130148-53-7Relevant academic research and scientific papers
Structure-Based Design of Highly Potent Toll-like Receptor 7/8 Dual Agonists for Cancer Immunotherapy
Wang, Zhisong,Gao, Yan,He, Lei,Sun, Shuhao,Xia, Tingting,Hu, Lu,Yao, Licheng,Wang, Liangliang,Li, Dan,Shi, Hui,Liao, Xuebin
supporting information, p. 7507 - 7532 (2021/06/28)
Activation of the toll-like receptors 7 and 8 has emerged as a promising strategy for cancer immunotherapy. Herein, we report the design and synthesis of a series of pyrido[3,2-d]pyrimidine-based toll-like receptor 7/8 dual agonists that exhibited potent and near-equivalent agonistic activities toward TLR7 and TLR8. In vitro, compounds 24e and 25a significantly induced the secretion of IFN-α, IFN-γ, TNF-α, IL-1β, IL-12p40, and IP-10 in human peripheral blood mononuclear cell assays. In vivo, compounds 24e, 24m, and 25a significantly suppressed tumor growth in CT26 tumor-bearing mice by remodeling the tumor microenvironment. Additionally, compounds 24e, 24m, and 25a markedly improved the antitumor activity of PD-1/PD-L1 blockade. In particular, compound 24e combined with the anti-PD-L1 antibody led to complete tumor regression. These results demonstrated that TLR7/8 agonists (24e, 24m, and 25a) held great potential as single agents or in combination with PD-1/PD-L1 blockade for cancer immunotherapy.
Synthesis of 2-Aminoquinazolinones via Carbonylative Coupling of ortho-Iodoanilines and Cyanamide
?kerbladh, Linda,Odell, Luke R.
, p. 2966 - 2973 (2016/04/26)
Herein, we describe a convenient and efficient synthesis of 2-aminoquinazolin-4(3H)-ones and N1-substituted 2-aminoquinazolin-4(1H)-ones by a domino carbonylation/cyclization process. The reaction proceeds via carbonylative coupling of readily available ortho-iodoanilines with cyanamide followed by in situ ring closure of an N-cyanobenzamide intermediate. The products were easily isolated by precipitation in moderate to excellent yields for a wide range of substrates, making this a highly attractive method for the synthesis of 2-aminoquinazolinones.
Regioselective Synthesis of Imidazoquinazoline Quinone Nucleosides and Quinazoline Amino Nucleosides. Studies of Their Xanthine Oxidase and Purine Nucleoside Phosphorylase Substrate Activity
O'Hara Dempcy, Robert,Skibo, Edward B.
, p. 776 - 785 (2007/10/02)
The regioselective synthesis of 3-ribofuranosylimidazoquinazoline-4,8,9(3H,7H)-trione (1) (benzoquinone-stretched-out inosine) and 8-(ribofuranosylamino)quinazolin-4(3H)-one (2) was carried out in conjunction with the design of reductive alkylating nucleosides and new purine nucleoside mimics, respectively.The preparation of 1 was carried out by regioselective ribosylation of 4-nitroimidazoquinazolin-8(3H,7H)-one (3) followed by nitro group reduction, Fremy oxidation, and deacetylation.Regiocontrol of ribosylation has steric origins: the 4-nitro group of 3 directs silylation to the N(1) position, which results in ribosylation exclusively at the N(3) position under Vorbrueggen reaction conditions.Regiocontrol during the preparation of 2 was possible by generating a stabilized ribofuranosyl carbocation, which selectively reacts with the amine group of the base.Nucleoside 1 is a purine-like quinone by virtue of its oxidation by xanthine oxidase.The potential inosine mimic 2 does not undergo phosphorolysis by purine nucleoside phosphorylase (PNPase), but the base form (8-aminoquinazolin-4(3H)-one) does bind to the PNPase active site as tightly as hypoxanthine.Factors which contribute to this binding behavior are discussed.
