- Photoinactivation of tyrosinase sensitized by folic acid photoproducts
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Tyrosinase catalyzes in mammals the first and rate-limiting step in the biosynthesis of the melanin, the main pigment of the skin. Pterins, heterocyclic compounds able to photoinduce oxidation of biomolecules, accumulate in the skin of patients suffering from vitiligo, where there is a lack of melanin. Folic acid (PteGlu) is a conjugated pterin widespread in biological systems. Aqueous solutions of tyrosinase were exposed to UV-A irradiation (350 nm) in the presence of PteGlu and its photoproducts (6-formylpterin and 6-carboxypterin). The reactions were followed by UV-Vis spectrophotometry, enzyme activity measurement, fluorescence spectroscopy and HPLC. In this work, we present data that demonstrate unequivocally that solutions of tyrosinase exposed to UV-A irradiation in the presence of PteGlu, undergo enzyme inactivation. However, PteGlu itself causes a negligible effect on the activity of the enzyme. In contrast, PteGlu photoproducts are efficient photosensitizers. The tyrosinase inactivation involves two different pathways: (i) a photosensitization process and (ii) the oxidation of the enzyme by the hydrogen peroxide produced during the photooxidation of PteGlu and its photoproduct. The former pathway affects both the active site and the tryptophan residues, whereas the latter affects only the active site. The biological implications of the results are discussed.
- Laura Dántola,Zurbano, Beatriz N.,Thomas, Andrés H.
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- 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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supporting information
p. 7507 - 7532
(2021/06/28)
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- Transformation of 6-tetrahydrobiopterin in aqueous solutions under UV-irradiation
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Melanogenesis disturbance leads to several pathologies, including vitiligo disease. Ultraviolet (UV) narrowband phototherapy (308 or 311 nm) is used in treating vitiligo; however, the mechanism of phototherapy is not yet understood. Vitiligo is accompanied by three-fivefold increased de-novo synthesis of (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (H4Bip), its excess and its further oxidation can be considered as significant factors in the pathogenesis of vitiligo. (H4Bip), as the phenylalanine 4-hydroxylase coenzyme, catalyzes the oxidation of phenylalanine to tyrosine (a melanin precursor). In this context, photo-transformation of H4Bip in aqueous buffer solutions has been studied. HPLC–MS/MS has demonstrated that pterin products of H4Bip autoxidation (7,8-dihydropterin (H2Ptr), dihydroxanthopterin and pterin) predominate over biopterin products (7,8-dihydrobiopterin (H2Bip) and biopterin). We have shown that UV irradiation accelerates the autoxidation while the products of oxidative degradation of H4Bip act as photosensitizers. The distinctive feature of photooxidation of H4Bip from autoxidation is the formation of dihydropterin (Н2Ptr)2 and dihydrobiopterin (Н2Bip)2 dimers. By means of HPLC–MS/MS it was found that formation of dihydropterin dimers is the predominant process. The signal of molecular ion of the dimer (Н2Ptr)2 (m/z = 331) was almost a thousand times higher than the signal of (Н2Bip)2 (m/z = 479). The key point of the dimerization is photoexcitation (at 310–320 nm) of the intermolecular complex (qH2Ptr-Н2Ptr) generated in dark. As a result of the photoreaction azacyclobutane dimers have been formed. In the case of alternation of dark and light intervals H4Bip converted into dimers with 96 % yield. The data obtained are discussed in the context of UV-B narrowband vitiligo phototherapy.
- Telegina, Taisiya A.,Lyudnikova, Tamara A.,Buglak, Andrey A.,Vechtomova, Yulia L.,Biryukov, Mikhail V.,Demin, Vladimir V.,Kritsky, Mikhail S.
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p. 155 - 162
(2017/09/06)
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- 7-Substituted pterins provide a new direction for ricin A chain inhibitors
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Ricin is a potent toxin found in castor seeds. The A chain, RTA, enzymaticlly depurinates a specific adenosine in ribosomal RNA, inhibiting protein synthesis. Ricin is a known chemical weapons threat having no effective antidote. This makes the discovery of new inhibitors of great importance. We have previously used 6-substituted pterins, such as pteroic acid, as an inhibitor platform with moderate success. We now report the success of 7-carboxy pterin (7CP) as an RTA inhibitor; its binding has been monitored using both kinetic and temperature shift assays and by X-ray crystallography. We also discuss the synthesis of various derivatives of 7CP, and their binding affinity and inhibitory effects, as part of a program to make effective RTA inhibitors.
