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Carbocyclic nucleosides (also referred to as carbanucleosides) are
nucleoside Nucleosides are glycosylamines that can be thought of as nucleotides without a phosphate group. A nucleoside consists simply of a nucleobase (also termed a nitrogenous base) and a five-carbon sugar (ribose or 2'-deoxyribose) whereas a nucleotide ...
analogues in which a
methylene group In organic chemistry, a methylene group is any part of a molecule that consists of two hydrogen atoms bound to a carbon atom, which is connected to the remainder of the molecule by two single bonds. The group may be represented as , where the '< ...
has replaced the oxygen atom of the
furanose A furanose is a collective term for carbohydrates that have a chemical structure that includes a five-membered ring system consisting of four carbon atoms and one oxygen atom. The name derives from its similarity to the oxygen heterocycle furan, bu ...
ring. These analogues have the
nucleobase Nucleobases, also known as ''nitrogenous bases'' or often simply ''bases'', are nitrogen-containing biological compounds that form nucleosides, which, in turn, are components of nucleotides, with all of these monomers constituting the basic b ...
attached at a simple alkyl carbon rather than being part of a
hemiaminal ether In organic chemistry, a hemiaminal (also carbinolamine) is a functional group or type of chemical compound that has a hydroxyl group and an amine attached to the same carbon atom: . R can be hydrogen or an alkyl group. Hemiaminals are intermediat ...
linkage. As a result, they have increased chemical stability. They also have increased metabolic stability because they are unaffected by
phosphorylases In biochemistry, phosphorylases are enzymes that catalyze the addition of a phosphate group from an inorganic phosphate (phosphate+hydrogen) to an acceptor. :A-B + P A + P-B They include allosteric enzymes that catalyze the production of gluc ...
and
hydrolases Hydrolase is a class of enzyme that commonly perform as biochemical catalysts that use water to break a chemical bond, which typically results in dividing a larger molecule into smaller molecules. Some common examples of hydrolase enzymes are este ...
that cleave the
glycosidic bond A glycosidic bond or glycosidic linkage is a type of covalent bond that joins a carbohydrate (sugar) molecule to another group, which may or may not be another carbohydrate. A glycosidic bond is formed between the hemiacetal or hemiketal group ...
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. 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.


Natural products

The 5-membered ring carbocyclic nucleosides aristeromycin, the analog of
adenosine Adenosine ( symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9-glycosidic bond. Adenosine is one of the four nucleoside building ...
, and neplanocin A, the
cyclopentene Cyclopentene is a chemical compound with the formula . It is a colorless liquid with a petrol-like odor. It has few applications, and thus is mainly used as a minor component of gasoline, present in concentrations of less than 1%. It is one of t ...
analog of aristeromycin, have been isolated from natural sources. They both exhibit significant
biological activity In pharmacology, biological activity or pharmacological activity describes the beneficial or adverse effects of a drug on living matter. When a drug is a complex chemical mixture, this activity is exerted by the substance's active ingredient or ...
as antiviral and antitumour agents.


Classes

A large number of novel carbocyclic nucleosides of
pyrimidine Pyrimidine (; ) is an aromatic, heterocyclic, organic compound similar to pyridine (). One of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring. The other ...
s and
purine Purine is a heterocyclic compound, heterocyclic aromatic organic compound that consists of two rings (pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which includ ...
s have been prepared, and many of these compounds are endowed with interesting biological activities.


Pyrimidine carbocyclic nucleosides

The cyclopentenylcytosine (CPE-C) was developed as a potent antitumor and antiviral agent (phase 1 trials) and exhibited potent anti-orthopoxvirus as well as anti-West Nile virus activities. Carbocyclic (E)-5-(2-bromovinyl)-2-deoxyuridine( (+) C-BVDU) GR95168 possesses activity against
herpes simplex virus Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known by their taxonomical names ''Human alphaherpesvirus 1'' and '' Human alphaherpesvirus 2'', are two members of the human ''Herpesviridae'' family, a set of viruses that produce viral inf ...
type l (HSV-1) and
varicella zoster virus Varicella-zoster virus (VZV), also known as human herpesvirus 3 (HHV-3, HHV3) or ''Human alphaherpesvirus 3'' (taxonomically), is one of nine known herpes viruses that can infect humans. It causes chickenpox (varicella) commonly affecting chil ...
(VZV, chicken pox and shingles) in-vitro and in-vivo.


