DOCSLIB.ORG

Preparation of Purine and Pyrimidine Carbocyclic Nucleoside Derivatives

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Preparation of Purine and Pyrimidine Carbocyclic Nucleoside Derivatives molecules Article Synthesis of Cyclobutane Analogue 4: Preparation of Purine and Pyrimidine Carbocyclic Nucleoside Derivatives Noha Hasaneen 1 , Abdelaziz Ebead 2, Murtaza Hassan 1, Hanan Afifi 3, Howard Hunter 1, Edward Lee-Ruff 1,*, Nadia S. El-Gohary 4, Azza R. Maarouf 4 and Ali A. El-Emam 4 1 Department of Chemistry, Faculty of Science, York University, Toronto, ON M3J 1P3, Canada 2 Chemistry Department, Faculty of Science, Arish University, Arish, Egypt 3 Basic Science Department, Faculty of Industrial Education, Beni-Suef University, Beni-Suef, Egypt 4 Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt * Correspondence: leeruff@yorku.ca; Tel.: 416-736-5443 Academic Editors: Katherine L. Seley-Radtke and Theodore K. Dayie Received: 2 August 2019; Accepted: 29 August 2019; Published: 5 September 2019 Abstract: The coupling of 2-bromo-3-benzoyloxycyclobutanone with purine under basic conditions produces two regioisomers consisting of the N-7 and N-9 alkylated products in equal amounts in their racemic forms. The distribution of the isomers is consistent with the charge delocalization between the N-7 and N-9 positions of the purinyl anion. The structural assignments and relative stereochemistry of each regioisomer were based on 1 and 2D NMR techniques. The relative stereochemistry of the C-2 and C-3 substituents in each regioisomer was the trans orientation consistent with steric factors in the coupling step. The N-9 regioisomer was reduced with sodium borohydride to give the all trans cyclobutanol as the major product in a stereoselective manner. The alcohol was debenzoylated with sodium methoxide in a transesterification step to give the nucleoside analogue. The regioisomeric pyrimidine nucleosides were prepared by Vorbrüggen coupling of the 3-hydroxymethylcyclobutanone triflate with either thymine or uracil followed by stereoselective hydride addition. Regiospecificity of the coupling at the N-1 position was observed and stereoselective reduction to the trans-disubstituted cyclobutanol structure assignments was based on NMR data. Keywords: nucleoside analogs; cyclobutanes; purine; uracil; thymine 1. Introduction Nucleosides constitute the components of nucleic acids. These are linked by phosphate units in the structures of DNA and RNA. Structural modifications of nucleosides (nucleoside analogs) result in changes to chemical and biological processes involving nucleic acids, resulting in their physiological properties as antiviral and anticancer agents [1,2]. Carbocyclic derivatives in which the ribose ring is replaced by a carbocycle enhances the metabolic stabilities of these potential drugs [3]. The cyclopentenyl derivatives Carbovir [4] and Abacavir [5] developed in the 1990s are some of the early examples of effective antiviral agents. With the observation of potent antiviral activity of the natural occurring Oxetanocin A, [6] the development and commercialization of the synthetic carbocyclic analogues, Cyclobut-A and Cyclobut-G (Lobucavir), as well as related analogs were realized [7–13]. In view of rapid mutations of viruses becoming resistant to current drug therapies, the quest for new Reverse Transcriptase (RT) inhibitors with structural modifications is an ongoing pursuit. In the current study we report the stereospecific synthesis of cyclobutanols to which a nucleobase is attached to the C-2 position of the carbocycle, and the C-3 position by a methylene pendant in a cis orientation to the alcohol function. Furthermore, the regiochemistry of both N-7 and N-9 isomers of purinonucleosides produced in the coupling reaction was unambiguously assigned. Molecules 2019, 24, 3235; doi:10.3390/molecules24183235 www.mdpi.com/journal/molecules Molecules 2019, 24, x 2 of 18 attached to the C-2 position of the carbocycle, and the C-3 position by a methylene pendant in a cis orientation to the alcohol function. Furthermore, the regiochemistry of both N-7 and N-9 isomers of Moleculespurinonucleosides2019, 24, 3235 produced in the coupling reaction was unambiguously assigned. 