Riboside Derivatives Research Articles

Hybrid chitosan gold nanoparticles for photothermal therapy and enhanced cytotoxic action of 6-mercaptopurine on breast cancer cell line

BackgroundOne of the most popular anti-inflammatory and anti-leukemic medications is 6-mercaptopurine, along with its riboside derivatives. Because of their potent adverse effects and limited biological half-life, they are rarely used. These problems might be solved by a novel medication delivery technique based on gold nanoparticles (AuNPs). In present work, gold/chitosan nanohybrid was manufactured and assessed for photothermal therapy as well as a drug carrier to minimize the unwanted harmful effects of 6-Mercaptopurine (6-MP). We estimate loading of 6-MP on gold nanoparticles by chitosan reduction (Au@CS NPs) creating (Au@CS-6MP).ResultsAuNPs were green sensitized in one step via chitosan. UV–visible spectroscopy, Zeta potential, TEM, FTIR spectroscopy, and HPLC technique for loading efficiency were used to characterize AuNPs and Au@CS-6MPC NPS. Our results estimate that AuNPs and Au@CS-6MPC NPS with small sizes of 16 ± 2 and 20 ± 4 nm, respectively, and Zeta potential 53.6 ± 5.2 and 55 ± 3 mV, respectively, and loading efficiency of 52% were achieved. Cytotoxicity of the Au@CS-6MPC NPs was significantly increased compared to free 6MP with IC50 1.11 µM. Cell viability was inhibited in AuNPs exposed to DPSS laser light, reaching 10% inhibition after 8 min.ConclusionsThe prepared Au@CS-6MPC NPs resulted in an additive effect in therapeutic managing of breast cancer. It can be predicted that this nanocomposite along with synergistic effect of laser light will definitely result in better therapeutic efficacy and reduced side effects of 6-MP in a combination photothermal chemotherapy treatment. This combination can be explored as future alternative for cancer therapy.

Synthesis and evaluation of 5-aminimidazole-4-carboxamide riboside derivatives as anti-fatigue agents

Fatigue has a negative influence on daily life and work, and serious or chronic fatigue can even cause health problems. Studies have shown that 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) can exert anti-fatigue effects by activating AMP-activated protein kinase (AMPK). In this study, six AICAR derivatives with substitution at the hydroxyl sites of the ribose moiety were synthesized and evaluated as anti-fatigue agents. All of the derivatives were demonstrated to effectively resist fatigue in animal models. The mice treated with the optimal compound ZHM-01 showed an 8.6-fold greater exhaustion distance in the running wheel test and a 5.1-fold greater exhaustion time in the weight-loaded swimming test than those of the blank control group. ZHM-01 treatment also reduced lactic acid (LA) and blood urea nitrogen (BUN) accumulation during exercise. In addition, ZHM-01 administration enhanced the phosphorylation of AMPK but did not excite the central nervous system. Moreover, ZHM-01 showed good biological safety in a 21-day toxicity evaluation. This study provides a new reference for the development of treatments for fatigue-related health problems.

The Origins and Roles of Methylthiolated Cytokinins: Evidence From Among Life Kingdoms.

Cytokinins (CKs) are a group of adenine-derived, small signaling molecules of crucial importance for growth and multiple developmental processes in plants. Biological roles of classical CKs: isopentenyladenine (iP), trans and cis isomers of zeatin (tZ, cZ), and dihydrozeatin, have been studied extensively and their functions are well defined in many aspects of plant physiology. In parallel, extensive knowledge exists for genes involved in tRNA modifications that lead to the production of tRNA-bound methylthiolated CKs, especially in bacterial and mammalian systems. However, not much is known about the origins, fates, and possible functions of the unbound methylthiolated CKs (2MeS-CKs) in biological systems. 2MeS-CKs are the free base or riboside derivatives of iP or Z-type CKs, modified by the addition of a thiol group (–SH) at position 2 of the adenine ring that is subsequently methylated. Based on the evidence to date, these distinctive CK conjugates are derived exclusively via the tRNA degradation pathway. This review summarizes the knowledge on the probable steps involved in the biosynthesis of unbound 2MeS-CKs across diverse kingdoms of life. Furthermore, it provides examples of CK profiles of organisms from which the presence of 2MeS-CKs have been detected and confirms a close association and balance between the production of classical CKs and 2MeS-CKs. Finally, it discusses available reports regarding the possible physiological functions of 2MeS-CKs in different biological systems.

