- Structure-Based Design of Highly Potent Toll-like Receptor 7/8 Dual Agonists for Cancer Immunotherapy
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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.
- Wang, Zhisong,Gao, Yan,He, Lei,Sun, Shuhao,Xia, Tingting,Hu, Lu,Yao, Licheng,Wang, Liangliang,Li, Dan,Shi, Hui,Liao, Xuebin
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- Reaction between 7,8-dihydropterins and hydrogen peroxide under physiological conditions
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In vitiligo, a common skin disorder that produces white patches of depigmentation, 7,8-dihydropterins accumulate in the presence of high concentration of H2O2. In this work, we present a study of the reaction between 7,8-dihydropterins and H2O2. The rate of the reaction, as well as the products formed, strongly depend on the chemical structure of the substituents. Electron-donor groups as substituents are the most reactive derivatives and undergo oxidation of the pterin moiety. The corresponding bimolecular rate constants at 37 °C in neutral aqueous solutions are reported. The biological implications of the results obtained are also discussed.
- Laura Dántola,Schuler, Tobias M.,Paula Denofrio,Vignoni, Mariana,Capparelli, Alberto L.,Lorente, Carolina,Thomas, Andrés H.
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p. 8692 - 8699
(2008/12/21)
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- Stability of 7,8-dihydropterins in air-equilibrated aqueous solutions
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6-Substituted 7,8-dihydropterins (=2-amino-7,8-dihydropteridin-4(1H)-ones) are heterocyclic compounds that occur in a wide range of living systems and participate in relevant biological functions. In airequilibrated aqueous solutions, these compounds react with dissolved O2 (autooxidation). The rates of these reactions as well as the products formed strongly depend on the chemical structure of the substituents. 7,8-Dihydro-6-methylpterin and 7,8-dihydro-6,7-dimethylpterin that bear electron-donor groups as substituents are the most reactive derivatives and undergo oxidation of the pterin moiety to yield the corresponding oxidized derivatives (6-methylpterin and 6,7-dimethylpterin, resp.). The oxidations of 7,8-dihydrobiopterin, 7,8-dihydroneopterin, and 7,8-dihydrofolic acid are slower, and they yield 7,8-dihydroxanthopterin as the main product. 7,8-Dihydroxanthopterin, 6-formyl-7,8-dihydropterin, and sepiapterin are rather stable, and their consumption in air-equilibrated solutions is negligible for several days. The pseudo-first-order rate constants of the reactions between these compounds and O2 at 25° and 40° are reported. The biological implications of the results obtained are also discussed.
- Dantola, M. Laura,Vignoni, Mariana,Capparelli, Alberto L.,Lorente, Carolina,Thomas, Andres H.
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p. 411 - 425
(2009/02/07)
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