2 of 16 We have already described the coupling of 6-chloropurine to the C-2 position and the C-3 positionWe haveby a methylene already described pendant the in coupling recent publications of 6-chloropurine [14,15]. to In the theC-2 currentposition study and we the reportC-3 position on the bycoupling a methylene reactions pendant of in recentthe publicationsparent purine [14, 15].nucleobase In the current to studythe weC report-2 position on the couplingof 3- reactionshydroxylmethylcyclobutanol, of the parent purine nucleobase and the coupling to the C-2 reactionsposition of ofpyrimidine 3-hydroxylmethylcyclobutanol, bases to a methylene bridged and the couplingC-3 cyclobutanol. reactions These of pyrimidine compounds bases constitute to a methylene novel bridgednucleosideC-3 analogscyclobutanol. with potential These compounds biological constituteactivities. novel nucleoside analogs with potential biological activities. 2. Results and Discussion 2.1. Synthesis of Purine Carbocyclic Analogues 2.1.1. N N-Alkylation-Alkylation of P Purineurine to Bromocyclobutanone 1 DirectDirect alkylation of heterocyclic bases (purine and pyrimidine) with alkyl halides is well documented [1616,,17]. Such Such an an approach approach also also bears bears some similarity to the reportedreported glycosylationglycosylation procedure ofof RobinsRobins [ 18[18],], where where the the sodium sodium salts salts of of a purinea purine base base react react with withα-halo-sugars α-halo-sugars to give to give the correspondingthe corresponding glyconucleosides. glyconucleosides. Based on these these observations, observations, we we prepared prepared cyclobutanone cyclobutanone derivatives derivatives possessing possessing purine purine as asan anα- αsubstituent-substituent using using the the following following method method [19]. [19 The]. Thepota potassiumssium salt of salt purine of purine (2), produced (2), produced in situ in using situ usingKOH KOHin the in presence the presence of tris(dioxa of tris(dioxa-3,6-heptyl)amine-3,6-heptyl)amine (TDA (TDA-1)-1) in acetonitrile, in acetonitrile, was was treated treated with with α- αbromocyclobutanone-bromocyclobutanone 1 1andand resulted resulted in in the the formation formation of of the the NN-9-9 coupledcoupled product product 33 inin an 11.7% yield as well as the N-7N-7 regioisomerregioisomer 44 inin anan 11.2%11.2% yieldyield (Scheme(Scheme1 1)).. TheThe assignmentassignment ofof thethe attachedattached sitesite ofof 1 13 the purine derivatives 33 and 4 was established usingusing 1D1D 1HH-- and 13CC-NMR-NMR as as well well as as 2D 2D COSY, COSY, HSQC HSQC,, and HMBC experiments. Scheme 1.1. Base assisted coupling of purine with Bromoketone 1.. A number of NMR studies have been reported [20–22] forfor thethe N-7N-7 andand N-9N-9 purinepurine alkylatedalkylated derivatives and certain patternspatterns emergeemerge forfor thethe 11H-H- andand 1313CC-chemical-chemical shifts. The The signals signals of H H-8,-8, C C-1’,-1’, C-8,C-8, and more significantlysignificantly C-4C-4 are shifted upfieldupfield for the N-9N-9 isomerisomer relativerelative toto thethe correspondingcorresponding signals for the N-7N-7 isomer. By contrast,contrast, the C-5C-5 signal for the N-9N-9 derivatives is deshielded relative to that for the N-7N-7 isomerisomer duedue toto thethe largerlarger stericsteric congestioncongestion existingexisting inin thethe N-7N-7 isomer.isomer. The regiochemistryregiochemistry of of3 3and and4 was4 was supported supported by theby the larger larger chemical chemical shift shift values