7724-76-7Relevant academic research and scientific papers
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.
New tools in nucleoside toolbox of tick-borne encephalitis virus reproduction inhibitors
Orlov, Alexey A.,Drenichev, Mikhail S.,Oslovsky, Vladimir E.,Kurochkin, Nikolay N.,Solyev, Pavel N.,Kozlovskaya, Liubov I.,Palyulin, Vladimir A.,Karganova, Galina G.,Mikhailov, Sergey N.,Osolodkin, Dmitry I.
supporting information, p. 1267 - 1273 (2017/06/19)
Design and development of nucleoside analogs is an established strategy in the antiviral drug discovery field. Nevertheless, for many viruses the coverage of structure-activity relationships (SAR) in the nucleoside chemical space is not sufficient. Here we present the nucleoside SAR exploration for tick-borne encephalitis virus (TBEV), a member of Flavivirus genus. Promising antiviral activity may be achieved by introduction of large hydrophobic substituents in the position 6 of adenosine or bulky silyl groups to the position 5′. Introduction of methyls to the ribose moiety does not lead to inhibition of TBEV reproduction. Possible mechanisms of action of these nucleosides include the inhibition of viral entry or interaction with TBEV non-structural protein 5 methyltransferase or RNA-dependent RNA polymerase domains.
Chemical modification of the plant isoprenoid cytokinin N 6-isopentenyladenosine yields a selective inhibitor of human enterovirus 71 replication
Tararov, Vitali I.,Tijsma, Aloys,Kolyachkina, Svetlana V.,Oslovsky, Vladimir E.,Neyts, Johan,Drenichev, Mikhail S.,Leyssen, Pieter,Mikhailov, Sergey N.
, p. 406 - 413 (2015/02/19)
In this study, we demonstrate that N6-isopentenyladenosine, which essentially is a plant cytokinin-like compound, exerts a potent and selective antiviral effect on the replication of human enterovirus 71 with an EC50 of 1.0 ± 0.2 ?1/4M and a selectivity index (SI) of 5.7. The synthesis of analogs with modification of the N6-position did not result in a lower EC50 value. However, in particular with the synthesis of N6-(5-hexene-2-yne-1-yl)adenosine (EC50 Combining double low line 4.3 ± 1.5 ?1/4M), the selectivity index was significantly increased: because of a reduction in the adverse effect of this compound on the host cells, an SI > 101 could be calculated. With this study, we for the first time provide proof that a compound class that is based on the plant cytokinin skeleton offers an interesting starting point for the development of novel antivirals against mammalian viruses, in the present context in particular against enterovirus 71.
Regioselective 1-N-Alkylation and rearrangement of adenosine derivatives
Oslovsky, Vladimir E.,Drenichev, Mikhail S.,Mikhailov, Sergey N.
, p. 475 - 499 (2015/10/19)
Several methods for the preparation of some N6-substituted adenosines based on selective 1-N-alkylation with subsequent Dimroth rearrangement were developed. The proposed methods seem to be effective for the preparation of natural N6-isopentenyl- and N6-benzyladenosines, which are known to possess pronounced biological activities. Direct 1-N-alkylation of 2′,3′,5′-tri-O-acetyladenosine and 3,5′-di-O-acetyl-2-deoxyadenosine with alkyl halides in N,N-dimethylformamide (DMF) in the presence of BaCO3 and KI gave 1-N-substituted derivatives with quantitative yields, whereas 1-N-alkylation of adenosine was accompanied by significant O-alkylation. Moreover, the reaction of trimethylsilyl derivatives of N6-acetyl-2,3,5′-tri-O-acetyladenosine and N6-acetyl-3,5′-di-O-acetyl-2-deoxyadenosine with alkyl halides leads to the formation of the stable 1-N-substituted adenosines. Dimroth rearrangement of 1-N-substituted adenosines in aqueous ammonia yields pure N6-substituted adenosines.
Chemical modification of the plant isoprenoid cytokinin N6-isopentenyladenosine yields a selective inhibitor of human enterovirus 71 replication
Tararov, Vitali I.,Tijsma, Aloys,Kolyachkina, Svetlana V.,Oslovsky, Vladimir E.,Neyts, Johan,Drenichev, Mikhail S.,Leyssen, Pieter,Mikhailov, Sergey N.