Nicotinamide Riboside Derivatives: Single Crystal Growth and Determination of X-ray Structures

For the first time, the X-ray structure of nicotinamide riboside could be determined. Five nicotinamide riboside (NR) derivatives in their native, thioamide and triacetyl protected form could be cr...

Synthesis of C-pyrimidyl nucleosides starting from alkynyl ribofuranosides

The synthesis of four C-pyrimidyl nucleosides is described by condensation of small nitrogen molecules (amidines and ureas) onto alkynyl riboside derivatives. These last compounds were obtained by indium mediated stereoselective alkynylation of suitably protected ribose derivatives and the condensation reaction conditions were studied in order to favor the N-attack of the nitrogen molecules leading to the pyrimidine ring formation.

Synthesis of Nucleosides through Direct Glycosylation of Nucleobases with 5-O-Monoprotected or 5-Modified Ribose: Improved Protocol, Scope, and Mechanism.

Simplifying access to synthetic nucleosides is of interest due to their widespread use as biochemical or anticancer and antiviral agents. Herein, a direct stereoselective method to access an expansive range of both natural and synthetic nucleosides up to a gram scale, through direct glycosylation of nucleobases with 5-O-tritylribose and other C5-modified ribose derivatives, is discussed in detail. The reaction proceeds through nucleophilic epoxide ring opening of an in situ formed 1,2-anhydrosugar (termed "anhydrose") under modified Mitsunobu reaction conditions. The scope of the reaction in the synthesis of diverse nucleosides and other 1-substituted riboside derivatives is described. In addition, a mechanistic insight into the formation of this key glycosyl donor intermediate is provided.

New C-Glycosylated α-Amino Acid Synthesis by Addition Reaction of an Amino Acid Organozinc Reagent on Carbohydrate-Derived Aldehydes

Two unreported C-glycosylated amino acid structures could be prepared by addition of an amino acid organozinc on carbohydrates bearing an aldehyde function. For this purpose, a new iodinated amino acid bearing a four-carbon side chain was conveniently prepared in two steps. Conversion into the corresponding organozinc reagent was optimal in acetonitrile using zinc/copper activated with 1,2-dibromoethane and trimethylsilyl chloride. A protocol was developed for the addition of this organozinc compound to simple aldehydes in acetonitrile using BF3 · OEt2 as a Lewis acid. When applied to riboside and glucoside aldehyde derivatives, this protocol led to new C-glycosylated amino acids in acceptable yields.

A New Method for Synthesis of 2-Alkoxyadenosine Analogs

O 6 -Methylguanosine and 2-amino-6-chloropurine riboside derivative were treated with isoamylnitrite in the presence of an appropriate alcohol to give the corresponding 2-alkoxy-6-methoxy (or chloro) purine riboside derivatives.

One-Pot Synthesis of 2-Nitrooxyalkoxylated Inosine Analogs Using Cyclic Ether and Isoamyl Nitrite

An O 6 -methylguanosine derivative (1) was treated with isoamyl nitrite in the presence of a cyclic ether such as trimethylene oxide, tetrahydrofuran, or tetrahydropyran to give the corresponding 2-nitrooxyalkoxy-6-methoxypurine riboside derivatives (2a-c).

