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Nukleozydy 8-azapurynowe : synteza i aktywność biologiczna

Głowacka I. E., Zdzienicka A.

Wiadomości Chemiczne

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2017

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[Z] 71, 3-4

147--174

EN

The synthetic approaches to 8-azapurine nucleosides and their biological activities have been reviewed. This class of compounds could serve as antimetabolites of purine nucleoside with potential clinical applications [1–6]. They were primarily synthesized by glycosylation of 8-azapurines, which could be easily prepared from appropriately substituted 4,5-diaminopyrimidines when reacted with nitric(III) acid [1]. Since in 8-azapurines at least three nitrogen atoms could serve as nucleophilic centers the regiochemistry of glycosylation was discussed in details. Generally, mixtures of N9, N8 and N7-substituted 8-azapurine nucleosides were formed when reactions were carried out at room temperature (kinetic control), while N9-substituted analogs were produced at elevated temperatures (thermodynamic control). On the other hand, no differences in the stereochemical outcome of glycosylation were noticed for canonical purine nucleobases and their 8-aza analogues since ratios of α and β anomers appeared to be closely related to the structure of a sugar component. Multidirectional biological activities of 8-azapurines and their nucleosides, including antitumor, antiviral and antibacterial, were presented for the most acclaimed examples. However, none of these compounds was approved as a drug. The current interest in 8-azapurines and their nucleosides takes advantage of a significant fluorescence (opposite to purines), which was found to be a pH-dependent thus providing an excellent tool for advanced studies in nucleic acid chemistry.

2

D-Rybono-1,4-lakton. Część 2, Wykorzystanie w syntezie organicznej – wybrane reakcje

Madaj J., Samaszko-Fiertek J., Ślusarz R., Dmochowska B.

Wiadomości Chemiczne

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2017

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[Z] 71, 11-12

861--885

EN

There are many examples of syntheses with d-ribono-1,4-lactone as a substrate. Among all, its biggest advantage is undoubtedly its accessibility. It can be synthesized on a large scale from naturally available raw materials. Its characteristic feature is the stable configuration of individual carbon atoms in multiple reaction conditions. Very important is the presence of a carbonyl moiety, allowing for a variety of additions which is crucial for carbon-carbon bond formation, the most difficult synthesis in organic chemistry. In this article we present selected examples of articles that were published after 1984. In this year, the second article describing the Use of d-Ribonolactone in Organic Synthesis [36] was published. After this time many articles describing the use of the entitled lactone as a substrate in organic synthesis were published. We thought it would be worthwhile to present in Polish a selection of them. C-Glycosides and nucleoside analogs are a particularly important type of synthesized products. Examples of their synthesis are presented in this work, namely, neplanocin A [5], B [31] and F [24], citreovirdin [14], 2-bromopyridin α- and β-d-ribofuranosides [10], 4-deazaformicin A [27] and varitriol [ 33].

3

1’-homonukleoz(t)ydy : synteza i aktywność biologiczna

Gotkowska J., Piotrowska D. G.

Wiadomości Chemiczne

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2016

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[Z] 70, 5-6

319--351

EN

Long-lasting interest in the synthesis of nucleos(t)ide analogues is dictated by hope to obtain compounds possessing antibacterial, antiviral and antitumor activities [1, 2]. Introduction of a methylene linker between an anomeric carbon and the nucleobase nitrogen atom produces a new class of compounds called 1’-homonucleos(t)ides as potentially active analogues. Although a sugar ring in nucleosides can be replaced by several cyclic or even acyclic moieties we focus attention on compounds containing the tetrahydrofuran ring. Since methods of attachment of nucleobases are limited to their alkylation with appropriate compounds and the de novo synthesis we discussed various synthetic approaches to substituted tetrahydrofuranes in racemic or optically pure forms. Various pentose and hexose derivatives were employed as starting materials and their transformations into the final sugar frameworks were detailed, thus revealing the importance of these class of compounds. To prepare deoxysugars Barton-McCombie reaction sequence was applied. A significant number of final 1’-homonucleos(t)ides were screened for antiviral and cytotoxic activity to identify a few very potent compounds. Thus, phosphonates trans- and cis-138a were as active against HCMV as ganciclovir. In addition trans- -138a inhibited the proliferation of several murine and human cancer cell lines with IC50s in the μM range. 1’-Homonucleosides 64b and 66b exhibited selective antiviral activity against HSV-1 TK– and HSV-2 TK– (MIC = 8–12 μg/mL). Compound 129 was found active against HCV (EC = 6.31 μM) and reduced growth of CCRF-CEM cells with IC50 = 5.73 μM. Despite limited activity observed so far for the known 1’-homonucleos( t)ides and their analogues, they deserve further interest both from the synthetic point of view and biological potential inherent in molecules having nucleobase scaffolds.

