Syntheses and Biological Evaluation of 5′-O-Myristoyl Derivatives of Thymidine against Human Immunodeficiency Virus

1997 ◽  
Vol 8 (5) ◽  
pp. 417-427 ◽  
Author(s):  
K Parang ◽  
LI Wiebe ◽  
EE Knaus
Keyword(s):  
Human Immunodeficiency Virus ◽  
Biological Evaluation ◽  
Log P ◽  
Moderate Activity ◽  
Porcine Liver ◽  
Activity Data ◽  
Structure Activity ◽  
Immunodeficiency Virus ◽  
Derivatives Of ◽  
Anti Hiv

A series of 5′- Oacyl derivatives of thymidine (dThd) were prepared by direct acylation of thymidine using the Mitsunobu reaction. Further reaction of the bromo analogues with sodium azide gave azido ester analogues. Anti-human immunodeficiency virus type 1 (HIV-1) activities were determined against HIV-infected T4 lymphocytes. 5′- O-(12-Azidododecanoyl)thymidine exhibited moderate activity (EC50 4.6 μM) against HIV-infected T4 lymphocytes. 5- O-(2-Bromotetradecanoyl)-thymidine was found to be the most stable ester (t1/2 15.3 min) to hydrolysis by porcine liver esterase in vitro. Partition coefficients (P) in n-octanol-phosphate buffer were determined (log10 P range 4.15–6.72) and compared with the theoretical values calculated (log10 P 3.96–6.53) using the PALLAS program. Anti-HIV structure-activity data suggest that the experimental partition coefficient should be in the log10 P 4.6–4.8 range for optimum anti-HIV activity. The structures of these thymidine analogues were optimized using molecular mechanics (MM+ force field) and semi-empirical quantum mechanics PM3 calculations. The moderately active compounds adopted a similar C-2′ endo sugar conformation and exhibited similar energies for the lowest energy conformer. A quantitative structure-activity relationship (QSAR) regression equation was developed, based on the optimized structures and anti-HIV data using the SciQSAR program, which showed that log P was a determinant of anti-HIV activity.

Synthesis, in Vitro Anti-Human Immunodeficiency Virus Structure—Activity Relationships and Biological Stability of 5′-O-Myristoyl Analogue Derivatives of 3′-Azido-2′,3′-Dideoxythymidine (AZT) as Potential Prodrugs

1998 ◽  
Vol 9 (4) ◽  
pp. 28-40 ◽  
Author(s):  
K Parang ◽  
LI Wiebe ◽  
EE Knaus
Keyword(s):  
Human Immunodeficiency Virus ◽  
Brain Homogenate ◽  
Rat Plasma ◽  
Log P ◽  
Porcine Liver ◽  
Liver Esterase ◽  
Structure Activity ◽  
Immunodeficiency Virus ◽  
Derivatives Of

5′- O-Myristoyl analogue derivatives of 3′-azido-2′,3′-dideoxythymidine (AZT), designed as potential double-barrelled prodrugs to AZT and the myristic acid analogues, were synthesized. Their ability to protect CEM cells against human immunodeficiency virus (HIV)-induced cytopathogenicity was determined and structure–activity paradigms were developed. 3′-Azido-2′,3′-dideoxy-5′- O-(4-oxate-tradecanoyl)thymidine (EC50=1.4 nM) and 3′-azido-2′,3′-deoxy-5′- O-(12-bromododecanoyl)thymidine (EC50=3.2 nM) were the most effective anti-HIV-1 agents, relative to AZT (EC50=10 nM). These myristoyl analogue derivatives were more lipophilic (calculated log P=4.5–8.1 range) than the parent compound AZT (log P=0.06), and a linear correlation between their log P and HPLC log retention timeswas observed. The ester cleavage half-lives ( t1/2) for esters upon in vitro incubation with porcine liver esterase, rat plasma or rat brain homogenate was dependent on the steric bulk, and electronegative inductive effect of the α-substituent (H, Br, F), of the 5′- O-myristoyl analogue moiety. 3′-Azido-2′,3′-dideoxy-5′- O-(11-(4-iodophenoxy) undecanoyl)-thymidine exhibited t1/2 values of 80.4, 3.7 and 150.0 min upon incubation with porcine liver esterase, rat plasma and rat brain homogenate, respectively.

Dimeric Macrocyclic Polyamines with Potent Inhibitory Activity against Human Immunodeficiency Virus

1995 ◽  
Vol 6 (5) ◽  
pp. 337-344 ◽  
Author(s):  
Y. Inouye ◽  
T. Kanamori ◽  
M. Sugiyama ◽  
T. Yoshida ◽  
T. Koike ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Cytopathic Effect ◽  
Syncytium Formation ◽  
Physiological Conditions ◽  
Structure Activity ◽  
Immunodeficiency Virus ◽  
Macrocyclic Polyamines ◽  
Anti Hiv ◽  
Viral Cytopathic Effect ◽  
Potent Inhibitory Activity

