Carbocyclic nucleoside

Last updated
Generic ribonucleoside with gycosidic bond and carbocyclic ribonucleoside analogue.svg

Carbocyclic nucleosides (also referred to as carbanucleosides) are nucleoside analogues in which a methylene group has replaced the oxygen atom of the furanose ring. [1] These analogues have the nucleobase attached at a simple alkyl carbon rather than being part of a hemiaminal ether linkage. As a result, they have increased chemical stability. They also have increased metabolic stability because they are unaffected by phosphorylases and hydrolases that cleave the glycosidic bond between the nucleobase and furanose ring of nucleosides. They retain many of the biological properties of the original nucleosides with respect to recognition by various enzymes and receptors.

Contents

Carbocyclic nucleosides were originally limited to a five-membered ring system, matching the ring-size of the nucleosides; however, this term has been broadened to three-, four-, and six-membered rings. [2] [3] [4]

3-, 4-, and 6-membered ring carbocyclic nucleosides 3,4,6 Carbo Nuc.svg
3-, 4-, and 6-membered ring carbocyclic nucleosides

Natural products

Aristeromycin.png
Aristeromycin
Neplanocin A.png
Neplanocin A

The 5-membered ring carbocyclic nucleosides aristeromycin, the analog of adenosine, and neplanocin A, the cyclopentene analog of aristeromycin, have been isolated from natural sources. They both exhibit significant biological activity as antiviral and antitumour agents. [1]

Classes

A large number of novel carbocyclic nucleosides of pyrimidines and purines have been prepared, and many of these compounds are endowed with interesting biological activities.

Pyrimidine carbocyclic nucleosides

Cyclopentenylcytosine (CPE-C).svg
Cyclopentenylcytosine (CPE-C)
Carbocyclic (E)-5-(2-bromovinyl)-2-deoxyuridine.svg
C-BVDU

The cyclopentenylcytosine (CPE-C) was developed as a potent antitumor and antiviral agent (phase 1 trials) [5] and exhibited potent anti-orthopoxvirus as well as anti-West Nile virus activities. [3] Carbocyclic (E)-5-(2-bromovinyl)-2-deoxyuridine( (+) C-BVDU) GR95168 possesses activity against herpes simplex virus type l (HSV-1) and varicella zoster virus (VZV, chicken pox and shingles) in-vitro and in-vivo. [6]

Purine carbocyclic nucleosides

The two guanine antiviral carbocyclic nucleosides, the anti-HIV agent abacavir and the anti-hepatitis B agent entecavir, are reverse-transcriptase inhibitors. Abacavir, was developed from racemic (±)-carbovir which was reported in 1988 by Robert Vince as the first carbocyclic nucleoside analogue to show potent activity against HIV with low cytotoxicity. [7] The (-) enantiomer of carbovir was later shown to be the biologically active form for inhibition of HIV. [8] However carbovir's low aqueous solubility and poor oral bioavailability, as well as inefficient central nervous system penetration prevented it from further developing as an anti-HIV agent. These difficulties were overcome by investigating prodrug analogues of (-) carbovir which lead to the 6-cyclopropylamino-2-aminopurine nucleoside abacavir, [9] which was approved in 1998 by the FDA for the treatment of HIV infection.

Entecavir, a guanosine analog, was reported in 1997 as a potent and selective inhibitor for the hepatitis B virus, [10] and approved by the FDA in March 2005 for oral treatment of hepatitis B infection. The fluorocarbocyclic nucleoside carbocyclic 2′-ara-fluoro-guanosine was reported in 1988 as the first example of a carbocyclic analogue of an unnatural nucleoside to exhibit greater anti-herpes activity against the herpesviruses HSV-1 and HSV-2 in-vitro than its furanose parent. [11]

Synthesis

There are two approaches used in the synthesis of carbocyclic nucleosides. [12] Linear approaches to chiral carbocyclic nucleosides 2 rely on the construction of the heterocyclic base onto a suitable protected chiral cyclopentylamine (1 → 2). In the convergent approach the intact heterocyclic base is coupled directly to a suitably protected functionalised carbocyclic moiety (3 → 2).