, p. 406 - 413 (2015/05/04)
In this study, we demonstrate that N6-isopentenyladenosine, which essentially is a plant cytokinin-like compound, exerts a potent and selective antiviral effect on the replication of human enterovirus 71 with an EC50 of 1.0 ± 0.2 mM and a selectivity index (SI) of 5.7. The synthesis of analogs with modification of the N6-position did not result in a lower EC50 value. However, in particular with the synthesis of N6-(5-hexene-2-yne-1-yl)adenosine (EC50 = 4.3 ± 1.5 mM), the selectivity index was significantly increased: because of a reduction in the adverse effect of this compound on the host cells, an SI 101 could be calculated. With this study, we for the first time provide proof that a compound class that is based on the plant cytokinin skeleton offers an interesting starting point for the development of novel antivirals against mammalian viruses, in the present context in particular against enterovirus 71.
A purine nucleoside phosphorylase in Solanum tuberosum L. (potato) with specificity for cytokinins contributes to the duration of tuber endodormancy
Bromley, Jennifer R.,Warnes, Barbara J.,Newell, Christine A.,Thomson, Jamie C.P.,James, Celia M.,Turnbull, Colin G.N.,Hanke, David E.
, p. 225 - 237 (2014/03/21)
StCKP1 (Solanum tuberosum cytokinin riboside phosphorylase) catalyses the interconversion of the N9-riboside form of the plant hormone CK (cytokinin), a subset of purines, with its most active free base form. StCKP1 prefers CK to unsubstituted aminopurines. The protein was discovered as a CK-binding activity in extracts of tuberizing potato stolon tips, from which it was isolated by affinity chromatography. The N-terminal amino acid sequence matched the translation product of a set of ESTs, enabling a complete mRNA sequence to be obtained by RACE-PCR. The predicted polypeptide includes a cleavable signal peptide and motifs for purine nucleoside phosphorylase activity. The expressed protein was assayed for purine nucleoside phosphorylase activity against CKs and adenine/adenosine. Isopentenyladenine, trans-zeatin, dihydrozeatin and adenine were converted into ribosides in the presence of ribose 1-phosphate. In the opposite direction, isopentenyladenosine, trans-zeatin riboside, dihydrozeatin riboside and adenosine were converted into their free bases in the presence of Pi. StCKP1 had no detectable ribohydrolase activity. Evidence is presented that StCKP1 is active in tubers as a negative regulator of CKs, prolonging endodormancy by a chill-reversible mechanism.
Peroxide-shunt substrate-specificity for the Salmonella typhimurium O 2-dependent tRNA modifying monooxygenase (MiaE)
Corder, Andra L.,Subedi, Bishnu P.,Zhang, Siai,Dark, Amanda M.,Foss Jr., Frank W.,Pierce, Brad S.
, p. 6182 - 6196 (2013/10/01)
Post-transcriptional modifications of tRNA are made to structurally diversify tRNA. These modifications alter noncovalent interactions within the ribosomal machinery, resulting in phenotypic changes related to cell metabolism, growth, and virulence. MiaE is a carboxylate bridged, nonheme diiron monooxygenase, which catalyzes the O2-dependent hydroxylation of a hypermodified-tRNA nucleoside at position 37 (2-methylthio-N6- isopentenyl-adenosine(37)-tRNA) [designated ms2i6A 37]. In this work, recombinant MiaE was cloned from Salmonella typhimurium, purified to homogeneity, and characterized by UV-visible and dual-mode X-band EPR spectroscopy for comparison to other nonheme diiron enzymes. Additionally, three nucleoside substrate-surrogates (i6A, Cl2i6A, and ms2i6A) and their corresponding hydroxylated products (io6A, Cl2io 6A, and ms2io6A) were synthesized to investigate the chemo- and stereospecificity of this enzyme. In the absence of the native electron transport chain, the peroxide-shunt was utilized to monitor the rate of substrate hydroxylation. Remarkably, regardless of the substrate (i6A, Cl2i6A, and ms2i6A) used in peroxide-shunt assays, hydroxylation of the terminal isopentenyl-C4-position was observed with >97% E-stereoselectivity. No other nonspecific hydroxylation products were observed in enzymatic assays. Steady-state kinetic experiments also demonstrate that the initial rate of MiaE hydroxylation is highly influenced by the substituent at the C2-position of the nucleoside base (v0/[E] for ms2i6A > i 6A > Cl2i6A). Indeed, the >3-fold rate enhancement exhibited by MiaE for the hydroxylation of the free ms 2i6A nucleoside relative to i6A is consistent with previous whole cell assays reporting the ms2io6A and io6A product distribution within native tRNA-substrates. This observation suggests that the nucleoside C2-substituent is a key point of interaction regulating MiaE substrate specificity.
