| 1. |
- Chen, Zhipeng, et al.
(author)
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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
- 2021
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In: Journal of Medicinal Chemistry. - Washington, DC : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 64:11, s. 7371-7389
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Journal article (peer-reviewed)abstract
- 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. © 2021 American Chemical Society
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| 2. |
- Hu, Fanjie, et al.
(author)
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Imidazole Scaffold Based Compounds in the Development of Therapeutic Drugs
- 2021
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In: Current Topics in Medicinal Chemistry. - Oak Park, IL : Bentham Science Publishers Ltd.. - 1568-0266 .- 1873-4294. ; 21:28, s. 2514-2528
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Journal article (peer-reviewed)abstract
- Imidazole has an important five-membered aromatic heterocyclic ring, which is available widely in natural products and synthetic molecules. The special structural characteristics of imidazole ring enable it to bind with a variety of enzymes and receptors through hydrogen bonds, coordination, ion-dipole and cation-π interactions, hydrophobic effects, and Van der Waals forces. These interactions promote several biological activities involving anti-tumor, anti-inflammatory, anti-microbial, and anti-viral properties. Herein, we review and discuss recent developments in using imidazole derivatives and their special pharmacological activities for the treatment of various diseases. © 2021 Bentham Science Publishers.
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