Linear & Convergent Synthesis of Carbocyclic Nucleosides Convergent and Linear Synthesis of Carbocyclic Nucleosides.svg
Linear & Convergent Synthesis of Carbocyclic Nucleosides

History

Related Research Articles

<span class="mw-page-title-main">Guanosine</span> Chemical compound

Guanosine (symbol G or Guo) is a purine nucleoside comprising guanine attached to a ribose (ribofuranose) ring via a β-N9-glycosidic bond. Guanosine can be phosphorylated to become guanosine monophosphate (GMP), cyclic guanosine monophosphate (cGMP), guanosine diphosphate (GDP), and guanosine triphosphate (GTP). These forms play important roles in various biochemical processes such as synthesis of nucleic acids and proteins, photosynthesis, muscle contraction, and intracellular signal transduction (cGMP). When guanine is attached by its N9 nitrogen to the C1 carbon of a deoxyribose ring it is known as deoxyguanosine.

<span class="mw-page-title-main">Ribavirin</span> Antiviral medication

Ribavirin, also known as tribavirin, is an antiviral medication used to treat RSV infection, hepatitis C and some viral hemorrhagic fevers. For hepatitis C, it is used in combination with other medications such as simeprevir, sofosbuvir, peginterferon alfa-2b or peginterferon alfa-2a. Among the viral hemorrhagic fevers it is sometimes used for Lassa fever, Crimean–Congo hemorrhagic fever, and Hantavirus infection but should not be used for Ebola or Marburg infections. Ribavirin is taken orally or inhaled. Despite widespread usage, since the 2010s it has faced scrutiny for a lack of efficacy in treating viral infections it has historically been prescribed for.

<span class="mw-page-title-main">Aciclovir</span> Antiviral medication used against herpes, chickenpox, and shingles

Aciclovir, also known as acyclovir, is an antiviral medication. It is primarily used for the treatment of herpes simplex virus infections, chickenpox, and shingles. Other uses include prevention of cytomegalovirus infections following transplant and severe complications of Epstein–Barr virus infection. It can be taken by mouth, applied as a cream, or injected.

Reverse-transcriptase inhibitors (RTIs) are a class of antiretroviral drugs used to treat HIV infection or AIDS, and in some cases hepatitis B. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase that is required for replication of HIV and other retroviruses.

<span class="mw-page-title-main">Lamivudine</span> Chemical compound

Lamivudine, commonly called 3TC, is an antiretroviral medication used to prevent and treat HIV/AIDS. It is also used to treat chronic hepatitis B when other options are not possible. It is effective against both HIV-1 and HIV-2. It is typically used in combination with other antiretrovirals such as zidovudine, dolutegravir, and abacavir. Lamivudine may be included as part of post-exposure prevention in those who have been potentially exposed to HIV. Lamivudine is taken by mouth as a liquid or tablet.

<span class="mw-page-title-main">Abacavir</span> Chemical compound

Abacavir, sold under the brand name Ziagen among others, is a medication used to treat HIV/AIDS. Similar to other nucleoside analog reverse-transcriptase inhibitors (NRTIs), abacavir is used together with other HIV medications, and is not recommended by itself. It is taken by mouth as a tablet or solution and may be used in children over the age of three months.

<span class="mw-page-title-main">Vidarabine</span> Chemical compound

Vidarabine or 9-β-D-arabinofuranosyladenine (ara-A) is an antiviral drug which is active against herpes simplex and varicella zoster viruses.

<span class="mw-page-title-main">Entecavir</span> Chemical compound

Entecavir (ETV), sold under the brand name Baraclude, is an antiviral medication used in the treatment of hepatitis B virus (HBV) infection. In those with both HIV/AIDS and HBV antiretroviral medication should also be used. Entecavir is taken by mouth as a tablet or solution.

<span class="mw-page-title-main">Nucleoside analogue</span> Biochemical compound

Nucleoside analogues are structural analogues of a nucleoside, which normally contain a nucleobase and a sugar. Nucleotide analogues are analogues of a nucleotide, which normally has one to three phosphates linked to a nucleoside. Both types of compounds can deviate from what they mimick in a number of ways, as changes can be made to any of the constituent parts. They are related to nucleic acid analogues.

