Carbocyclic Nucleosides Research Articles

Palladium-Catalyzed Decarboxylative Rearrangements of Allyl 2,2,2-Trifluoroethyl Malonates: Direct Access to Homoallylic Esters

Homoallylic esters are obtained in a single transformation from allyl 2,2,2-trifluoroethyl malonates by using a Pd(0) catalyst. Facile decarboxylation of allyl 2,2,2-trifluoroethyl malonates is attributed to a decrease in pK(a) compared to allyl methyl malonates. Subsequent reduction of the homoallylic 2,2,2-trifluoroethyl ester provides a (hydroxyethyl)cyclopentenyl derivative that represents a key intermediate in the synthesis of carbocyclic nucleosides. A select allyl 2,2,2-trifluoroethyl malonate undergoes a decarboxylative Claisen rearrangement to provide a regioisomeric homoallylic ester.

A greener enantioselective synthesis of the antiviral agent North-methanocarbathymidine (N-MCT) from 2-deoxy- d-ribose

An enantioselective synthesis of suitably protected (1 R,2 S,4 S,5 S)-4-amino-1-(hydroxymethyl)bicyclo[3.1.0]hexan-2-ol, a key starting material for the synthesis of conformationally locked carbocyclic nucleosides, including the antiviral active North-methanocarbathymidine, is reported. Starting from 2-deoxyribose the target Boc-protected amine was prepared in 33% overall yield under conditions that are ecologically friendlier than previous methods.

ChemInform Abstract: Synthesis and Biological Activity of Selected Carbocyclic Nucleosides

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The nucleoside analogue D-carba T blocks HIV-1 reverse transcription.

A major pathway for HIV-1 resistance to nucleoside reverse transcriptase inhibitors (NRTIs) involves reverse transcriptase (RT) mutations that enhance ATP-dependent pyrophosphorolysis, which excises NRTIs from the end of viral DNA. We analyzed novel NRTIs for their ability to inhibit DNA synthesis of excision-proficient HIV-1 RT mutants. D-carba T is a carbocyclic nucleoside that has a 3' hydroxyl on the pseudosugar. The 3' hydroxyl group allows RT to incorporate additional dNTPs, which should protect D-carba TMP from excision. D-carba T can be converted to the triphosphate form by host cell kinases with moderate efficiency. D-carba T-TP is efficiently incorporated by HIV-1 RT; however, the next dNTP is added slowly to a D-carba TMP at the primer terminus. D-carba T effectively inhibits viral vectors that replicate using NRTI-resistant HIV-1 RTs, and there is no obvious toxicity in cultured cells. NRTIs based on the carbocyclic pseudosugar may offer an effective approach for the treatment of HIV-1 infections.

Contrasting Behavior of Conformationally Locked Carbocyclic Nucleosides of Adenosine and Cytidine as Substrates for Deaminases

In addition to the already known differences between adenosine deaminase (ADA) and cytidine deaminase (CDA) in terms of their tertiary structure, the sphere of Zn+2 coordination, and their reverse stereochemical preference, we present evidence that the enzymes also differ significantly in terms of the North/South conformational preferences for their substrates and the extent to which the lack of the O(4′) oxygen affects the kinetics of the enzymatic deamination of carbocyclic substrates. The carbocyclic nucleoside substrates used in this study have either a flexible cyclopentane ring or a rigid bicyclo[3.1.0]hexane scaffold.

Base-Functionalized Carbocyclic Nucleosides: Design, Synthesis, and Mechanism of Antiviral Activity

New carbocyclic ribonucleosides with unsaturated groups at the C-2 position of the nucleobase were designed as potential RNA antiviral compounds. The design was based on the expectation that the monophosphates of these compounds would be inhibitors of the enzyme, IMPDH. Appropriate methodologies were developed to achieve the target molecules. Results from the initial in vitro antiviral studies are mentioned. The IMPDH-associated mechanism of the antiviral activity of the most active compound is supported by enzyme inhibition studies.

