956896-99-4Relevant academic research and scientific papers
Design, Synthesis, Antiviral Activity, and Pre-Formulation Development of Poly- L -Arginine-Fatty Acyl Derivatives of Nucleoside Reverse Transcriptase Inhibitors
Pemmaraju, Bhanu P.,Malekar, Swapnil,Agarwal, Hitesh K.,Tiwari, Rakesh K.,Oh, Donghoon,Doncel, Gustavo F.,Worthen, David R.,Parang, Keykavous
, p. 1 - 15 (2015/10/19)
The objective of this work was to design conjugates of anti-HIV nucleosides conjugated with fatty acids and cell-penetrating poly-L-arginine (polyArg) peptides. Three conjugates of polyArg cell-penetrating peptides with fatty acyl derivatives of alovudine
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
, p. 4861 - 4871 (2012/07/31)
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 (EC50 = 0.2-2.3 μM) were more potent than the corresponding monosubstituted N4-fatty acyl (EC50 = 0.4-29.4 μM) and 5′-O-N4-disubstituted (EC50 = 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 (EC50 = 0.2-0.9 μM) exhibiting at least 16-36-fold higher anti-HIV activity against cell-free virus than 1 (EC50 = 11.4-32.7 μM). The EC90 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.
Synthesis and anti-HIV activities of symmetrical dicarboxylate esters of dinucleoside reverse transcriptase inhibitors
Agarwal, Hitesh K.,Buckheit, Karen W.,Buckheit Jr., Robert W.,Parang, Keykavous
, p. 5451 - 5454 (2012/09/22)
Three nucleoside analogues, 3′-fluoro-2′,3′- dideoxythymidine (FLT), 3′-azido-2′,3′-dideoxythymidine (AZT), and 2′,3′-dideoxy-3′-thiacytidine (3TC) were conjugated with three different dicarboxylic acids to afford the long chain dicarboxylate esters of nucleosides. In general, dinucleoside ester conjugates of FLT and 3TC with long chain dicarboxylic acids exhibited higher anti-HIV activity than their parent nucleosides. Dodecanoate and tetradecanoate dinucleoside ester derivatives of FLT were found to be the most potent compounds with EC 50 values of 0.8-1.0 nM and 3-4 nM against HIV-1US/92/727 and HIV-1IIIB cells, respectively. The anti-HIV activity of the 3TC conjugates containing long chain dicarboxylate diester (EC50 = 3-60 nM) was improved by 1.5-66 fold when compared to 3TC (EC50 = 90-200 nM). This study reveals that the symmetrical ester conjugation of dicarboxylic acids with a number of nucleosides results in conjugates with improved anti-HIV profile.