Non-nucleoside reverse-transcriptase inhibitors (NNRTIs) are antiretroviral drugs used in the treatment of human immunodeficiency virus (HIV). NNRTIs inhibit reverse transcriptase (RT), an enzyme that controls the replication of the genetic material of HIV. RT is one of the most popular targets in the field of antiretroviral drug development.

Discovery and development of nucleoside and nucleotide reverse-transcriptase inhibitors began in the 1980s when the AIDS epidemic hit Western societies. NRTIs inhibit the reverse transcriptase (RT), an enzyme that controls the replication of the genetic material of the human immunodeficiency virus (HIV). The first NRTI was zidovudine, approved by the U.S. Food and Drug Administration (FDA) in 1987, which was the first step towards treatment of HIV. Six NRTI agents and one NtRTI have followed. The NRTIs and the NtRTI are analogues of endogenous 2´-deoxy-nucleoside and nucleotide. Drug-resistant viruses are an inevitable consequence of prolonged exposure of HIV-1 to anti-HIV drugs.

<span class="mw-page-title-main">Vince lactam</span> Chemical compound

Vince lactam is the commercial name given to the bicyclic molecule γ-lactam 2-azabicyclo[2.2.1]hept-5-en-3-one. This lactam is a versatile chemical intermediate used in organic and medicinal chemistry. It is used as a synthetic precursor for three drugs. It is named after Robert Vince who has used the structural features of this molecule for the preparation of carbocyclic nucleosides. Vince's work with this lactam eventually led to his synthesis of abacavir. Peramivir synthesis is also dependent on Vince lactam starting material.

Topological inhibitors are rigid three-dimensional molecules of inorganic, organic, and hybrid compounds that form multicentered supramolecular interactions in vacant cavities of protein macromolecules and their complexes.

<span class="mw-page-title-main">MK-608</span> Chemical compound

MK-608 is an antiviral drug, an adenosine analog. It was originally developed by Merck & Co. as a treatment for hepatitis C, but despite promising results in animal studies, it was ultimately unsuccessful in clinical trials. Subsequently it has been widely used in antiviral research and has shown activity against a range of viruses, including Dengue fever, tick-borne encephalitis virus, poliovirus, and most recently Zika virus, in both in vitro and animal models. Since it has already failed in human clinical trials previously, it is unlikely MK-608 itself will be developed as an antiviral medication, but the continuing lack of treatment options for these emerging viral diseases means that much research continues using MK-608 and related antiviral drugs.

HSV epigenetics is the epigenetic modification of herpes simplex virus (HSV) genetic code.

<span class="mw-page-title-main">NS5B inhibitor</span> Class of pharmaceutical drugs

Non-structural protein 5B (NS5B) inhibitors are a class of direct-acting antivirals widely used in the treatment of chronic hepatitis C. Depending on site of action and chemical composition, NS5B inhibitors may be categorized into three classes—nucleoside active site inhibitors (NIs), non-nucleoside allosteric inhibitors, and pyrophosphate analogues. Subsequently, all three classes are then subclassified. All inhibit RNA synthesis by NS5B but at different stages/sites resulting in inability of viral RNA replication. Expression of direct-acting NS5B inhibitors does not take place in cells that are not infected by hepatitis C virus, which seems to be beneficial for this class of drugs.

<span class="mw-page-title-main">EICAR (antiviral)</span> Chemical compound

EICAR (5-Ethynyl-1-beta-D-ribofuranosylImidazole-4-CARboxamide) is a nucleoside analogue which has both anti-cancer and antiviral effects, and was originally developed for the treatment of leukemia, but was unsuccessful in human clinical trials. It has broad spectrum antiviral effects with activity against pox viruses, Semliki forest virus, Junin virus, reovirus, influenza, measles virus and respiratory syncytial virus among others, although it is not active against coronaviridae such as SARS-CoV-1. This useful spectrum of activity means that EICAR and related derivatives continue to be investigated for the treatment of viral diseases.

<span class="mw-page-title-main">Azvudine</span> Antiviral drug

Azvudine is an antiviral drug which acts as a reverse transcriptase inhibitor. It was discovered for the treatment of hepatitis C and has since been investigated for use against other viral diseases such as AIDS and COVID-19, for which it was granted conditional approval in China.

