Carbocyclic nucleoside explained

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.

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]}

Natural products

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.

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

The cyclopentenylcytosine (CPE-C) was developed as a potent antitumor and antiviral agent (phase 1 trials)^[4] and exhibited potent anti-orthopoxvirus as well as anti-West Nile virus activities.^[5] 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).

History

• 1966: First described synthesis of the racemic (±) carbocyclic analogue of adenosine.^[13]
• 1968: The (-) enantiomer, named aristeromycin. was isolated as a metabolite of Streptomyces citricolor.^[14]
• 1981: Isolation of the neplanocin family of carbocyclic nucleosides and in particular the cyclopentenyl derivative neplanocin A from Ampukwiella regularis ^[15]
• 1983: The first enantiospecific synthesis of (-) aristeromycin and (-) neplanocin A ^[16]
• 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.^[1]
• 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.^[11]
• 1988: Review of Glaxo's synthesis of fluorocarbocyclic nucleosides ^[17]
• 1988: (±)-Carbovir first reported with potent anti-HIV activity and low cytotoxicity ^[7]
• 1992: First comprehensive review of the synthesis of chiral carbocyclic nucleosides.^[12]
• 1994: A review covering the racemic cyclopentyl carbocyclic nucleosides ^[18] was broadened to include the bioactivity of carbocyclic nucleosides in 1998 ^[19]
• 1997: Abacavir, prodrug of (-)Carbovir reported,^[9] 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 anti-hepatitis B inhibitor,^[10] 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.^[20]
• 2003: Review of new progresses in the enantioselective synthesis and biological properties of carbocyclic nucleosides including 3, 4 and 6 membered carbocyclic rings.^[3]
• 2011: Review covers the most recent advances in the synthesis and biological activity of carbocyclic nucleosides up to September 2010.^[5]
• 2013: Two reviews of the most representative methods of asymmetric synthesis of carbocyclic nucleosides since 1998 ^{[21] [22]}
• 2014: Review of the synthesis of carbocyclic nucleosides involving ring-closing metathesis (RCM) as a key step.^[23]

Notes and References

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