values of H-8 of ( δH8.41-8 (δ ppm), 8.41 C-1’ppm), (δ C69.8-1’ (δ ppm), 69.8 ppm), C-8 (δ C146.8-8 (δ 146.8 ppm), ppm) and, C-4and (Cδ-160.24 (δ 160.2 ppm) ppm) signals signals for for the theN-7 Nisomer-7 isomer4 (Figures4 (Figure1s and1 and2) as2) comparedas compared to theto the H-8 H ( -δ88.12 (δ 8.12 ppm), ppm), C-1’ C (δ-1’68.2 (δ 68.2 ppm), ppm), C-8 (Cδ-1448 (δ ppm), 144 ppm) and, C-4 and (δ C150.8-4 (δ ppm)150.8 signalsppm) signals for the forN-9 thealkylated N-9 alkylated derivatives derivatives3 (Figures 3 3(Figure and4).sThis 3 and regiochemistry 4). This regiochemistry was also supported was also bysupported the chemical by the shift chemical of the C-5shift signal of the (δ C133.6-5 signal ppm) (δ of 133.63, which ppm) was of shifted3, which downfield was shifted relative downfield to the C-5relative signal to (theδ 124.1 C-5 ppm)signal for (δ the124.1N-7 ppm)component for the N4 -(Figures7 component1 and2 4, Table(Figures1). The1 and High 2, Table Resolution 1). The Mass High Spectrometry data (HRMS) was consistent with the molecular composition of both 3 and 4. Molecules 2019, 24, x 3 of 18 Resolution Mass Spectrometry data (HRMS) was consistent with the molecular composition of both 3 and 4. Molecules 2019, 24, x 3 of 18 Molecules 2019, 24, 3235 3 of 16 Resolution Mass Spectrometry data (HRMS) was consistent with the molecular composition of both 3 and 4. Figure 1. 13C-NMR spectrum for ketone 4. 13 FigureFigure 1.1. 13CC-NMR-NMR spectrum spectrum for ketone for ketone 4. 4. Molecules 2019, 24, x 1 4 of 18 FigureFigure 2. 2.1H-NMRH-NMR spectrum spectrum for ketone for 4. ketone 4. Figure 2. 1H-NMR spectrum for ketone 4. 13 FigureFigure 3 3.. 13C-C-NMRNMR spectrum spectrum for ketone for 3 ketone. 3. Figure 4. 1H-NMR spectrum for ketone 3. Table 1. 1H- and 13C-NMR chemical shifts (ppm) for 3 and 4 ketones. N-9-ketone 3 N-7-ketone 4 H-8 8.12 8.41 C-1’ 68.2 69.8 C-4 150.8 160.2 C-5 133.6 124.1 C-8 144 146.8 The 2D HMBC spectra for 3 and 4 also supported the regiochemical assignments. Correlations between H-1’ and C-8 and C-4 signals were observed with the absence of any correlation with C-5 for Molecules 2019, 24, x 4 of 18 Figure 3.
Load more

Recommended publications
  • Rational Design and Synthesis of New Nucleoside Analogues Bearing a Cyclohexane Core
    Rational Design and Synthesis of New Nucleoside Analogues Bearing a Cyclohexane Core Beatriz Domínguez Pérez Ph.D. Thesis Ph.D. in Chemistry Supervisors: Dr. Ramon Alibés Arqués Dr. Félix Busqué Sánchez Dr. Jean-Didier Márechal Departament de Química Facultat de Ciències 2015 Memòria presentada per aspirar al Grau de Doctor per Beatriz Domínguez Pérez Beatriz Domínguez Pérez Vist i plau, Dr. Ramon Alibés Arqués Dr. Félix Busqué Sánchez Dr. Jean-Didier Maréchal Bellaterra, 13 de maig de 2015 “When you make the finding yourself-even if you’re the last person on Earth to see the light- you’ll never forget it” Carl Sagan A mis padres, a mi hermana A Jonatan Table of contents Abbreviations................................................................................................................................ 1 I. General introduction ............................................................................................. 5 1. Viruses ................................................................................................................................. 7 1.1. Virus replication ............................................................................................................. 8 1.2. Viral diseases in humans ................................................................................................ 9 2. Antiviral drugs ................................................................................................................... 10 2.1. Nucleoside analogues .................................................................................................