Katherine Seley-Radtke is an American medicinal chemist who specializes in the discovery and design of novel nucleoside or nucleotide based enzyme inhibitors that may be used to treat infections or cancer. She has authored over 90 peer-reviewed publications, is an inventor of five issued US patents, and is a professor in the department of chemistry and biochemistry at the University of Maryland, Baltimore County. Her international impact includes scientific collaborations, policy advising and diplomatic appointments in biosecurity efforts.

<span class="mw-page-title-main">Sangivamycin</span> Chemical compound

Sangivamycin is a natural product originally isolated from Streptomyces rimosus, which is a nucleoside analogue. It acts as an inhibitor of protein kinase C. It has antibiotic, antiviral and anti-cancer properties and has been investigated for various medical applications, though never approved for clinical use itself. However, a number of related derivatives continue to be researched.

References

  1. 1 2 3 Marquez VE, Lim MI (January 1986). "Carbocyclic nucleosides". Medicinal Research Reviews. 6 (1): 1–40. doi:10.1002/med.2610060102. PMID   3512934. S2CID   221956841.
  2. ↑ Zhu XF (March 2000). "The latest progress in the synthesis of carbocyclic nucleosides". Nucleosides, Nucleotides & Nucleic Acids. 19 (3): 651–690. doi:10.1080/15257770008035015. PMID   10843500. S2CID   43360920.
  3. 1 2 3 Wang J; Rawal RK; Chu CK (August 2011). "Recent Advances in Carbocyclic Nucleosides: Synthesis and Biological Activity". In L-H Zhang, Z Xi and J Chattopadhyaya (ed.). Medicinal Chemistry of Nucleic Acids . Hoboken: John Wiley & Sons. pp.  1–100. ISBN   9780470596685.
  4. 1 2 Rodrguez JB, Comin MJ (March 2003). "New progresses in the enantioselective synthesis and biological properties of carbocyclic nucleosides". Mini Reviews in Medicinal Chemistry. 3 (2): 95–114. doi:10.2174/1389557033405331. hdl: 11336/90989 . PMID   12570843.
  5. ↑ Marquez, V. E. (April 1996). "CARBQCYCLIC NUCLEOSIDES". In E. De Clercq (ed.). Advances in Antiviral Drug Design. Vol. 2. JAI Press Inc. pp. 89–146. ISBN   1-55938-693-2.
  6. ↑ Cameron JM (December 1993). "New antiherpes drugs in development". Reviews in Medical Virology. 3 (4): 225–236. doi:10.1002/rmv.1980030406. S2CID   84289059.
  7. 1 2 Vince R, Hua M, Brownell J, Daluge S, Lee F, Shannon WM, Lavelle GC, Qualls J, Weislow OS, Kiser R, Canonico PG (October 1988). "Potent and selective activity of a new carbocyclic nucleoside analog (carbovir: NSC 614846) against human immunodeficiency virus in vitro". Biochemical and Biophysical Research Communications. 156 (2): 1046–1053. doi:10.1016/S0006-291X(88)80950-1. PMID   2847711.
  8. ↑ Carter SG, Kessler JA, Rankin CD (June 1990). "Activities of (-)-carbovir and 3'-azido-3'-deoxythymidine against human immunodeficiency virus in vitro". Antimicrobial Agents and Chemotherapy. 34 (6): 1297–1300. doi:10.1128/AAC.34.6.1297. PMC   171808 . PMID   2393292.
  9. 1 2 Daluge SM, Good SS, Faletto MB, Miller WH, St Clair MH, Boone LR, Tisdale M, Parry NR, Reardon JE, Dornsife RE, Averett DR (May 1997). "1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity". Antimicrobial Agents and Chemotherapy. 41 (5): 1082–1093. doi:10.1128/AAC.41.5.1082. PMC   163855 . PMID   9145874.
