57500-07-9Relevant articles and documents
Targeting nuclear protein TDP-43 by cell division cycle kinase 7 inhibitors: A new therapeutic approach for amyotrophic lateral sclerosis
Rojas-Prats, Elisa,Martinez-Gonzalez, Loreto,Gonzalo-Consuegra, Claudia,Liachko, Nicole F.,Perez, Concepción,Ramírez, David,Kraemer, Brian C.,Martin-Requero, ángeles,Perez, Daniel I.,Gil, Carmen,de Lago, Eva,Martinez, Ana
supporting information, (2020/11/12)
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no known cure. Aggregates of the nuclear protein TDP-43 have been recognized as a hallmark of proteinopathy in both familial and sporadic cases of ALS. Post-translational modifications of this protein, include hyperphosphorylation, cause disruption of TDP-43 homeostasis and as a consequence, promotion of its neurotoxicity. Among the kinases involved in these changes, cell division cycle kinase 7 (CDC7) plays an important role by directly phosphorylating TDP-43. In the present manuscript the discovery, synthesis, and optimization of a new family of selective and ATP-competitive CDC7 inhibitors based on 6-mercaptopurine scaffold are described. Moreover, we demonstrate the ability of these inhibitors to reduce TDP-43 phosphorylation in both cell cultures and transgenic animal models such as C. elegans and Prp-hTDP43 (A315T) mice. Altogether, the compounds described here may be useful as versatile tools to explore the role of CDC7 in TDP-43 phosphorylation and also as new drug candidates for the future development of ALS therapies.
Synthesis and biological evaluation of new HIV-1 protease inhibitors with purine bases as P2-ligands
Zhu, Mei,Dong, Biao,Zhang, Guo-Ning,Wang, Ju-Xian,Cen, Shan,Wang, Yu-Cheng
supporting information, p. 1541 - 1545 (2019/04/25)
Introducing purine bases to P2-ligands might enhance the potency of Human Immunodeficiency Virus-1 (HIV-1) protease inhibitory because of the carbonyl and NH groups promoting the formation of extensive H-bonding interactions. In this work, thirty-three compounds are synthesized and evaluated, among which inhibitors 16a, 16f and 16j containing N-2-(6-substituted-9H-purin-9-yl)acetamide as the P2-ligands along with 4-methoxylphenylsulfonamide as the P2′-ligand, display potent inhibitory effect on the activity of HIV-1 protease with IC50 43 nM, 42 nM and 68 nM in vitro, respectively.
Chemoenzymatic synthesis of cytokinins from nucleosides: Ribose as a blocking group
Oslovsky, Vladimir E.,Solyev, Pavel N.,Polyakov, Konstantin M.,Alexeev, Cyril S.,Mikhailov, Sergey N.
, p. 2156 - 2163 (2018/03/26)
Nucleoside phosphorylases are involved in the salvage pathways of nucleoside biosynthesis and catalyze the reversible reaction of a nucleobase with α-d-ribose-1-phosphate to yield a corresponding nucleoside and an inorganic phosphate. The equilibrium of these reactions is shifted towards nucleosides, especially in the case of purines. Purine nucleoside phosphorylase (PNP, EC 2.4.2.1) is widely used in labs and industry for the synthesis of nucleosides of practical importance. Bacterial PNPs have relatively broad substrate specificity utilizing a wide range of purines with different substituents to form the corresponding nucleosides. To shift the reaction in the opposite direction we have used arsenolysis instead of phosphorolysis. This reaction is irreversible due to the hydrolysis of the resulting α-d-ribose-1-arsenate. As a result, heterocyclic bases are formed in quantitative yields and can be easily isolated. We have developed a novel method for the preparation of cytokinins based on the enzymatic cleavage of the N-glycosidic bond of N6-substituted adenosines in the presence of PNP and Na2HAsO4. According to the HPLC analysis the conversion proceeds in quantitative yields. In the proposed strategy the ribose residue acts as a protective group. No contamination of the final products with AsO43- has been detected via HPLC-HRMS; simple analytical arsenate detection via ESI-MS has been proposed.
N6-isopentenyladenosine a new potential anti-angiogenic compound that targets human microvascular endothelial cells in vitro
Castiglioni, Sara,Romeo, Valentina,Casati, Silvana,Ottria, Roberta,Perrotta, Cristiana,Ciuffreda, Pierangela,Maier, Jeanette A. M.