    [Show full text]
  • Nucleobase Coupling by Mitsunobu Reaction Towards Nucleoside Analogs
    The Free Internet Journal Review for Organic Chemistry Archive for Arkivoc 2021, part iv, 0-0 Organic Chemistry to be inserted by editorial office Nucleobase coupling by Mitsunobu reaction towards nucleoside analogs Eduardo C. de Sousa and Amélia P. Rauter Centro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa Ed C8, Piso 5, Campo Grande, 1749-016 Lisboa, Portugal Email: [email protected] This paper is dedicated to Prof. Dr. Horst Kunz on the occasion of his 80th anniversary Received 09-21-2020 Accepted Manuscript 11-29-2020 Published on line 12-20-2020 Abstract The coupling of a nucleobase is a key step in the synthesis of most nucleoside analogs, e.g. carbocyclic nucleosides, isonucleosides and acyclic nucleosides. The synthetic strategies for nucleosides based on N- glycosylation are not applied when the nucleobase is not linked to the anomeric center. Thus, other methods have been employed, mainly those based on the alkylation of nucleobases. The Mitsunobu reaction, in which a hydroxy group is replaced by a nucleophile, has also been extensively applied, generating a diversity of molecules, including pharmaceuticals and their precursors. In this review the usefulness of this reaction for the coupling of nucleobases to non-anomeric positions of sugars, carbasugars and other homocyclic and linear structures is highlighted and discussed, covering purines and pyrimidines as pronucleophiles. * Keywords: Mitsunobu reaction, carbocyclic nucleosides, isonucleosides, acyclic nucleosides, synthesis DOI: https://doi.org/10.24820/ark.5550190.p011.377 Page 1 ©AUTHOR(S) Arkivoc 2021, iv, 0-0 de Sousa, E. C. et al. Table of Contents 1. Introduction 1.1.
    [Show full text]
  • Nucleoside Analogs with Fleximer Nucleobase
    DOI 10.1007/s10593-020-02713-5 Chemistry of Heterocyclic Compounds 2020, 56(6), 636–643 Nucleoside analogs with fleximer nucleobase Mikhail V. Chudinov1* 1MIREA - Russian Technological University, Lomonosov Institute of Fine Chemical Tehnology, 78 Vernadsky Ave., Moscow 119454, Russia, е-mail: [email protected] Translated from Khimiya Geterotsiklicheskikh Soedinenii, Submitted February 28, 2020 2020, 56(6), 636–643 Accepted after revision April 15, 2020 This review article is devoted to the so-called fleximer nucleoside analogs, containing two or more planar moieties in the heterocyclic base, connected by a bond that permits rotation. Such analogs have been proposed as molecular probes for detecting enzyme–substrate interactions and studying the transcription and translation of nucleic acids, but subsequently have attracted the interest of researchers by their antiviral and antitumor activity. The methods used in the synthesis of such compounds, along with their structural features and also biological activity are considered in this review. Keywords: pyrimidine, riboside, triazole, antitumor activity, antiviral activity, fleximer, nucleoside analogs. The term "fleximers" was introduced in 2001 by the heterocyclic base was the assembly of a fused tricyclic Seley research group,1 referring to synthetic analogs of system with a central thiophene ring. This tricyclic system nucleosides in which the purine base has been "splitted" was subjected to Raney nickel desulfurization, providing into two linked heterocycles – imidazole and pyrimidine. the desired fleximer1 (Scheme 1). Similarly to any other Initially intended as model compounds for studying the synthesis of nucleoside analogs, there was the issue of which binding sites of enzymes and characterizing the interactions synthetic step would be most convenient for the formation between proteins and nucleic acids, compounds of this type of the glycosidic bond.
