroxy-2α,17α-dimethyl-5α-androstane-3-one), an androgenic steroid and schedule III-controlled substance; dimethazine, an azine-linked dimer of methasterone; and methylstenbolone (2,17α-dimethyl-17β-hydroxy-5α-androst-1-en-3-one), a related androgenic steroid. Methasterone and extracts of certain supplement capsules were identified as highly androgenic in luciferase assays by using an androgen receptor promoter construct. This androgenicity persisted for several days after cell exposure to the compounds. The presence of these components in implicated lots were associated with adverse health effects and the hospitalization of one patient and the presentation of symptoms of severe virilization in a child. These findings underscore the need for more rigorous oversight of the nutritional supplement industry.

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Indication	Highest Phase	Country/Location	Organization	Date
Thrombocytopenia	Preclinical	US	Pharmagenesis, Inc.	-

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