Radical-mediated stannylation of vinyl sulfones: access to novel 4′-modified neplanocin A analogues

Synthesis of 4′-substituted (halogeno, phenyl, ethynyl, and cyano) neplanocin A analogues was carried out. A cyclopentenol derivative having a vinylstannane structure was designed as key-intermediate in this study, which was prepared based on radical-mediated sulfur-extrusive stannylation. The resulting stannylated cyclopentenol 15 was successfully condensed with 6-chloropurine through the Mitsunobu reaction, leading to the carbocyclic nucleoside 20. Compound 20 was converted to its adenine counterpart 21 by treatment with NH 3/MeOH, during which the 4′-stannyl group remained intact. The title compounds were prepared by using 21 or the 4′-iodo derivative ( 22) mostly through the Stille reaction.

ChemInform Abstract: Synthesis of Novel Carbocyclic Nucleoside Analogues Derived from 7‐Oxabicyclo[2.2.1]heptane‐2‐methanol.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Novel Synthesis and anti‐HIV Activity of 4′‐Branched Exomethylene Carbocyclic Nucleosides Using a Ring‐Closing Metathesis of Triene.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

グリコシド結合形成反応の開発と新規生物活性ヌクレオシド誘導体合成への展開

Nucleoside antimetabolites act an important role in the fields of cancer and viral chemotherapies. To search new agents effective for tumor and virus, many attempts were made for synthesizing novel nucleoside derivatives. Construction of the glycosidic bond is a key reaction to synthesize new nucleoside derivatives. We have been focused the synthesis of novel biologically active nucleoside derivatives by developing novel “glycosylation” reactions. Our first successful example was the synthesis of 4′-thionucleoside by using the Pummerer-type thioglycosylation reaction. As a result, we found potent antineoplastic nucleoside, 4′-thioFAC, and some novel 4′-thionucleosides possessing antiherpes virus activities. Secondary, we developed a new entry to isonucleosides in which the Mitsunobu reaction with neighboring sulfur assistance was employed as a nucleobase introducing reaction. We also developed a conceptually new method for synthesizing carbocyclic nucleosides based on hypervalent iodine chemistry. The mechanism of this oxidative coupling reaction was investigated.

Contrasting Behavior of Conformationally Locked Carbocyclic Nucleosides of Adenosine and Cytidine as Substrates for Deaminases

Contrasting Behavior of Conformationally Locked Carbocyclic Nucleosides of Adenosine and Cytidine as Substrates for Deaminases

Synthesis of novel carbocyclic nucleoside analogues derived from 7-oxabicyclo[2.2.1]heptane-2-methanol

Hydroboration of [(1R*,2R*,4R*)-7-oxabicyclo[2.2.1]hept-5-en-2-yl]methyl benzoate (5), which was prepared by Diels–Alder reaction of furan with acrolein and subsequent reduction and benzoylation of the Diels–Alder product, afforded [(1R*,2S*,4S*,6S*)-6-hydroxy-7-oxabicyclo[2.2.1]heptan-2-yl]methyl benzoate (6) and [(1R*,2R*,4R*,5S*)-5-hydroxy-7-oxabicyclo[2.2.1]heptan-2-yl]methyl benzoate (7). The key intermediates, [(1R*,2S*,4S*,6R*)-6-hydroxy-7-oxabicyclo[2.2.1]heptan-2-yl]methyl benzoate (10) and [(1R*,2R*,4R*,5R*)-5-hydroxy-7-oxabicyclo[2.2.1]heptan-2-yl]methyl benzoate (11), were prepared from6and7, respectively, by oxidation with pyridinium dichromate and subsequent reduction of the thus obtained ketones. The Mitsunobu reaction of10and11with 6-chloropurine and subsequent reductive deprotection with diisobutylaluminium hydride afforded 6-chloropurine derivatives, which were converted to other purine analogues. Thymine analogues were prepared by Mitsunobu reaction of10and11with 3-benzoyl-5-methylpyrimidine-2,4(1H,3H)-dione and subsequent methanolysis. The target compounds were tested for the activity againstCoxsackievirus.