    [Show full text]
  • The First Intermolecular Interrupted Imino-Nazarov Reaction
    Chemical Science View Article Online EDGE ARTICLE View Journal | View Issue The first intermolecular interrupted imino-Nazarov reaction: expeditious access to carbocyclic Cite this: Chem. Sci.,2016,7,1100 nucleoside analogues† Ronny William, Wei Lin Leng, Siming Wang and Xue-Wei Liu* The analogous imino-variant of the Nazarov reaction suffers from unfavorable energetics associated with the ring closure process, thereby limiting the utility of this class of reactions. In this report, the realization of the first intermolecular interrupted imino-Nazarov reaction utilizing silylated pyrimidine derivatives as Received 21st September 2015 nucleophilic trapping partners culminated in an expedient synthetic route to carbocyclic nucleoside Accepted 27th October 2015 analogues. The potential application of silylated nucleobases to intercept the oxyallyl cation in other DOI: 10.1039/c5sc03559g variants of the Nazarov reaction provides vast opportunities to develop new strategies for the formation www.rsc.org/chemicalscience of carbocyclic nucleoside analogues. Creative Commons Attribution 3.0 Unported Licence. Carbocyclic nucleosides represent an emerging class of privi- intercept the cyclopentenyl cation formed following cyclization leged therapeutic compounds which exhibit interesting bio- in inter- or intramolecular fashion, allowing rapid access to logical properties.1,2 Substitution of endocyclic oxygen by more elaborate cyclopentanoid compounds.8 The imino variant a methylene unit in a carbocyclic nucleoside derivative imparts of the Nazarov
    [Show full text]
  • The Role of Nucleotide Excision by Reverse Transcriptase in HIV Drug Resistance
    Viruses 2010, 2, 372-394; doi:10.3390/v2020372 OPEN ACCESS viruses ISSN 1999-4915 www.mdpi.com/journal/viruses Review The Role of Nucleotide Excision by Reverse Transcriptase in HIV Drug Resistance Antonio J. Acosta-Hoyos and Walter A. Scott * Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, P.O. Box 016129, Miami, FL 33101-6129, USA; E-Mail: [email protected] (A.J.A.-H.) * Author to whom correspondence should be addressed; E-Mail: [email protected] (W.A.S.); Tel.: +1-305-243-6359; Fax: +1-305-243-3955. Received: 10 December 2009; in revised form: 15 January 2010 / Accepted: 25 January 2010 / Published: 28 January 2010 Abstract: Nucleoside reverse transcriptase (RT) inhibitors of HIV block viral replication through the ability of HIV RT to incorporate chain-terminating nucleotide analogs during viral DNA synthesis. Once incorporated, the chain-terminating residue must be removed before DNA synthesis can continue. Removal can be accomplished by the excision activity of HIV RT, which catalyzes the transfer of the 3'-terminal residue on the blocked DNA chain to an acceptor substrate, probably ATP in most infected cells. Mutations of RT that enhance excision activity are the most common cause of resistance to 3'-azido-3'- deoxythymidine (AZT) and exhibit low-level cross-resistance to most other nucleoside RT inhibitors. The resistance to AZT is suppressed by a number of additional mutations in RT, most of which were identified because they conferred resistance to other RT inhibitors. Here we review current understanding of the biochemical mechanisms responsible for increased or decreased excision activity due to these mutations.
