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 language | English (US) |
|---|---|
| Pages (from-to) | 4861-4871 |
| Number of pages | 11 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 55 |
| Issue number | 10 |
| DOIs | |
| State | Published - May 24 2012 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - Synthesis and biological evaluation of fatty acyl ester derivatives of (-)-2′,3′-dideoxy-3′-thiacytidine
AU - Agarwal, Hitesh K.
AU - Chhikara, Bhupender S.
AU - Hanley, Michael J.
AU - Ye, Guofeng
AU - Doncel, Gustavo F.
AU - Parang, Keykavous
PY - 2012/5/24
Y1 - 2012/5/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84861494284&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84861494284&partnerID=8YFLogxK
U2 - 10.1021/jm300492q
DO - 10.1021/jm300492q
M3 - Article
C2 - 22533850
AN - SCOPUS:84861494284
VL - 55
SP - 4861
EP - 4871
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 10
ER -