  10. 1 2 Bisacchi GS, Chao ST, Bachard C, Daris JP, Innaimo S, Jacobs GA, Kocy O, Lapointe P, Martel A, Merchant ZL, Slusarchyk WA (January 1997). "BMS-200475, a novel carbocyclic 2′-deoxyguanosine analog with potent and selective anti-hepatitis B virus activity in vitro". Bioorganic & Medicinal Chemistry Letters. 7 (2): 127–132. doi:10.1016/S0960-894X(96)00594-X.
  11. 1 2 Borthwick AD, Butt S, Biggadike K, Exall AM, Roberts SM, Youds PM, Kirk BE, Booth BR, Cameron JM, Cox SW, Marr CL (1988). "Synthesis and enzymatic resolution of carbocyclic 2-ara-fluoro-guanosine: a potent new anti-herpetic agent". Journal of the Chemical Society, Chemical Communications (10): 656–658. doi:10.1039/C39880000656.
  12. 1 2 Borthwick AD, Biggadike K (1992). "Synthesis of chiral carbocyclic nucleosides". Tetrahedron. 48 (4): 571–623. doi:10.1016/S0040-4020(01)88122-9.
  13. ↑ Shealy YF, Clayton JD (August 1966). "9-[β-DL-2α, 3α-Dihydroxy-4β-(hydroxymethyl)-cyclopentyl] adenine, the Carbocyclic Analog of Adenosine". Journal of the American Chemical Society. 88 (16): 3885–3887. doi:10.1021/ja00968a055.
  14. ↑ Kusaka T, Yamamoto H, Shibata M, Muroi M, Kishi T, Mizuno K (1968). "Streptomyces citricolor nov. sp. and a new antibiotic, aristeromycin". The Journal of Antibiotics. 21 (4): 255–263. doi: 10.7164/antibiotics.21.255 . PMID   5671989.
  15. ↑ Yaginuma S, Muto N, Tsujino M, Sudate Y, Hayashi M, Otani M (1981). "Studies on neplanocin A, new antitumor antibiotic. I. Producing organism, isolation and characterization". The Journal of Antibiotics. 34 (4): 359–366. doi: 10.7164/antibiotics.34.359 . PMID   7275815.
  16. ↑ Arita M, Adachi K, Ito Y, Sawai H, Ohno M (June 1983). "Enantioselective synthesis of the carbocyclic nucleosides (-)-aristeromycin and (-)-neplanocin A by a chemicoenzymatic approach". Journal of the American Chemical Society. 105 (12): 4049–4055. doi:10.1021/ja00350a050.
  17. ↑ Roberts SM; Biggadike K; Borthwick AD; Kirk BE (1988). "Synthesis of Some Antiviral Carbocyclic Nucleosides". In P R Leeming (ed.). Topics in Medicinal Chemistry. London: Royal Society of Chemistry. pp. 172–188. ISBN   0-85186-726-X.
  18. ↑ Agrofoglio L, Suhas E, Farese A, Condom R, Challand SR, Earl RA, Guedj R (December 1994). "Synthesis of carbocyclic nucleosides". Tetrahedron. 50 (36): 10611–10670. doi:10.1016/S0040-4020(01)89258-9.
  19. ↑ Agrofoglio LA; Challand SR (1998). "The chemistry of carbocyclic nucleosides, Biological activity of carbocyclic nucleosides". In Agrofoglio LA, Challand SR (ed.). Acyclic, Carbocyclic and L-nucleosides. Dordrecht: Kluwer Academic Publishers. pp. 174–284. ISBN   978-94-010-3734-1.
  20. ↑ Crimmins MT (August 1998). "New developments in the enantioselective synthesis of cyclopentyl carbocyclic nucleosides". Tetrahedron. 54 (32): 9229–9272. doi:10.1016/S0040-4020(98)00320-2.
  21. ↑ Leclerc E (February 2013). "Chemical synthesis of carbocyclic analogues of nucleosides". Chemical Synthesis of Nucleoside Analogues. Hoboken: John Wiley & Sons. pp. 535–604. doi:10.1002/9781118498088.ch12. ISBN   9781118498088.
  22. ↑ Boutureira O, Matheu MI, Díaz Y, Castillón S (March 2013). "Advances in the enantioselective synthesis of carbocyclic nucleosides". Chemical Society Reviews. 42 (12): 5056–5072. doi:10.1039/C3CS00003F. PMID   23471263.
  23. ↑ Mulamoottil VA, Nayak A, Jeong LS (July 2014). "Recent Advances in the Synthesis of Carbocyclic Nucleosides via Ring-Closing Metathesis". Asian Journal of Organic Chemistry. 3 (7): 748–761. doi:10.1002/ajoc.201402032.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.