Purine carbocyclic nucleosides

The two guanine antiviral carbocyclic nucleosides, the anti-
HIV The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...
agent
abacavir 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 recom ...
and the anti-
hepatitis B Hepatitis B is an infectious disease caused by the ''Hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection. Many people have no symptoms during an initial infection. Fo ...
agent
entecavir 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 ...
, are
reverse-transcriptase inhibitors 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 replicatio ...
. Abacavir, was developed from
racemic In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...
(±)-carbovir which was reported in 1988 by
Robert Vince Robert Vince (born April 1, 1962) is a Canadians, Canadian director, producer, writer and screenwriter. He has been involved in movie production since the late 1980s and has been directing movies since 2000, such as ''MVP: Most Valuable Primate'' ...
as the first carbocyclic nucleoside analogue to show potent activity against HIV with low cytotoxicity. The (-)
enantiomer In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...
of carbovir was later shown to be the biologically active form for inhibition of HIV. 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 A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...
analogues of (-) carbovir which lead to the 6-cyclopropylamino-2-aminopurine nucleoside abacavir, which was approved in 1998 by the FDA for the treatment of HIV infection. File:(-) Carbovir.svg, (-)Carbovir File:Abacavir.svg,
Abacavir 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 recom ...
File:Entecavir structure.svg,
Entecavir 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 ...
File:Carbocyclic 2'-ara-fluoro-guanosine.png, Carbocyclic 2′-''ara''-fluoro-guanosine
Entecavir, a
guanosine 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 (c ...
analog, was reported in 1997 as a potent and selective inhibitor for the
hepatitis B virus ''Hepatitis B virus'' (HBV) is a partially double-stranded DNA virus, a species of the genus ''Orthohepadnavirus'' and a member of the ''Hepadnaviridae'' family of viruses. This virus causes the disease hepatitis B. Disease Despite there bein ...
, and approved by the
FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
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.


Synthesis

There are two approaches used in the synthesis of carbocyclic nucleosides. 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).


History

* 1966: First described synthesis of the racemic (±) carbocyclic analogue of adenosine. * 1968: The (-) enantiomer, named aristeromycin. was isolated as a metabolite of ''Streptomyces citricolor''. * 1981: Isolation of the neplanocin family of carbocyclic nucleosides and in particular the cyclopentenyl derivative neplanocin A from ''Ampukwiella regularis'' * 1983: The first enantiospecific synthesis of (-) aristeromycin and (-) neplanocin A * 1986: The first comprehensive review of carbocyclic nucleosides including the linear chemical syntheses and the biological properties of these early racemic analogues and of the natural products aristeromycin and neplanocin A. * 1988: The first fluorocarbocyclic nucleoside C-AFG synthesised that was 1000-fold more active than the furanose parent nucleoside against HSV-1 and HSV-2 in-vitro. * 1988: Review of Glaxo's synthesis of fluorocarbocyclic nucleosides *1988: (±)-Carbovir first reported with potent anti-HIV activity and low cytotoxicity *1992: First comprehensive review of the synthesis of chiral carbocyclic nucleosides. *1994: A review covering the racemic cyclopentyl carbocyclic nucleosides was broadened to include the bioactivity of carbocyclic nucleosides in 1998 *1997: Abacavir, prodrug of (-)Carbovir reported, approved by the FDA in December 1998, for the treatment of HIV infection under the trade name of Ziagen™. *1997: First report of Entecavir (BMS-200475) as potent and selective antihepatitis B inhibitor, approved by the FDA in March 2005 for oral treatment of hepatitis B infection. trade names Baraclude or Entaliv. *1998: Review of new developments in the enantioselective synthesis of cyclopentyl carbocyclic nucleosides. *2003: Review of new progresses in the enantioselective synthesis and biological properties of carbocyclic nucleosides including 3, 4 and 6 membered carbocyclic rings. *2011: Review covers the most recent advances in the synthesis and biological activity of carbocyclic nucleosides up to September 2010. *2013: Two reviews of the most representative methods of asymmetric synthesis of carbocyclic nucleosides since 1998 *2014: Review of the synthesis of carbocyclic nucleosides involving ring-closing metathesis (RCM) as a key step.


References

{{Reflist, 2 Nucleosides