Free accessResearch articleFirst published online 2002-8
Synthesis of Methylenecyclobutane Analogues of Nucleosides with Axial Chirality and Their Phosphoralaninates: A New Pronucleotide Effective against Epstein-Barr Virus
Methylenecyclobutane analogues of 2′-deoxyadenosine, 2′-deoxyguanosine and 2′- deoxycytidine, and the corresponding phosphoralaninate pronucleotides comprising adenine and guanine bases, were synthesized as potential antiviral agents. Phosphoralaninate of adenine methylenecyclobutane was a potent inhibitor of replication of Epstein-Barr virus (EBV) in Daudi cell culture. Phosphoralaninate of guanine analogue was inactive but both pronucleotides were substrates for porcine liver esterase. Adenine methylenecyclobutane analogue was deaminated by adenosine deaminase.
AdamiakRWBialaE & SkalskiB (1985) New, ionic side-products in oligonucleotide synthesis: Formation and reactivity of fluorescent N-/purin-6-yl/pyridinium salts. Nucleic Acids Research13: 2989–3003.
2.
BalzariniJKarlssonAAquaroSPernoC-FCahardDNaesensLDe ClercqE & McGuiganC (1996) Mechanism of anti-HIV action of masked alaninyl d4T-MP derivatives. Proceedings of the National Academy of Sciences USA93: 7295–7299.
3.
FranchettiPCappelacciLGrifantiniMMessiniLSheikhaGALoiAGTramontanoEDe MontisASpigaMG & La CollaP (1994) Synthesis and evaluation of the anti-HIV activity of aza and deaza analogues of isoddA and their phosphates as prodrugs. Journal of Medicinal Chemistry37: 3534–3541.
4.
GuanH-PKsebatiMBChengY-CDrachJCKernER & ZemlickaJ (2000a) Spiropentane mimics of nucleosides: Analogues of 2′-deoxyadenosine and 2′-deoxyguanosine. Synthesis of all stereoisomers, isomeric assignment, and biological activity. The Journal of Organic Chemistry65: 1280–1290.
5.
GuanH-PKsebatiMBKernER & ZemlickaJ (2000b) Approaches to unsaturated analogues of nucleosides comprising four- and six-membered rings. Journal of Organic Chemistry65: 5177–5184.
6.
JonesBCNMDrachJCCorbettTHKesselD & ZemlickaJ (1995) (±)-N9-(2-Hydroxymethyl)spiro[3.3]hept-6-yl)adenine. The first biologically active saturated analogue of adenallene with axial dissymmetry. Journal of Organic Chemistry60: 6277–6280.
7.
KaiwarVReeseCBGrayEJ & NeidleS (1995) Synthesis of 9-[cis-3-(hydroxymethyl)cyclobutyl]-adenine and -guanine. Journal of the Chemical Society, Perkin Transactions12281–2287.
8.
McGuiganCBidoisLHiouniABallatoreCDe ClercqE & BalzariniJ (2000) Phosphoramidate derivatives of stavudine as inhibitors of HIV: Unnatural amino acids may substitute for alanine. Antiviral Chemistry & Chemotherapy11: 111–116 (and references cited therein).
9.
McGuiganCTsangH-WSuttonPDe ClercqE & BalzariniJ (1998) Synthesis and anti-HIV activity of some novel chain extended phosphoramidate derivatives of d4T (stavudine): Esterase hydrolysis as a rapid predictive test for antiviral potency. Antiviral Chemistry & Chemotherapy9: 109–115.
10.
MeierC (1998) Pro-nucleotides — Recent advances in the design of efficient tool for the delivery of biologically active nucleoside monophosphates. Synlett233–242.
11.
PhadtareS & ZemlickaJ (1989) Nucleic acid derived allenols: Unusual analogues of nucleosides with antiretroviral activity. Journal of the American Chemical Society111: 5925–5931.
12.
PigouPE & SchiesserCH (1988) Convenient route to 1,3-disubstituted cyclobutanes: An inexpensive synthesis of 3-cyclobutanecarboxylic acid. Journal of Organic Chemistry53: 3841–3843.
13.
QiuY-LGeiserFKiraTGullenEChengY-CPtakRGBreitenbachJMDrachJCHartlineCBKernER & ZemlickaJ (2000) Synthesis and enantioselectivity of the antiviral effects of (R,Z)-, (S,Z)-methylenecyclopropane analogues of purine nucleosides and phosphoralaninate prodrugs: Influence of heterocyclic base, type of virus and host cells. Antiviral Chemistry & Chemotherapy11: 191–202 (and references cited therein).
14.
QiuY-LKsebatiMBPtakRGBoreasYFBreitenbachJMLinJ-SChengY-CKernERDrachJC & ZemlickaJ (1998a) (Z)- and (E)-2((Hydroxymethyl)cyclo-propylidene)methyladenine and -guanine. New nucleoside analogues with a broad-spectrum of antiviral activity. Journal of Medicinal Chemistry41: 10–23.
15.
QiuY-LPtakRGBreitenbachJMLinJ-SChengY-CDrachJCKernER & ZemlickaJ (1998b) (Z)- and (E)-2-(hydroxymethyl-cyclopropylidene)methyl-purines and pyrimidines. Antiviral Chemistry & Chemotherapy9: 341–352.
16.
QiuY-LPtakRGBreitenbachJMLinJ-SChengY-CDrachJCKernER & ZemlickaJ (1999) Synthesis and antiviral activity of phosphoralaninate derivatives of methylenecyclopropane analogues of nucleosides. Antiviral Research43: 37–53.
17.
SaboulardDNaesensLCahardDSalgadoAPathiranaRVelazquezSMcGuiganCDe ClercqE & BalzariniJ (1999) Characterization of the activation pathway of phosphoramidate triester prodrugs of stavudine and zidovudine. Molecular Pharmacology56: 693–704.
18.
StevensC & De KimpeN (1996) A new entry into 2-azabicyclo[2.1.1]hexanes via 3-(chloromethyl)cyclobutanone. Journal of Organic Chemistry61: 2174–2178.
19.
UchidaHKodamaENYoshimuraKMaedaYKosalaraksaPMarounVQiuY-LZemlickaJ & MitsuyaH (1999) In vitro anti-human immunodeficiency virus activities of Z- and E-methylenecyclopropane nucleoside analogues and their phosphoro-L-alaninate diesters. Antimicrobial Agents and Chemotherapy43: 1487–1490.
20.
WagnerCRIyerVV & McInteeEJ (2000) Pronucleotides: Toward the in vivo delivery of antiviral and anticancer nucleotides. Medicinal Research Reviews20: 417–451.
21.
WinterHMaedaYMitsuyaH & ZemlickaJ (1996) Phosphodiester amidates of allenic nucleoside analogues: Anti-HIV activity and possible mechanism of action. Journal of Medicinal Chemistry39: 3300–3306.
22.
ZemlickaJ (1993) AIlenols derived from nucleic acid bases — A new class of anti-HIV agents: Chemistry and biological activity. In Nucleosides and Nucleotides as Antitumor and Antiviral Agents, 1993; pp. 73–100. Edited by ChuCK & BakerDC. New York: Plenum.
ZemlickaJ (2002a) Unusual analogues of nucleosides: Chemistry and biological activity. In Recent Advances in Nucleosides: Chemistry and Chemothherapy; pp. 327–357. Edited by ChuCK. Amsterdam: Elsevier Science.
25.
ZemlickaJ (2002b) Lipophilic phosphoramidates as antiviral pronucleotides. Biochim. Biophys. Acta — Molecular Basis of Disease1587: 276–286.