    [Show full text]
  • Abacavir Pathway Julia M
    276 PharmGKB summary PharmGKB summary: abacavir pathway Julia M. Barbarinoa, Deanna L. Kroetzc, Russ B. Altmana,b and Teri E. Kleina Pharmacogenetics and Genomics 2014, 24:276–282 Correspondence to Teri E. Klein, PhD, Department of Genetics, 318 Campus Drive, Clark Center Room S221A, MC: 5448, Stanford, CA 94305, USA Keywords: abacavir, HIV, HLA-B, HLA-B*57:01, HSP70-HOM, hypersensitivity, Tel: + 1 650 736 0156; fax: + 1 650 725 3863; e-mail: [email protected] pharmacodynamics, pharmacogenetics, pharmacokinetics, PharmGKB Received 4 December 2013 Accepted 5 February 2014 Departments of aGenetics, bBioengineering, Stanford University, Stanford and cDepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA Introduction P450 (CYP) enzymes are predicted [2]. In addition, in- Abacavir is a nucleoside reverse transcriptase inhibitor vitro studies have shown that abacavir is unlikely to (NRTI) used for treatment of HIV infection. HIV inhibit CYP enzymes at clinically relevant concentra- infection is usually treated with antiretroviral therapy tions [14]. As non-NRTIs and protease inhibitors are regimens, which consist of three or more different drugs primarily metabolized by CYP enzymes [15], this may used in combination. Typical antiretrovirals used in these eliminate the potential for drug interactions with regimens include NRTIs, non-NRTIs, protease inhibi- these types of antiretrovirals. No clinically significant tors, and integrase strand inhibitors [1]. Abacavir makes pharmacokinetic
    [Show full text]
  • Advances and Perspectives in the Management of Varicella-Zoster Virus Infections
    molecules Review Advances and Perspectives in the Management of Varicella-Zoster Virus Infections Graciela Andrei * and Robert Snoeck Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium; [email protected] * Correspondence: [email protected]; Tel.: +32-16-32-19-51 Abstract: Varicella-zoster virus (VZV), a common and ubiquitous human-restricted pathogen, causes a primary infection (varicella or chickenpox) followed by establishment of latency in sensory ganglia. The virus can reactivate, causing herpes zoster (HZ, shingles) and leading to significant morbidity but rarely mortality, although in immunocompromised hosts, VZV can cause severe disseminated and occasionally fatal disease. We discuss VZV diseases and the decrease in their incidence due to the introduction of live-attenuated vaccines to prevent varicella or HZ. We also focus on acyclovir, valacyclovir, and famciclovir (FDA approved drugs to treat VZV infections), brivudine (used in some European countries) and amenamevir (a helicase-primase inhibitor, approved in Japan) that augur the beginning of a new era of anti-VZV therapy. Valnivudine hydrochloride (FV-100) and valomaciclovir stearate (in advanced stage of development) and several new molecules potentially good as anti-VZV candidates described during the last year are examined. We reflect on the role of antiviral agents in the treatment of VZV-associated diseases, as a large percentage of the at-risk population is not immunized, and on the limitations of currently FDA-approved anti-VZV drugs. Their low efficacy in controlling HZ pain and post-herpetic neuralgia development, and the need of Citation: Andrei, G.; Snoeck, R. multiple dosing regimens requiring daily dose adaptation for patients with renal failure urges the Advances and Perspectives in the development of novel anti-VZV drugs.
    [Show full text]
  • Nucleosides As Anti-Hepatitis B Virus Agents
    FABAD J. Phann. Sci., 26, 129-136, 2001 BİLİMSEL TARAMALAR/ SCIENTIFIC REVIEWS Nucleosides as Anti-Hepatitis B Virus Agents Süreyya ÖLGEN* 0 Nucleosides as Aııti-Hepavtis B Virus Ageııts Anti-Hepatit B Virüs Ajanı Nükleositler analogs, such as 3TC, FTC and Sunımary : The nucleoside Özet : Yalnızca 3TC, FTC ve L-FMAU gibi bir sınıf niik­ L-FMAU appear to be the anly promising class of conı­ leosit analoğu, kronik HBV infeksiyonlarının tedavisi için pounds far the managenıent of chronic HBV infection. in ümit verici bileşikler olarak ortaya çıkmışlardır. Bu der­ this paper, anti-HBV effects of these compounds and some lemede, bu bileşiklerin ve .'ion zamanlarda sentezlenen diğer other new derivatives, which were synthesized recently, were bazı yeni bileşiklerin anti-HBV etkileri tartışılmıştır. discııssed. Anahtar kelimeler: Nukleositler, Anti-Hepatit bi­ Key Words: Nııcleosides, Anti·hepatitis Agents, HBV in· fection leşikler, HBV enfeksiyonu Received 15.5.2001 Revised 27.6.2001 Accepted 28.6.2001 Pandemic morbidity and morta!ity due to the hep­ Hepatitis B virus (HBV) can cause a serious form of atitis B virus (HBV) have been responsible for the in­ hepatitis. HBV infection is responsible for both acute tensive efforts in discovering more effective and less and chronic hepatitis. Acute HBV infection can be toxic antiviral agents. Additionally, despite over 300 variable with most individuals showing no obvious million HBV chronic carriers, no effective and safe clinical sign of the disease. Generally, at the end of in­ chemotherapeutic agents are available today for the cubation period, a flue-like il!ness with fever, fatigue, treatment of these patients.