- Pruet, Jeff M.,Jasheway, Karl R.,Manzano, Lawrence A.,Bai, Yan,Anslyn, Eric V.,Robertus, Jon D.
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experimental part
p. 3608 - 3615
(2011/11/01)
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- One-step synthesis of lumazine and xanthine: First co-crystal of lumazine and perchloric acid with a unique monohydrated hydronium ion (H 5O2+) mediated supramolecular assembly of the lumazine dimer
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A perchloric acid mediated one-step synthesis of lumazine derivatives from pterins and xanthine from guanine is reported. However, 2-pivaloylamino derivatives of pterins underwent simple hydrolysis of the pivaloylamino group generating free pterin compounds, but the 2-oxo derivatives, that is, the lumazine compounds, were not obtained. A novel supramolecular assembly is constructed by the unique hydrogen bonding of H5O2 + bridging two hydrogen-bonded dimers of lumazine to form the co-crystal 21 with aqueous perchloric acid. In contrast, N2-pivaloyl- 6-bromo-5-deazapterin was simply hydrolysed to form the protonated deazapterin 22, which forms a unique six-membered cyclic hydrogen-bonded structure leading to the generation of a polymeric supramolecular assembly. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
- Goswami, Shyamaprosad,Maity, Annada C.,Fun, Hoong-Kun
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p. 4056 - 4064
(2008/02/13)
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- Pteridines. Part CXIII. Protection of Pteridines
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The low solubulity of pterins can drastically be improved by N2-acylation or formation of the N2-[(dimethylamino)methylene] derivatives. Both types of compounds can be alkylated under Mitsunobu conditions to form from N2-acylpterins (see 2 and 3) and their derivatives (see 5, 6, 8, 9, 11, 13, 15, and 17) selectively the O4-alkyl derivatives 22-31, whereas the electron-donating [(dimethylamino)methyleneamino] function in 46-51 gives, in a selective reaction, the N(3)-substitution (->52-61). N2,N2-Dimethylpterins and 18 and 19 and N2-methylpterins 20 and 21 direct alkylation also to the O4-position (->32-35, 38 and 39). Deacylation can be achieved under very mild conditions by solvolysis with MeOH (22->40, 26->41), and displacement of the O4-[2-(4-nitrophenyl)ethyl] group proceeds with ammonia at room temperature to the corresponding pteridin-2,4-diamine 42-45. Cleavage of the N2-[(dimethylamino)methylene] group works well with ammonia (->62-67). The advantage of applying the 2-(4-nitrophenyl)ethyl (npe) group as blocking group is seen in its selective removal by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) under aprotic conditions without harming the other substituents.
- Yao, Qizheng,Pfleiderer, Wolfgang
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- RING TRANSFORMATION OF PTERINS TO GUANINES
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7-Alkoxypterins undergo a ring contraction into guanine derivatives and demethoxylation by activated aluminum.
- Sugimoto, Takashi,Nishioka, Noriko,Murata, Shizuaki,Matsuura, Sadao
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p. 2091 - 2092
(2007/10/02)
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- Pterins. VIII. The Absolute Configuration at C 6 of Natural 2-Amino-6--5,6,7,8-tetrahydropteridin-4(3H)-one (L-erythro-5,6,7,8-tetrahydrobiopterin)
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The conformation of the side chain of 5,6,7,8-tetrahydrobiopterin (6) in 0.5 M DCl/D2O is predominantly quasi-equatorial (deduced from 3J (13C 4a, 1H 6) 1.1 Hz), and is the same as that of the methyl group in 2-methyl-1,2,3,4-tetrahydroquinoxaline and in 2-amino-6-methyl-5,6,7,8-tetrahydropteridin-4(3H)-one in the same solvent.Because (-)-2S)-2-methyl-1,2,3,4-tetrahydroquinoxaline (4) and (-)-(6S)-2-amino-6-methyl-5,6,7,8-tetrahydropteridin-4(3H)-one (5) have the same conformation and negative c.d. spectra (Θ 248 nm and 263 nm respectively) as does the natural 5,6,7,8-tetrahydrobiopterin (Θ minimum at 265 nm) in 0.1 M hydrochloric acid, then the absolute conformations of the tetrahydropyrazine rings and the absolute configurations at the chiral crntres C2, C6, and C6 of compounds (4),(5) and (6) respectively are the same.Hence the absolute configuration at C6 in natural 5,6,7,8-tetrahydrobiopterin is R.A convenient synthesis of biopterrin on a gram scale is described.
- Armarego, Wilfred L. F.,Waring, Paul,Paal, Bela
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p. 785 - 793
(2007/10/02)
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