cycloSal-2',3'-dideoxy-2',3'-didehydrothymidine monophosphate (cycloSal-d4TMP): synthesis and antiviral evaluation of a new d4TMP delivery system

Journal of Medicinal Chemistry
C MeierJan Balzarini

Abstract

The synthesis, hydrolysis, and antiviral evaluation of novel, lipophilic cycloSal-d4TMP derivatives 3a-h of the anti-HIV dideoxynucleoside 2',3'-dideoxy-2',3'-didehydrothymidine (d4T, 1) are reported. This pro-nucleotide concept has been designed to deliver d4TMP (2) by selective chemical hydrolysis. All compounds 3a-h were synthesized using phosphorus(III) chemistry in good yields and in somewhat lower yields using phosphorus(V) chemistry starting from substituted salicyl alcohols 6a-h. The phosphotriesters 3 were obtained without stereochemical preference with respect to the configuration at the phosphorus center as 1:1 diastereomeric mixtures. However, a few of the triesters 3 could be separated into the diastereomers by means of semipreparative HPLC. In a 1-octanol/phosphate buffer mixture, all compounds 3 exhibited 9-100-fold higher lipophilicity as judged from their Pa values as compared to d4T (1). Furthermore, in hydrolysis studies 3 decomposed under mild aqueous basic conditions releasing solely d4TMP (2) and the diols 6 following the designed tandem reaction sequence. A correlation of the electronic properties introduced by the substituents and the half-lives of triesters 3 was observed. Thus, by varying the substitue...Continue Reading

References

Jul 1, 1977·Journal of Medicinal Chemistry·J Engels, E J Schlaeger
Feb 1, 1989·Journal of Medicinal Chemistry·M M MansuriJ P Sommadossi
Dec 1, 1980·Journal of Medicinal Chemistry·V J Stella, K J Himmelstein
May 1, 1995·Antiviral Research·R J Jones, N Bischofberger
Apr 2, 1993·Journal of Medicinal Chemistry·C SergheraertM Lemaitre
Jun 1, 1995·Antiviral Research·S A RiddlerJ W Mellors

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Citations

Nov 4, 2000·Medicinal Research Reviews·C R WagnerE J McIntee
Oct 9, 2002·Medicinal Research Reviews·Erik De Clercq
May 15, 2002·Archives of Pharmacal Research·Henry J LeeDong-Hoon Ko
May 12, 2001·Il Farmaco·E De Clercq
Jun 6, 2000·Advanced Drug Delivery Reviews·L I Wiebe, E E Knaus
Mar 5, 2003·Bioorganic & Medicinal Chemistry·Carsten Schultz
Jul 26, 2012·Journal of Medicinal Chemistry·Edwuin H Rios MoralesChris Meier
Oct 6, 2012·Chemical Research in Toxicology·Tareisha DunlapGregory R J Thatcher
Aug 5, 1999·Nucleosides & Nucleotides·A LompP Wutzler
Aug 5, 1999·Nucleosides & Nucleotides·M Lorey, C Meier
Apr 23, 2009·Expert Opinion on Drug Delivery·Larryn W Peterson, Charles E McKenna
Sep 9, 2015·Journal of Medicinal Chemistry·Gregory M RankinSally-Ann Poulsen
Jan 6, 2015·Chemical Biology & Drug Design·Ngoc HuynhSally-Ann Poulsen
Dec 9, 2009·European Journal of Medicinal Chemistry·Karine BarralKarine Alvarez
Aug 22, 2014·Chemical Reviews·Ugo PradereRaymond F Schinazi
Dec 31, 2003·The Journal of Biological Chemistry·Wolfgang H G LauxRoger A Johnson
Sep 21, 2001·Nucleosides, Nucleotides & Nucleic Acids·C MeierP Wutzler
Mar 20, 2002·Antiviral Chemistry & Chemotherapy·J BalzariniC Meier
Jan 27, 2011·Chemistry : a European Journal·Edwuin H Rios MoralesChris Meier
Nov 23, 2007·Angewandte Chemie·Silke WendickeChris Meier
Jul 2, 2009·Chemistry : a European Journal·Saskia WolfChris Meier
Jul 18, 2002·Nature Reviews. Drug Discovery·Erik De Clercq
Oct 28, 2015·Nature Communications·Tristan GollnestChris Meier
Aug 5, 1999·Nucleosides & Nucleotides·F Mugnier, C Meier
Oct 27, 2005·Nucleosides, Nucleotides & Nucleic Acids·D VukadinovićC Meier
Mar 27, 2004·Nucleosides, Nucleotides & Nucleic Acids·Chris MeierJan Balzarini
Aug 31, 2019·Future Medicinal Chemistry·Kenneth M Heidel, Cynthia S Dowd
Mar 18, 2006·Antiviral Chemistry & Chemotherapy·Andreas SauerbreiPeter Wutzler
Sep 21, 2001·Nucleosides, Nucleotides & Nucleic Acids·J RenzeC Meier
Apr 8, 2014·Organic & Biomolecular Chemistry·Hui-Jing LiYan-Chao Wu

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