    [Show full text]
  • Nucleobase Coupling by Mitsunobu Reaction Towards Nucleoside Analogs
    A Platinum Open Access Journal Review for Organic Chemistry Free to Authors and Readers DOAJ Seal Arkivoc 2021, part iv, 241-267 Nucleobase coupling by Mitsunobu reaction towards nucleoside analogs Eduardo C. de Sousa and Amélia P. Rauter Centro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa Ed C8, Piso 5, Campo Grande, 1749-016 Lisboa, Portugal Email: [email protected] This paper is dedicated to Prof. Dr. Horst Kunz on the occasion of his 80th anniversary Received 09-21-2020 Accepted Manuscript 11-29-2020 Published on line 12-20-2020 Abstract The coupling of a nucleobase is a key step in the synthesis of most nucleoside analogs, e.g. carbocyclic nucleosides, isonucleosides and acyclic nucleosides. The synthetic strategies for nucleosides based on N- glycosylation are not applied when the nucleobase is not linked to the anomeric center. Thus, other methods have been employed, mainly those based on the alkylation of nucleobases. The Mitsunobu reaction, in which a hydroxy group is replaced by a nucleophile, has also been extensively applied, generating a diversity of molecules, including pharmaceuticals and their precursors. In this review the usefulness of this reaction for the coupling of nucleobases to non-anomeric positions of sugars, carbasugars and other homocyclic and linear structures is highlighted and discussed, covering purines and pyrimidines as pronucleophiles. * Keywords: Mitsunobu reaction, carbocyclic nucleosides, isonucleosides, acyclic nucleosides, synthesis DOI: https://doi.org/10.24820/ark.5550190.p011.377 Page 241 ©AUTHOR(S) Arkivoc 2021, iv, 241-267 de Sousa, E. C. et al. Table of Contents 1. Introduction 1.1.
    [Show full text]
  • DONG WU Synthesis of Carbocyclic L-Nucleosides (Under the Direction of Dr C.K.Chu)
    DONG WU Synthesis Of Carbocyclic L-Nucleosides (Under the Direction of Dr C.K.Chu) Nucleosides have been studied as potential anti-viral and anti-cancer agents. A number of nucleosides have been discovered with significant antiviral activity. However, toxicities and side effects as well as the emergence of drug resistant viral strains limit the usefulness of the currently available nucleosides as anti-viral agents. Furthermore, the disadvantage of normal nucleosides and their analogs is that the glycosidic bond is subjected to enzymatic hydrolysis by phosphorylase. To overcome these problems, we need to synthesize new agents, among which are carbocyclic nucleoside analogs. In this thesis, the new carbocyclic L-Nucleoside with 5’-methylene group was synthesized and the new scheme was designed to synthesize the similar analogs. INDEX WORDS: Carbocyclic L-Nucleosides, Enzymatic Hydrolysis, Antiviral Agents, 5’-Methylene Group. SYNTHESIS OF CARBOCYCLIC L-NUCLEOSIDES by DONG WU B.S., Beijing Medical University, China, 1997 A Thesis Submitted to the Graduate Faculty Of The University of Georgia in Partial Fulfillment of the Requirements for the Degree MASTER OF SCIENCE ATHENS, GEORGIA 2001 2000 Dong Wu All Right Reserved SYNTHESIS OF L-CARBOCYCLIC NUCLEOSIDES by DONG WU Approved: Major Professor: Chung K. Chu Committee: Tony Capomacchia Robert Lu Electronic Version Approved: Gordhan L. Patel Dean of the Graduate School The University of Georgia December 2001 DEDICATION To my parents, who have endowed intelligence in me; To my brother, who has instilled in me courage; and To my lovely son, Xi-Kai Isaac Wu, who has given great joys to us. iv ACKNOWLEDGEMENTS I would especially like to thank my major Professor, Dr.
