3054-01-1Relevant articles and documents
Fluorovinylsulfones and -Sulfonates as Potent Covalent Reversible Inhibitors of the Trypanosomal Cysteine Protease Rhodesain: Structure-Activity Relationship, Inhibition Mechanism, Metabolism, and in Vivo Studies
Jung, Sascha,Fuchs, Natalie,Johe, Patrick,Wagner, Annika,Diehl, Erika,Yuliani, Tri,Zimmer, Collin,Barthels, Fabian,Zimmermann, Robert A.,Klein, Philipp,Waigel, Waldemar,Meyr, Jessica,Opatz, Till,Tenzer, Stefan,Distler, Ute,R?der, Hans-Joachim,Kersten, Christian,Engels, Bernd,Hellmich, Ute A.,Klein, Jochen,Schirmeister, Tanja
, p. 12322 - 12358 (2021/09/02)
Rhodesain is a major cysteine protease of Trypanosoma brucei rhodesiense, a pathogen causing Human African Trypanosomiasis, and a validated drug target. Recently, we reported the development of α-halovinylsulfones as a new class of covalent reversible cysteine protease inhibitors. Here, α-fluorovinylsulfones/-sulfonates were optimized for rhodesain based on molecular modeling approaches. 2d, the most potent and selective inhibitor in the series, shows a single-digit nanomolar affinity and high selectivity toward mammalian cathepsins B and L. Enzymatic dilution assays and MS experiments indicate that 2d is a slow-tight binder (Ki = 3 nM). Furthermore, the nonfluorinated 2d-(H) shows favorable metabolism and biodistribution by accumulation in mice brain tissue after intraperitoneal and oral administration. The highest antitrypanosomal activity was observed for inhibitors with an N-terminal 2,3-dihydrobenzo[b][1,4]dioxine group and a 4-Me-Phe residue in P2 (2e/4e) with nanomolar EC50 values (0.14/0.80 μM). The different mechanisms of reversible and irreversible inhibitors were explained using QM/MM calculations and MD simulations.
Tanshinol and H2 S/NO Donor binding, preparation method thereof and application in pharmacy (by machine translation)
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Paragraph 0113-0115, (2020/08/18)
The invention belongs to the field of chemical pharmacy, and relates to active ingredient tanshinol and H in Chinese herbal medicine Salvia miltiorrhiza. 2 S/NO Donors and its preparation method and use in pharmacy, especially in the preparation of medicines for preventing and treating cardiovascular and cerebrovascular diseases and inflammation related diseases. To the invention, through in-vitro oxidative stress injury and inflammation model experiments, the results show that H is obviously inhibited. 2 O2 In vivo activity experiment results show that the conjugate is capable of remarkably inhibiting the release of inflammatory cytokines induced by LPS (LPS), reducing inflammation-induced mouse peritoneal macrophages, obviously inhibiting the release of inflammatory cytokines induced by LPS, and showing the result that the compound can be used for preparing drugs for preventing and treating cardiovascular and cerebrovascular diseases and inflammatory diseases. (by machine translation)
Structure-activity relationship study and biological evaluation of SAC-Garlic acid conjugates as novel anti-inflammatory agents
Bi, Jingjie,Wang, Wenqing,Du, Junxi,Chen, Kun,Cheng, Kui
, p. 233 - 245 (2019/07/02)
A series of S-allyl-L-cysteine (SAC) with garlic acid conjugates as anti-inflammatory agents were designed and synthesized. Among the 40 tested compounds, SMU-8c exhibited the most potent inhibitory activity to Pam3CSK4-induced nitric oxide (NO) in RAW264.7 macrophages with IC50 of 22.54 ± 2.60 μM. The structure-activity relationship (SAR) study suggested that the esterified carboxyl group, carbon chain extension and methoxylation phenol hydroxy could improve the anti-inflammatory efficacy. Preliminary anti-inflammatory mechanism studies showed that SMU-8c significantly down-regulated the levels of Pam3CSK4 triggered TNF-α cytokine in human THP-1 cells, mouse RAW 264.7 macrophages, as well as in ex-vivo human peripheral blood mononuclear cells (PBMC) with no influence on cell viability. SMU-8c specifically blocked the Pam3CSK4 ignited secreted embryonic alkaline phosphatase (SEAP) signaling with no influence to Poly I:C or LPS triggered TLR3 or TLR4 signaling. Moreover, SMU-8c suppressed TLR2 in HEK-Blue hTLR2 cells and inhibited the formation of TLR1-TLR2, and TLR2-TLR6 complex in human PBMC. In summary, SMU-8c inhibited the TLR2 signaling pathway to down-regulate the inflammation cytokines, such as NO, SEAP and TNF-α, to realize its anti-inflammatory activity.