, p. 533 - 545 (2018/12/04)
N6-isopentenyladenosine is an anti-proliferative and pro-apoptotic atypical nucleoside for normal and tumor cells. Considering the role of angiogenesis in various diseases, we investigated the cytotoxic effect of N6-isopentenyladenosine on human microvascular endothelial cells, protagonists in angiogenesis. Our results show that N6-isopentenyladenosine induced a significant reduction of cell viability, upregulated p21 and promoted caspase-3 cleavage in a dose dependent manner leading to apoptotic cell death as detected by FACS analysis. To understand structure-function relationship of N6-isopentenyladenosine, we investigated the effect of some N6-isopentenyladenosine analogs. Our results suggest that N6-isopentenyladenosine and some of its derivatives are potentially novel angiostatic agents and might be associated with other anti-angiogenic compounds for a better outcome.
An efficient synthesis of substituted cytosines and purines under focused microwave irradiation
Huang, Ling-Kuen,Cherng, Yen-Chih,Cheng, Yann-Ru,Jang, Jing-Pei,Chao, Yi-Ling,Cherng, Yie-Jia
, p. 5323 - 5327 (2008/02/01)
A rapid nucleophilic displacement reaction of 6-chloropurine, 2-amino-6-chloropurine and 5-bromocytosine with various nucleophiles under focused microwave irradiation is described. Using this method, the desired products were obtained with the yields up to 99% in?a?short reaction time.
Synthesis and antitumor activity of methyltriazene prodrugs simultaneously releasing DNA-methylating agents and the antiresistance drug O 6-benzylguanine
Wanner, Martin J.,Koch, Melle,Koomen, Gerrit-Jan
, p. 6875 - 6883 (2007/10/03)
Active resistance of tumor cells against DNA alkylating agents arises by the production of high levels of the DNA repair protein O6- alkylguanine-DNA alkyltransferase (AGT). This resistance during treatment with, for example, the anticancer agent temozolomide can be reversed by administration of O6-benzylguanine, a purine that transfers its benzyl group to AGT and irreversibly inactivates it. Stimulated by the favorable therapeutic properties of temozolomide we designed and synthesized DNA-methylating triazenes built on the anti-resistance benzylguanine ring system. The condensation reaction between 2-nitrosopurines and acylhydrazines proved to be very suitable to prepare acylated methyltriazenes. Fine-tuning of the release rate of both the methylating agent (diazomethane) and of O6-benzylguanine was accomplished by variation of the hydrolysis-sensitive acyl substituent in 5. Hydrolysis studies were performed with 1H NMR and revealed that the p-nitrophenyl substituted triazene 26 showed an optimal hydrolysis rate (t 1/2 = 23 min) and almost 100% selectivity for the desired fragmentation route. In vitro antitumor studies in the 60 human tumor cell line panel of the National Cancer Institute confirmed the superior properties ofp-nitrophenyl-protected methyl triazene 26, showing mean IC50 values of 10 μM. compared to 100 μM for temozolomide. In analogy with temozolomide, triazene 26 showed however low preference for each of the cancer subpanels, with IC50 values between 8 and 14 μM.
An efficient one-pot synthesis of 6-alkoxy-8,9-dialkylpurines via reaction of 5-amino-4-chloro-6-alkylaminopyrimidines with N,N-dimethylalkaneamides and alkoxide ions
Baraldi, Pier Giovanni,Broceta, Asier Unciti,Infantas, Maria Josè Pineda De Las,Mochun, Juan Josè Dìaz,Espinosa, Antonio,Romagnoli, Romeo
, p. 7607 - 7611 (2007/10/03)
The synthesis of a number of new 6-alkoxy-8,9-(disubstituted)purines has been accomplished by the cyclization of the corresponding intermediate 5-amino-4-chloro-6-(alkylamino)pyrimidines promoted by alkoxides and various N,N-dimethyl amides, where the latter act as solvent-reagents. By this three-component condensation reaction we are able to introduce an alkyl group in the 8 position of the purine ring with the concomitant nucleophilic replacement of the 6-chloro group with an alkoxy moiety.
SYNTHESIS AND N-ALKYLATION OF 6-BENZYLOXYPURINE UNDER PHASE-TRANSFER CONDITIONS
Ramzaeva, N.,Goldberg, Yu.,Alksnis, E.,Lidaks, M.
, p. 1669 - 1676 (2007/10/02)
Synthesis of 6-benzyloxypurine and its N-alkylation under phase-transfer conditions represents a high-yield and simple procedure for the preparation of 9- and 7-substituted 6-benzyloxypurines and, therefore, related hypoxanthines.
