- Design, Synthesis, and Structure-Activity Relationship of N-Aryl- N′-(thiophen-2-yl)thiourea Derivatives as Novel and Specific Human TLR1/2 Agonists for Potential Cancer Immunotherapy
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The previous virtual screening of ten million compounds yielded two novel nonlipopeptide-like chemotypes as TLR2 agonists. Herein, we present the chemical optimization of our initial hit, 1-phenyl-3-(thiophen-2-yl)urea, which resulted in the identification of SMU-C80 (EC50 = 31.02 ± 1.01 nM) as a TLR2-specific agonist with a 370-fold improvement in bioactivity. Mechanistic studies revealed that SMU-C80, through TLR1/2, recruits the adaptor protein MyD88 and triggers the NF-κB pathway to release cytokines such as TNF-α and IL-1β from human, but not murine, cells. To the best of our knowledge, it is the first species-specific TLR1/2 agonist reported until now. Moreover, SMU-C80 increased the percentage of T, B, and NK cells ex vivo and activated the immune cells, which suppressed cancer cell growth in vitro. In summary, we obtained a highly efficient and specific human TLR1/2 agonist that acts through the MyD88 and NF-κB pathway, facilitating cytokine release and the simultaneous activation of immune cells that in turn affects the apoptosis of cancer cells.
- Chen, Zhipeng,Zhang, Lina,Yang, Junjie,Zheng, Lu,Hu, Fanjie,Duan, Siqin,Nandakumar, Kutty Selva,Liu, Shuwen,Yin, Hang,Cheng, Kui
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supporting information
p. 7371 - 7389
(2021/06/28)
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- Cycloalkyl thienopyrimidinone compounds as well as preparation method and application thereof
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The invention relates to a parent nucleus compound containing cycloalkyl[4,5]thieno[2,3-d]pyrimidin-4 (3H)-one, and the parent nucleus compound has the following structure shown in the specification,wherein R1, X, m and n are defined in the specification.
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Paragraph 0031-0035; 0036-0039
(2020/07/12)
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- Synthesis of urea analogues bearing N-alkyl-N’-(thiophen-2-yl) scaffold and evaluation of their innate immune response to toll-like receptors
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Previous high throughput virtual screening of 10 million-compound and following cell based validation led to the discovery of a novel, nonlipopeptide-like chemotype ZINC 6662436, as toll-like receptor 2 (TLR2) agonists. In this report, compounds belonging
- Chen, Zhipeng,Cen, Xiaohong,Yang, Junjie,Lin, Zhiman,Liu, Meihuan,Cheng, Kui
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- Structure based design of selective SHP2 inhibitors by De novo design, synthesis and biological evaluation
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SHP2 phosphatase, encoded by the PTPN11 gene, is a non-receptor PTP, which plays an important role in growth factor, cytokine, integrin, hormone signaling pathways, and regulates cellular responses, such as proliferation, differentiation, adhesion migrati
- Liu, Wen-Shan,Jin, Wen-Yan,Zhou, Liang,Lu, Xing-Hua,Li, Wei-Ya,Ma, Ying,Wang, Run-Ling
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p. 759 - 774
(2019/07/17)
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- An NMDAR positive and negative allosteric modulator series share a binding site and are interconverted by methyl groups
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N-methyl-D-aspartate receptors (NMDARs) are an important receptor in the brain and have been implicated in multiple neurological disorders. Many non-selective NMDAR-targeting drugs are poorly tolerated, leading to efforts to target NMDAR subtyp
- Perszyk, Riley,Katzman, Brooke M.,Kusumoto, Hirofumi,Kell, Steven A.,Epplin, Matthew P.,Tahirovic, Yesim A.,Moore, Rhonda L.,Menaldino, David,Burger, Pieter,Liotta, Dennis C.,Traynelis, Stephen F.
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- Design, synthesis, molecular docking and biological evaluation of thiophen-2-iminothiazolidine derivatives for use against Trypanosoma cruzi
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In this study, we designed and synthesized a series of thiophen-2-iminothiazolidine derivatives from thiophen-2-thioureic with good anti-Trypanosoma cruzi activity. Several of the final compounds displayed remarkable trypanocidal activity. The ability of the new compounds to inhibit the activity of the enzyme cruzain, the major cysteine protease of T. cruzi, was also explored. The compounds 3b, 4b, 8b and 8c were the most active derivatives against amastigote form, with significant IC50values between 9.7 and 6.03?μM. The 8c derivative showed the highest potency against cruzain (IC50?=?2.4?μM). Molecular docking study showed that this compound can interact with subsites S1 and S2 simultaneously, and the negative values for the theoretical energy binding (Eb?=??7.39?kcal·mol?1) indicates interaction (via dipole–dipole) between the hybridized sulfur sp3atom at the thiazolidine ring and Gly66. Finally, the results suggest that the thiophen-2-iminothiazolidines synthesized are important lead compounds for the continuing battle against Chagas disease.
- Silva-Júnior,Silva,Fran?a,Silva,Barreto,Silva,Ferreira,Gatto,Moreira,Siqueira-Neto,Mendon?a-Júnior,Lima,Bortoluzzi,Scotti,Scotti,Meneghetti,Aquino,Araújo-Júnior
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p. 4228 - 4240
(2016/08/23)
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- Novel thiophene derivatives as PTP1B inhibitors with selectivity and cellular activity
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A series of novel thiophene derivatives was designed, synthesized and their activities as competitive inhibitors of protein tyrosine phosphatase (PTPs) 1B (PTP1B) inhibitors were evaluated. All the compounds showed inhibitory potencies, and 10 of these exhibited moderate inhibitory activities with IC50 values less than 10 μM. The activity of the most potent compound P28 (IC50 = 2.1 μM) was 15 times higher than that of the hit compound P01. Further, four representative compounds (P19, P22, P28, and P31) demonstrated remarkably high selectivities against other PTPs (e.g., PTPα, LAR, CD45, and TCPTP); P19 exhibited greater than sixfold selectivity over highly homologous TCPTP. More importantly, these compounds are permeable to cell membranes. The treatment of CHO-K1 cells with P28 (10 μM) resulted in increased phosphorylation of AKT, which suggested extensive cellular activity of this compound. The novel chemical entities reported in this study could be used for overcoming the poor selectivity and low cellular activity of PTP1B inhibitors and might represent a starting point for development of therapeutic PTP inhibitors.
- Ye, Deju,Zhang, Yu,Wang, Fei,Zheng, Mingfang,Zhang, Xu,Luo, Xiaomin,Shen, Xu,Jiang, Hualiang,Liu, Hong
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scheme or table
p. 1773 - 1782
(2010/05/02)
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- NOVEL COMPOUNDS AS CANNABINOID RECEPTOR LIGANDS
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The present application relates to cannabinoid receptor ligands containing compounds of formula (I) wherein A, R1, R2, and R3 are as defined in the specification. The present application also relates to compositions comprising such compounds, and methods of treating conditions and disorders using such compounds and compositions.
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Page/Page column 45
(2009/01/24)
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- ANTHELMINTIC AND INSECTICIDAL THIOPHENE DERIVATIVES
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Novel anthelmintic compositions containing thiophene derivatives as active ingredients are disclosed.
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