N6-acetyl-2,3,5-tri-O-acetyladenosine; A convenient, missed out substrate for regioselective N6-alkylations
Tararov, Vitali I.,Kolyachkina, Svetlana V.,Alexeev, Cyril S.,Mikhailov, Sergey N.
, p. 2483 - 2489 (2011/09/20)
A simple and efficient route to N6-acetyl-2,3,5-tri-O- acetyladenosine (1) was developed based on selective N-deacetylation of pentaacetylated adenosine 2 with methanol at room temperature in the presence of imidazole. Preparative synthesis of 1 was elaborated utilizing a crude mixture of 2 and 1 which is produced by reaction of adenosine with acetic anhydride in pyridine at elevated temperatures. The total yield of 1 was 80-85% starting with adenosine. It was shown that 1 is a convenient substrate for selective N 6-alkylations. The study revealed the same regioselectivity in base-promoted reactions of 1 with activated alkyl halides and Mitsunobu reactions of 1 with alcohols. A series of N6-alkyladenosines 5a-f were prepared. Cytokinins 6b,d,e were prepared by enzymatic transformation of parent nucleoside derivatives 5b,d,e using a combination of nucleoside phosphorylase and alkaline phosphatase. Georg Thieme Verlag Stuttgart, New York.
N6-Substituted adenosines. Cytokinin and antitumor activities
Kolyachkina, Svetlana V.,Tararov, Vitali I.,Alexeev, Cyril S.,Krivosheev, Dmitry M.,Romanov, Georgy A.,Stepanova, Evgenia V.,Solomko, Eliso S.,Inshakov, Andrey N.,Mikhailov, Sergey N.
scheme or table, p. 1361 - 1378 (2012/04/04)
A series of N6-adenosine derivatives were synthesized by alkylation of N6-acetyl-2',3',5'-tri-O-acetyladenosine (1) with alkyl halides and alcohols. It was shown that propargyl derivative 2a is a good substrate for copper(I) catalyzed Huisgen [3+2] cycloaddition with azides. This click-reaction can be used for preparation of the libraries of 1,2,3-triazolyl modified adenosines. Biological activities of N6-adenosines were studied in two plant and six human cancer cell assays. The remarkable parallel between cytokinin and cytotoxic activities was found. The most cytokinin active compounds 3c-3e at the same time appeared to be the most potent cytotoxic agents.
High-throughput five minute microwave accelerated glycosylation approach to the synthesis of nucleoside libraries
Bookser, Brett C.,Raffaele, Nicholas B.
, p. 173 - 179 (2007/10/03)
The Vorbrueggen glycosylation reaction was adapted into a one-step 5 min/130 °C microwave assisted reaction. Triethanolamine in acetontrile containing 2% water was determined to be optimal for the neutralization of trimethylsilyl inflate allowing for direct MPLC purification of the reaction mixture. When coupled with a NH3/methanol deprotection reaction, a high-throughput method of nucleoside library synthesis was enabled. The method was demonstrated by examining the ribosylation of 48 nitrogen containing heteroaromatic bases that included 25 purines, four pyrazolopyrimidines, two 8-azapurines, one 2-azapurine, two imidazopyridines, two benzimidazoles, three imidazoles, three 1,2,4-triazoles, two pyrimidines, two 3-deazapyrimidines, one quinazolinedione, and one alloxazine. Of these, 32 yielded single regioisomer products, and six resulted in separable mixtures. Seven examples provided inseparable regioisomer mixtures of -two to three compounds (16 nucleosides), and three examples failed to yield isolable products. For the 45 single isomers isolated, the average two-step overall yield ± SD was 26 ± 16%, and the average purity ± SD was 95 ± 6%. A total of 58 different nucleosides were prepared of which 15 had not previously been accessed directly from glycosylation/deprotection of a readily available base.
