4815-36-5Relevant articles and documents
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
Chen, Zhipeng,Zhang, Lina,Yang, Junjie,Zheng, Lu,Hu, Fanjie,Duan, Siqin,Nandakumar, Kutty Selva,Liu, Shuwen,Yin, Hang,Cheng, Kui
supporting information, p. 7371 - 7389 (2021/06/28)
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.
Design, molecular docking and biological evaluation of fused thienopyrimidines and quinazoline
Kaliraj,Jeyalakshmi,Kathiravan,Madhavan,Devi, Arikketh
, p. 537 - 544 (2021/02/27)
The anticancer activity of the condensed pyrimidine and quinazoline moieties are pronounced with a different pathway. Thienopyrimidine is considered as ring equivalent bioisosteres of quinazolines and present in other heterocyclic compounds including thienopyrimidine. The present investigation focused on the synthesis of thienopyrimidine and quinazoline derivatives for their anticancer activity against the human oral squamous carcinoma-3 (HSC-3) cell line. The synthesized compound confirmed for their structural characteristics from spectral analysis and tested for anti-proliferative activity from MTT assay. The electron-withdrawing group in 4-chloro thienopyrimidines and amino ester derivate/facilitate the inhibition of cancer cells. Further probing by docking studies revealed that the compounds exhibit possible interactions with VEGF, FGFR and c-Met proteins, which are known to have a role in the pathogenesis of oral squamous cell carcinoma. Among the derivatives a moderate activity demonstrated by substituted 4-chloro-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-pyrimidine (4a) and ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (1a) derivatives. Lack of chirality and the presence of bulky substituents in few of the compounds were found to be the cause for lower potency.
Design, Synthesis, and Biological Evaluation of 6-Substituted Thieno[3,2- d]pyrimidine Analogues as Dual Epidermal Growth Factor Receptor Kinase and Microtubule Inhibitors
Romagnoli, Romeo,Prencipe, Filippo,Oliva, Paola,Baraldi, Stefania,Baraldi, Pier Giovanni,Schiaffino Ortega, Santiago,Chayah, Mariem,Kimatrai Salvador, Maria,Lopez-Cara, Luisa Carlota,Brancale, Andrea,Ferla, Salvatore,Hamel, Ernest,Ronca, Roberto,Bortolozzi, Roberta,Mariotto, Elena,Mattiuzzo, Elena,Viola, Giampietro
supporting information, p. 1274 - 1290 (2019/01/30)
The clinical evidence for the success of tyrosine kinase inhibitors in combination with microtubule-targeting agents prompted us to design and develop single agents that possess both epidermal growth factor receptor (EGFR) kinase and tubulin polymerization inhibitory properties. A series of 6-aryl/heteroaryl-4-(3′,4′,5′-trimethoxyanilino)thieno[3,2-d]pyrimidine derivatives were discovered as novel dual tubulin polymerization and EGFR kinase inhibitors. The 4-(3′,4′,5′-trimethoxyanilino)-6-(p-tolyl)thieno[3,2-d]pyrimidine derivative 6g was the most potent compound of the series as an antiproliferative agent, with half-maximal inhibitory concentration (IC50) values in the single- or double-digit nanomolar range. Compound 6g bound to tubulin in the colchicine site and inhibited tubulin assembly with an IC50 value of 0.71 μM, and 6g inhibited EGFR activity with an IC50 value of 30 nM. Our data suggested that the excellent in vitro and in vivo profile of 6g may be derived from its dual inhibition of tubulin polymerization and EGFR kinase.