Gold Nanoparticles Enhance the Anti-Leukemia Action of a 6-Mercaptopurine Chemotherapeutic Agent

6-mercaptopurine and its riboside derivatives are some of the most widely utilized anti-leukemic and anti-inflammatory drugs. Their short biological half-life and severe side effects limit their use. A new delivery method for these drugs based on 4-5 nm gold nanoparticles can potentially resolve these issues. We have found substantial enhancement of the antiproliferative effect against K-562 leukemia cells of Au nanoparticles bearing 6-mercaptopurine-9-beta-d-ribofuranoside compared to the same drug in typically administered free form. The improvement was attributed to enhanced intracellular transport followed by the subsequent release in lysosomes. Enhanced activity and nanoparticle carriers will make possible the reduction of the overall concentration of the drug, renal clearance, and, thus, side effects. The nanoparticles with mercaptopurine also showed excellent stability over 1 year without loss of inhibitory activity.

The synthesis of N 2,N 6-substituted diaminopurine ribosides

A series of new 2,6-substituted diaminopurine riboside derivatives were synthesized by activation of protected xantosine with sulfonyl chlorides followed by treatment with various amines. The relationship between the reactivity of intermediates and the nature of the activating agents was studied.

NAD-analogues as potential anticancer agents: conformational restrictions as basis for selectivity.

Cofactor type inhibitors (NAD-analogues) of IMP-dehydrogenase (IMPDH) were synthesized and their application as potential anticancer agents are discussed. C-nucleoside isosteres of NAD, C-NAD and C-PAD, showed an effective competitive inhibition of IMPDH, C-NAD but not C-PAD caused extremely potent inhibition of alcohol dehydrogenase. We also synthesized compounds in which nicotinamide riboside was replaced with tiazofurin (TAD-analogues) and the 2' and 3'-positions of adenosine part were fluorinated. The ribose ring of 2'-deoxy-2'-fluoroadenosine is in the C3'-endo conformation whereas 3'-deoxy-3'-fluoroadenosine favors the C2'-endo sugar pucker. These derivatives are good inhibitors of IMPDH type II, the isoenzyme dominant in neoplastic cells. In contrast, all these analogues showed rather week inhibitory activity against alcohol dehydrogenase. Nicotinamide riboside derivatives in which the base and the sugar are linked through an oxygen or a methylene bridge were synthesized. NAD-analogues containing such conformationally restricted nicotinamide nucleoside moiety (syn or anti) are expected to be selective inhibitors of B-specific (IMPDH) or A-specific dehydrogenases, respectively.

Reaction of trans-4- N-acetoxy- N-acetylaminostilbene with guanosine, deoxyguanosine, RNA and DNA in vitro: predominant product is a cyclic N2, N3-guanine adduct

The model ultimate carcinogen trans-4- N-acetoxy- N-acetylaminostilbene was reacted with guanosine, deoxyguanosine, RNA and DNA using differently labeled reactants. The nucleoside as well as the deoxynucleoside yielded predominantly four cyclic guanine adducts: ( S, S)- and ( R, R)-guanine- N 2, β- N3, α- N-acetyl-aminobibenzyl and the regioisomers with the N 2, α- N3, β-attachment in a ratio of 9:9:1:1. The same adducts predominate in RNA and DNA which demonstrates that guanine reacts most avidly among the bases. The stability of the N-glycosidic bond is quite different between ribosides and deoxyribosides. Under neutral conditions, the riboside derivatives are stable, whereas deoxyribose is cleaved off rather readily. As a consequence DNA depurinizes to some extent during the in vitro reaction and during enzymatic digestion. On the other hand, N 2, N3-attachment of the acetylaminostilbene moiety to guanine appears to impair the activity of nucleases for steric reasons. This could explain the incomplete enzymatic hydrolysis of modified nucleic acids. The results provide an important basis for further investigations to identify the nucleic acid adducts generated in vivo.