    [Show full text]
  • V Nucleoside/Nucleotide RT Inhibitor (NRTI) Resistance
    Nucleoside/nucleotide RT inhibitor (NRTI) resistance HIV-1 RT The RT enzyme is responsible for RNA-dependent DNA polymerization and DNA- dependent DNA polymerization. RT is a heterodimer consisting of p66 and p51 subunits. The p51 subunit is composed of the first 440 amino acids of the pol gene. The p66 subunit is composed of all 560 amino acids of the pol gene. Although the p51 and p66 subunits share 440 amino acids, their relative arrangements are significantly different. The p66 subunit contains the DNA-binding groove and the active site; the p51 subunit displays no enzymatic activity and functions as a scaffold for the enzymatically active p66 subunit. The general shape of the polymerase domain of the p66 subunit can be likened to a human hand with subdomains referred to as fingers, palm, and thumb. The remainder of the p66 subunit contains an RNase H subdomain and a connection subdomain (reviewed in (Larder & Stammers, 1999; Sarafianos et al., 1999b)). Most RT inhibitor resistance mutations are in the 5' polymerase coding regions, particularly in the "fingers" and "palm" subdomains (Figure 4). Structural information for RT is available from X-ray crystallographic studies of unliganded RT (Rodgers et al., 1995), RT bound to an NNRTI (Kohlstaedt & Steitz, 1992), RT bound to double-stranded DNA (Jacobo-Molina et al., 1993), RT bound to double-stranded DNA and the incomping dNTP (ternary complex) (Huang et al., 1998), and an RT bound to double stranded DNA containing an AZT-terminated DNA primer pre- and post-translocation (Sarafianos et al., 2002). There have been fewer structural determinations of mutant RT enzymes than of mutant protease enzymes (Ren et al., 1998; Sarafianos et al., 1999a; Sarafianos et al., 2001; Stammers et al., 2001; Chamberlain et al., 2002).
    [Show full text]
  • 6',6'-Difluoro-Aristeromycin Is a Potent Inhibitor of MERS-Coronavirus
    bioRxiv preprint doi: https://doi.org/10.1101/2021.05.20.445077; this version posted May 21, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 To be submitted to Antimicrobial Agents and Chemotherapy 2 6′,6′-Difluoro-aristeromycin is a potent inhibitor of MERS-coronavirus replication 3 4 Natacha S. Ogando1, Jessika C. Zevenhoven-Dobbe1, Dnyandev B. Jarhad2, Sushil Kumar Tripathi2, Hyuk 3 2 1# 1 5 Woo Lee , Lak Shin Jeong , Eric J. Snijder , Clara C. Posthuma * 6 7 1 Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, 8 Leiden, The Netherlands 9 2 Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 10 08826, Korea 11 3 Future Medicine Company Ltd., Seongnam, Gyeonggi-do 13449, Korea 12 #Address correspondence to Eric J. Snijder; [email protected] 13 * Present address: Netherlands Commission on Genetic Modification, Bilthoven, The Netherlands 14 15 Running title: Antiviral activity of DFA against coronaviruses 16 Abstract: 250 words 17 Figures: 5 18 Tables: 2 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.05.20.445077; this version posted May 21, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license.
    [Show full text]