Synthesis of novel racemic carbocyclic nucleoside analogues derived from 4,8-dioxatricyclo[4.2.1.03,7]nonane-9-methanol and 4-oxatricyclo[4.3.1.03,7]decane-10-methanol, compounds with activity against Coxsackie viruses

(1R*,2R*,3R*,4S*)-7-Oxabicyclo[2.2.1]hept-5-ene-2,3-dimethanol (10) and (1R*,2R*,3R*,4S*)-bicyclo[2.2.2]oct-5-ene-2,3-dimethanol (14), which were prepared by the Diels–Alder reaction and subsequent reduction with lithium aluminium hydride, were treated with benzyl azidoformate to give benzylN-[(1R*,2R*,3S*,6S*,7S*,9S*)-9-(hydroxymethyl)-4,8-dioxatricyclo[4.2.1.03,7]nonan-2-yl]carbamate (11) and benzylN-[(1R*,2R*,3R*,6R*,7S*,10S*)-10-(hydroxymethyl)-4-oxatricyclo[4.3.1.03,7]decan-2-yl]carbamate (15). Hydrogenolysis of carbamates11or15afforded (1R*,2R*,3S*,6S*,7S*,9S*)-2-amino-4,8-dioxatricyclo[4.2.1.03,7]nonane-9-methanol (12) or (1R*,2R*,3R*,6R*,7S*,10S*)-2-amino-4-oxatricyclo[4.3.1.03,7]decane-10-methanol (16). The amines12and16were transformed to thymine and purine nucleoside analogues. The target compounds were tested for the activity againstCoxsackievirus.

Design, synthesis, and anti-HIV activity of 4′-modified carbocyclic nucleoside phosphonate reverse transcriptase inhibitors

A diphosphate of a novel cyclopentyl based nucleoside phosphonate with potent inhibition of HIV reverse transcriptase (RT) ( 20, IC 50 = 0.13 μM) has been discovered. In cell culture the parent phosphonate diacid 9 demonstrated antiviral activity EC 50 = 16 μM, within two-fold of GS-9148, a prodrug of which is currently under clinical investigation, and within 5-fold of tenofovir (PMPA). In vitro cellular metabolism studies using 9 confirmed that the active diphosphate metabolite is produced albeit at a lower efficiency relative to GS-9148.

Synthesis and Anti-Hepatitis B Virus and Anti-Hepatitis C Virus Activities of 7-Deazaneplanocin A Analogues in Vitro

A series of 7-deazaneplanocin A (7-DNPA, 2) analogues were synthesized and evaluated for in vitro antiviral activity against HBV and HCV. The syntheses of target carbocyclic nucleosides were accomplished via a convergent procedure. 7-Substitutions were introduced by using 7-substituted-7-deaza heterocyclic base precursors (F, Cl, Br, and I) or via substitution reactions after the synthesis of the carbocyclic nucleosides. Among the synthesized compounds, 2, 13-15, 24, and 27 exhibited significant anti-HCV activity (EC(50) ranged from 1.8 to 20.1 microM) and compounds 2, 15, 22, and 24 demonstrated moderate to potent anti-HBV activity (EC(50) = 0.3-3.3 microM). In addition, compound 24 also showed activity against lamivudine- and adefovir-associated HBV mutants.

Syntheses of New Spirocarbocyclic Nucleoside Analogs Using Iminonitroso Diels−Alder Reactions

N-Cbz- and Boc-protected spirocyclic dienes were prepared by dialkylation of cyclopentadiene. These dienes coupled efficiently in a series of iminonitroso Diels-Alder reactions to produce a series of new spirocyclic adducts. Hydrogenolysis of these adducts afforded new spirocycles that contain multiple handles for further functionalization. Furthermore, stereocontrolled dihydroxylation and reductive cleavage of the spirocyclic adducts generated versatile scaffolds for the syntheses and derivatization of novel spirocyclic carbocyclic nucleoside analogs.