4

C-nukleozydy : synteza i aktywność biologiczna

Grabkowska-Drużyc M., Piotrowska D. G.

Wiadomości Chemiczne

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2015

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[Z] 69, 3-4

197--225

EN

Studies on synthesis and biological activity of modified nucleoside and nucleotide analogues have been an active field of research in medicinal chemistry for years [1, 2]. High biological activity of naturally occurring C-nucleosides, for example showdomycin 5, formycins A 41 and B 42 motivated many research groups to study their analogues and structurally similar compounds. Furthermore, since C-nucleosides lack N-glycosidic bond they are more resistant to enzymatic hydrolysis [3]. This review collects selected methods of synthesis of C-nucleoside analogues which were analyzed to point out the most interesting and inspiring synthetic strategies, in many cases based on contemporary achievements. These strategies first of all take advantage of the formation of the C–C bond between the anomeric carbon atom of the sugar or pseudosugar moieties and the carbon atom of the modified nucleobases. Less common approach relies on the de novo construction of heterocyclic rings employed as nucleobase substitutes. Though years many new compounds sometimes of significant structural complexity have been obtained and characterized to find several examples endowed with high antiviral and cytostatic activity. The biological activity of the C-nucleoside analogues screened so far encourages us to continue a search for new potential drugs within compounds equipped with this attractive structural motif.

5

Bioaktywne N-acyloamidofosforanowe pochodne nukleozydów

Kulik K.

Wiadomości Chemiczne

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2013

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[Z] 67, 9-10

877--897

EN

Natural nucleotide antibiotics such as Agrocin 84, Dinoguellin, Microcin C and Phosmidosine have a N-acylphosphoramidate linkage at the 5’-hydroxyl of the adenosine derivatives (Fig. 1, 2) [1–3]. They exhibit interesting antifungal, antiemetics and anticancer properties. To synthesize these products, the construction of the N-acylphosphoramidate linkages seems to be a key step. Many groups have described the preparation of such a type of analogues but none of those methods was general. Grandas has for the first time reported the synthesis, of N-acylphosphoramidate peptide-oligonucleotide hybrids via condensation of N-phosphitylated carboxyamides with alcohols in the presence of 1H-tetrazole [9]. Based on this strategy Sekine synthesized aminoacyl adenylate (aa-AMP) analogues which could be useful in the studies on the recognition mechanism of the aminoacylation of tRNA and other biochemical reactions [10]. Since aa-AMPs are extremely unstable under aqueous conditions more stable analogues were required. Aminoacyl-adenylate analogues having an N-acylphosphoramidate linkage (aa-AMPN) could behave as potent, selective asparagine synthetase (AS) inhibitors because of its structural similarity to β-aspartyl-AMP (β AspAMP) which is natural product of AS [17]. Among natural N-acylphosphormiadates, Phosmidosine which connects a nucleoside analogue, 8-oxoadenosine, with an L-proline residue is unique because of its significant antitumor activities and property of stopping cell growth at the G1 phase in the cell cycle (Fig. 2) [2, 13]. The main difficulty during the synthesis of this compound is an extreme instability under weak basic conditions which excludes the use of labile protecting group of basic properties [14]. Stability studies have shown that under basic conditions phosphoryl group of Phosmidosine underwent rapid N–N migration (Scheme 9) [16]. Many modifications have been introduced to improve Phosmidosine properties [16]. Analogues such as demethylated species (Phosmidosine B) have proven to be stable under both basic and acid conditions and are also potential candidates for antitumor drugs [14].

6

Izoksazolidynowe analogi nukleozydów

Kokosza K., Piotrowska D. G.

Wiadomości Chemiczne

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2012

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[Z] 66, 11-12

1041-1070

EN

Compounds having isoxazolidine moiety are of special interest since they show a broad spectrum of biological activity, including anticancer [1–5], antiviral [6], antibacterial [7–9] and antifungal activities [9–12]. Extensive studies on isoxazolidine moiety containing compounds resulted in discovery of several potentially antiviral and anticancer drugs (e.g. pyridemine-A 1 [2, 3], as well as isoxazolidines substituted with thymine and 5-fluorouracil 52a (AdT) [38–40] and 59 [(–)-AdFU] [41–43], respectively). In this review the most spectacular examples of the synthesis of isoxazolidine analogues of nucleosides are discussed and their biological activity is emphasized.

7

Wykorzystanie reakcji 1,3-dipolarnej cykloaddycji Huisgena do modyfikacji nukleozydów i ligonukleotydów

Radzikowska E.

