Synthesis and biological evaluation of fatty acyl ester derivatives of (-)-2′,3′-dideoxy-3′-thiacytidine

Hitesh K. Agarwal, Bhupender S. Chhikara, Michael J. Hanley, Guofeng Ye, Gustavo F. Doncel, Keykavous Parang

Research output: Contribution to journalArticle

Abstract

A number of fatty acyl derivatives of (-)-2′,3′-dideoxy- 3′-thiacytidine (lamivudine, 3TC, 1) were synthesized and evaluated for their anti-HIV activity. The monosubstituted 5′-O-fatty acyl derivatives of 3TC (EC 50 = 0.2-2.3 μM) were more potent than the corresponding monosubstituted N 4-fatty acyl (EC 50 = 0.4-29.4 μM) and 5′-O-N 4-disubstituted (EC 50 = 72.6 to >154.0 μM) derivatives of the nucleoside. 5′-O-Myristoyl (16) and 5′-O-12-azidododecanoyl derivatives (17) were found to be the most potent compounds (EC 50 = 0.2-0.9 μM) exhibiting at least 16-36-fold higher anti-HIV activity against cell-free virus than 1 (EC 50 = 11.4-32.7 μM). The EC 90 values for 16 against B-subtype and C-subtype clinical isolates were several folds lower than those of 1. The cellular uptake studies confirmed that compound 16 accumulated intracellularly after 1 h of incubation with CCRF-CEM cells and underwent intracellular hydrolysis. 5′-O-Fatty acyl derivatives of 1 showed significantly higher anti-HIV activity than the corresponding physical mixtures against the B-subtype virus.

Original languageEnglish (US)
Pages (from-to)4861-4871
Number of pages11
JournalJournal of Medicinal Chemistry
Volume55
Issue number10
DOIs
StatePublished - May 24 2012
Externally publishedYes

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Lamivudine
Esters
HIV
Cercopithecine Herpesvirus 1
Nucleosides
Hydrolysis
Viruses

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Synthesis and biological evaluation of fatty acyl ester derivatives of (-)-2′,3′-dideoxy-3′-thiacytidine. / Agarwal, Hitesh K.; Chhikara, Bhupender S.; Hanley, Michael J.; Ye, Guofeng; Doncel, Gustavo F.; Parang, Keykavous.

In: Journal of Medicinal Chemistry, Vol. 55, No. 10, 24.05.2012, p. 4861-4871.

Research output: Contribution to journalArticle

Agarwal, Hitesh K. ; Chhikara, Bhupender S. ; Hanley, Michael J. ; Ye, Guofeng ; Doncel, Gustavo F. ; Parang, Keykavous. / Synthesis and biological evaluation of fatty acyl ester derivatives of (-)-2′,3′-dideoxy-3′-thiacytidine. In: Journal of Medicinal Chemistry. 2012 ; Vol. 55, No. 10. pp. 4861-4871.
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