Novel Synthesis and Anti-HIV Activity of 4′-Branched Exomethylene Carbocyclic Nucleosides Using a Ring-Closing Metathesis of Triene

The exomethylene of 6 was successfully constructed from the aldehyde 5 using Eschenmoser's reagents. A triene compound 7 was cyclized successfully using Grubbs’ II catalyst to give an exomethylene carbocycle nucleus for the target compound. A Mitsunobu reaction was successfully used to condense the natural bases (adenine, thymine, uracil, and cytosine). The synthesized cytosine analogue 20 showed moderate anti-HIV activity (EC50 = 10.67 μM).

Synthesis and Anti-HIV-1 Activity of Carbocyclic Versions of Stavudine Analogues Using a Ring-closing Metathesis

An efficient synthetic route for carbocyclic versions of stavudine analogues and their evaluation on antiviral activity are described. The construction of an ethynylated quaternary carbon at the 4'-position of carbocyclic nucleosides was accomplished using Claisen rearrangement of 11 and ring-closing metathesis (RCM) of dienyne 14 as key transformations. An antiviral evaluation of the synthesized compounds, 20, 21, 22, and 25 against HIV-1, HSV-1, HSV-2, and HCMV showed that only the guanine analogue 25 is moderately active against HIV-1 in the MT-4 cell line ( = 11.91 mol).歸猠桥慰ｿｿｿｿ頀뢔잖⨀뢔잖⨀᠁킔잖⨀킔잖⨀᠂잖⨀잖⨀᠄•잖⨀•잖⨀㡯җ⨀耂Іဎ歸猠晲慭攠桥慰ｿｿｿｿꀁ袕잖⨀袕잖⨀ ꂕ잖⨀ꂕ잖⨀ 뢕잖⨀뢕잖⨀‐킕잖⨀킕잖⨀䤀돀ₔ잖⨀끯җ⨀끯җ⨀倀焀댐잖⨀⥫儀댐잖⨀⥫Ԁ餂돀잖⨀塨?⨀⣀Ɨ⨀䂙잖⨀℁덀備잖⨀ ⣀Ɨ⨀耂І栂歸猠晲慭攠桥慰ｿｿｿｿꀁ㢗잖⨀㢗잖⨀ 傗잖⨀傗잖⨀ 梗잖⨀梗잖⨀‐肗잖⨀肗잖⨀ᘀᔀᘀ䄀대ꂖ잖⨀꩑ࠄ䑒⑉匰㈱彁啉也䕎呉呔䌀ꢗ잖⨀㄀대삗잖⨀꩑ࠄ섻잖⨀ȀᘀĀ餀돀˜잖⨀타Ɨ⨀타Ɨ⨀⣀Ɨ⨀耀 ㈀鹑ࠄ肘잖⨀ȈᘀĀ贇᠀Ę Ā䤀댐゘잖⨀⥫Ѐ餂돀잖⨀／ࠀ⣀Ɨ⨀섁덀

Synthesis of d- and l-Carbocyclic Nucleosides via Rhodium-Catalyzed Asymmetric Hydroacylation as the Key Step

D- and L-carbocyclic nucleosides were obtained by a new procedure involving an enantioselective rhodium/duphos-catalyzed hydroacylation reaction as the key step. The 3-hydroxymethyl-cyclopentanol intermediate was obtained by stereoselective reduction of ketone and by dynamic kinetic resolution (DKR).

Synthesis of Carbocyclic 2-Substituted Adenine Nucleoside and Related Analogs

2-Iodonoraristeromycin, 2-iodoaristeromycin and related analogs were synthesized to investigate their inhibitory activities against human and Plasmodium falciparum S-adenosyl-L-homocysteine hydrolases.