Wiadomości Chemiczne

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2011

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[Z] 65, 3-4

207-234

EN

The 1,3-dipolar cycloaddition reaction between azides and terminal alkynes, known as the Huisgen reaction, constitutes a powerful tool for the synthesis of versatile molecules containing carbon – heteroatom bond. The use of a copper(I) salt in this reaction allowed Sharpless to develop the concept of „click chemistry” [1]. This strategy is based on reactions between small units characterized by mild reaction conditions, versatility, high yields and stereospecificity. The chemistry of nucleic acids and nucleoside analogues is undergoing rapid developments and numerous compounds from these classes of compounds are used in medicinal treatment. Analogues of nucleoside constitute a class of drugs that possesses either anticancer or/and antiviral activity (against HIV, HSV, VZV or HCV viruses) [3]. Many modified oligonucleotides show biological activity. As potential drugs oligonucleotides are employed in antisense, antigen and aptamer strategies. An antisense therapeutic agent acts on the pathogenic mRNA causing inactivation of the target whereas an antigen agent acts on DNA and aptamer on unwanted protein. It is not surprising that number of research groups are trying to join the concept of click chemistry with nucleic acids chemistry. In this way, it is possible to obtain new molecules like base- or sugar-modified nucleosides, nucleosides, bioconjugates and olignucleotides. The copper-catalyzed 1,3-dipolar cycloaddition CuAAC allows to functionalize DNA, for example by labelling it through attaching small molecules to DNA. Two general strategies have been developed for this purpose: presynthetic and postsynthetic labelling. In the presynthetic method nucleotide monomers are labelled before DNA synthesis and purification. In the postsynthetic strategy DNA containing small reactive groups is synthesized first and then it is conjugated with the desired molecules. CuAAC is also a convenient method for the synthesis of modified oligonucleotides in which phosphodiester linkage is replaced by 1,2,3- -triazole or for a solid phase synthesis. Such molecules appear to be useful in medicine, molecular diagnostic (e.g. fluorescent dyes) or mechanistic molecular model in the future.

8

Chemiczno-enzymatyczna strategia konstrukcji proleków nukleozydowych

Kaczmarek R., Kulik K., Baraniak J.

Wiadomości Chemiczne

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2007

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[Z] 61, 5-6

417-443

EN

Several nucleoside analogues have found successful application as antiviral and anticancer agents. Their mode of action differs, but in the most general terms they have been developed as inhibitors or competitors of natural 2'-deoxynucleosides in the process of their conversion to the corresponding nucleoside-5'-triphosphates. As such, they can be incorporated into a growing viral DNA strand by a DNA polymerase resulting in chain termination. In cancer therapy, modified nucleosides, after being phosphorylated to the corresponding monophosphates, block DNA biosynthesis by deactivating nucleoside syntheses. Hence biological activity of nucleoside analogues in most cases depends on the intracellular phosphorylation by viral and/or cellular kinases to their respective mono-, di-, and triphosphate derivatives. Among the three successive activating phosphorylation steps the first one has fundamental importance as the rate-limiting step. Several different enzymes can perform this initial phosphorylation, depending on the nature of the aglycone. Also, the presence and activity of the intracellular enzymes necessary for the activation of nucleoside analogues are highly dependent on the host species, the cell type, and the stage in the cell cycle. Moreover, in many cases, nucleoside analogues are poor substrates for the cellular kinases needed for their activation. For all these reasons, intracellular nucleoside monophosphate (NMP) delivery has been considered for overcoming the first phosphorylation step. Unfortunately, NMPs themselves cannot be used as potential chemotherapeutic agents. Owing to their high polarity, these compounds are not able to penetrate cellular membrane or the blood-brain barrier easily. Therefore, in order to reduce the phosphate negative charge and enable the modified nucleotide to enter the cell, many nucleotides modified on the phos-phate moiety by so-called masking group have been synthesized. A suitable nucleotide prodrug (so-called pronucleotide) has to fulfill two requirements: i) it has to be lipophilic enough for passive diffusion of the membrane and the blood-brain barrier; ii) it should be able to deliver the nucleoside by chemical or enzymatic hydrolysis leaving a non-toxic masking group. Many strategies using various protecting groups for the phosphate moiety have been deve-loped to achieve this goal. The majority of strategies for unmasking pronucleotides that have been examined to date have involved substrate-nonspecific enzymes to remove one or more groups that are attached to the 5'MP moiety. Carboxylesterases (CEs) have attracted considerable attention, since they include bis(pivaloyloxymethyl) [(bis(POM)] and S-acyl-2-thioethyl (SATE) moieties which are initially unmasked by CE-mediated cleavage. A combination of aryl ester and amino acid phosphoramidate groups as a particular class of enzyme-labile protecting groups was developed for the delivery of antiviral nucleoside prodrugs. An endogenous phosphoramidase was responsible and necessary for the biological activity of those compounds in living cells. On the other side almost all approaches based on chemical hydrolysis reported so far were unable to deliver the nucleotide selectively exept the cycloSal approach. This review will predominantly concentrate on the different approaches to the design of nucleotide prodrugs. Keywords: prodrug, pronucleotide, nucleoside analogues, antiviral activity, anticancer acti-vity, masking groups.