Simplified synthesis of 5-mercaptouracil riboside derivatives

Simplified synthesis of 5-mercaptouracil riboside derivatives

Reaction between 2′,3′,5′-tri-O-acetyladenosine and aryl chloroformates. 2′,3′,5′-Tri-O-acetyl-N(6)-phenoxycarbonyladenosine as an intermediate in the synthesis of 6-ureidopurine ribosides

Reaction between 2′,3′,5′-tri-O-acetyladenosine (6) and p-nitrophenyl chloroformate in pyridine solution at 20 °C or between (6) and phenyl chloroformate in pyridine solution at 70 °C gives the protected symmetrical urea derivative (7b) in moderate or high yield. Deacetylation of (7b) gives the corresponding unprotected urea (7a). Treatment of (6) with an excess of phenyl chloroformate in pyridine solution at 20 °C gives the bisphenoxycarbonyl derivative (10) which, on reaction with morpholine in dioxan solution, is rapidly converted into 2′,3′,5′-tri-O-acetyl-N(6)-phenoxycarbonyladenosine (3c). Compound (3c) readily reacts with cyclohexylamine, ammonia, and glycine methyl ester at 20 °C to give, after deacetylation, the corresponding 6-ureidopurine riboside derivatives (9b, c, and d; R1= H) in high yields.

Metabolism of methylated purines in Escherichia coli: derepression of purine biosynthesis.

Love, Samuel H. (Bowman Gray School of Medicine, Wake Forest College, Winston-Salem, N.C.), and Charles N. Remy. Metabolism of methylated purines in Escherichia coli: derepression of purine biosynthesis. J. Bacteriol. 91:1037-1049. 1966.-Various methylated purines were examined for their effects on growth of purine-requiring mutants of Escherichia coli, strains W-11 and B-96, and for their effects on purine biosynthesis. 6-Methylaminopurine and 6-methoxypurine stimulated the accumulation of purine precursor derivatives (ribosyl-5-aminoimidazole and ribosyl-5-amino-4-imidazole carboxamide) beyond their ability to support growth. Information obtained from in vivo and in vitro systems demonstrated that the metabolism of 6-methylaminopurine and 6-methoxypurine utilized identical pathways. The riboside derivatives are formed either by direct ribosidation via nucleoside phosphorylase or, indirectly, by dephosphorylation of the 5'-phosphoribosyl derivatives which are synthesized via adenylate pyrophosphorylase. Information obtained with the aid of strain W-11/DAP (lacking adenylate pyrophosphorylase) demonstrated that both pathways were important to the growing cells. Regardless of the metabolic pathway by which they are synthesized, the ribosyl derivatives are demethylaminated (demethylated) by adenosine deaminase to yield inosine. The final conversion of inosine to inosinic acid via the intermediate formation of hypoxanthine accounts for the net conversion of the methylated bases to inosinic acid. The utilization of the bases is sufficiently rate-limiting to cause derepression of the early enzymes required for the de novo synthesis of purine, thus accounting for the elevated accumulation of purine precursors originally observed.

FURTHER OBSERVATIONS ON THE ENZYMATIC REDUCTION OF TETRAZOLIUM SALTS BY MONOAMINES

Studies on the role of purines as cofactors in the enzymatic reduction of tetrazolium salts by monoamines have led to the following results: (1) With whole rat liver extracts as the source of enzymes, several purines exhibit cofactor activity either as the free base or as the corresponding riboside and ribotide derivatives. (2) In contrast to this, mitochondrial material from rat liver is active only if adenylic acid or one of several ribotidic derivatives containing an adenylyl or similar moiety is used as cofactor. (3) Mitochondrial material utilizes hypoxanthine as cofactor for the amine/tetrazolium system only in combination with the supernatant obtained by centrifugation of tissue homogenates at 20,000 g. The additional factor present in this supernatant portion is heat-labile and nondialyzable. The possibility that this additional factor is an enzyme or enzymes converting the free base to the ribotide is discussed.Inhibition studies have revealed that the amine/tetrazolium enzyme system is sensitive to several metal-binding agents, but no direct evidence for the role of a metal in the enzymatic reaction could be obtained. It was also found that nicotinamide and adenine, neither of which exhibits cofactor activity, are potent inhibitors of the enzyme system studied.

Riboside Derivatives of 6-Methyl-asym-triazine-3,5(2,4)-dione1

Riboside Derivatives of 6-Methyl-asym-triazine-3,5(2,4)-dione¹