The structure-activity relationships of monomeric and dimeric macrocyclic polyamines were studied in an attempt to find potent inhibitors of human immunodeficiency virus (HIV) types 1 and 2. In general, dimeric polyamines are superior as HIV inhibitors to their monomeric counterparts, and the activity of a dimer is proportional to that of its constituent monomers. For the monomeric compounds, the amount of positive charge on the monomer rings under physiological conditions was more important for anti-HIV activity than the ring size. On the basis of these findings, the 14-membered tetraamine cyclam was selected as the component of dimeric compounds with potentially high activity. Of the series of newly synthesized bicyclams, in which the monomeric cyclams were linked at each C-6 position, a compound with an aIkyI chain bridge three carbons in length was found to exhibit the maximum anti-HIV activity. For one particular strain (HIV-2GH-1), syncytium formation was inhibited by the bicyclams at a similar concentration to that required to inhibit the viral cytopathic effect.

scholarly journals Synthesis and Evaluation of Some Symmetrical Phosphate Dimer Derivatives of 3′-Modified Nucleosides as Potential anti-HIV Agents

1996 ◽  
Vol 7 (6) ◽  
pp. 330-337 ◽  
Author(s):  
C. McGuigan ◽  
H.-W. Tsang ◽  
N. Mahmood ◽  
A. J. Hay
Keyword(s):  
Human Immunodeficiency Virus ◽  
Analytical Data ◽  
Modified Nucleosides ◽  
Nucleoside Analogues ◽  
Immunodeficiency Virus ◽  
Anti Hiv Agents ◽  
Derivatives Of ◽  
Anti Hiv ◽  
Hiv 1

Novel symmetrical nucIeotide-(5′,5′)-dimers of 3′-O-acetylthymidine, 3′-O-methylthymidine, 3′-O-ethylthymidine, 3′-O-n-propylthymidine and 3′-azido-3′-deoxythymidine (AZT) were synthesized as membrane soluble pro-drugs. These were prepared using phosphorodichloridate chemistry and were characterised by spectroscopic and analytical data. In-vitro evaluation of the derivatives in cells acutely infected with the human immunodeficiency virus (HIV-1) demonstrated a range of activities. These derivatives were generally found to display poor inhibition of HIV proliferation. Derivatives containing AZT moieties were found to be potent, but such compounds were less active than the parent nucleoside. The data indicated that the AZT-containing compounds act primarily via the release of the free nucleoside. However, in some cases, the dimers of certain inactive nucleoside analogues were found to be active. In these cases, release of the nucleoside alone cannot account for the activity.

scholarly journals 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

1998 ◽  
Vol 9 (2) ◽  
pp. 109-115 ◽  
Author(s):  
C McGuigan ◽  
H-W Tsang ◽  
PW Sutton ◽  
E De Clercq ◽  
J Balzarini
Keyword(s):  
Human Immunodeficiency Virus ◽  
Selective Inhibitor ◽  
Amino Acid Derivatives ◽  
Predictive Test ◽  
Immunodeficiency Virus ◽  
Nucleoside Phosphoramidates ◽  
High Yields ◽  
Derivatives Of ◽  
Anti Hiv

Novel chain-extended nucleoside phosphoramidates of the anti-human immunodeficiency virus (HIV) drug d4T (stavudine) have been prepared as possible membrane-permeable prodrugs of the bio-active free 5′-monophosphates. Phosphorochloridate chemistry gave the target compounds in moderate to high yields, and all materials were fully characterized by spectroscopic and analytical methods. The compounds are related to the previously reported phenyl methoxyalaninyl derivative of d4T, which was shown to be a potent and selective inhibitor of HIV. In this study theamino acid nitrogen and ester moieties were separated by methylene spacers of between two and six carbon atoms. In vitro evaluation of these compounds indicated an almost complete lack of anti-HIV activity, the compounds being several orders of magnitude less potent than the corresponding α-amino acid derivatives. The reasons for the virtual lack of anti-HIV activity appear to involve poor enzyme-mediated hydrolysis.

scholarly journals Sophorolipids, Microbial Glycolipids with Anti-Human Immunodeficiency Virus and Sperm-Immobilizing Activities

2005 ◽  
Vol 49 (10) ◽  
pp. 4093-4100 ◽  
Author(s):  
Vishal Shah ◽  
Gustavo F. Doncel ◽  
Theodoros Seyoum ◽  
Kristin M. Eaton ◽  
Irina Zalenskaya ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Cytotoxic Activities ◽  
Cell Toxicity ◽  
Human Semen ◽  
Virucidal Activity ◽  
Structure Activity ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Topical Microbicide

ABSTRACT The increased incidence of human immunodeficiency virus (HIV)/AIDS disease in women aged 15 to 49 years has identified the urgent need for a female-controlled, efficacious, and safe vaginal topical microbicide. To meet this challenge, sophorolipid (SL) produced by Candida bombicola and its structural analogs have been studied in this report for their spermicidal, anti-HIV, and cytotoxic activities. The sophorolipid diacetate ethyl ester derivative is the most potent spermicidal and virucidal agent of the series of SLs studied. Its virucidal activity against HIV and sperm-immobilizing activity against human semen are similar to those of nonoxynol-9. However, it also induced enough vaginal cell toxicity to raise concerns about its applicability for long-term microbicidal contraception. Its structure-activity relationship has been established for creating new analogs with less cytotoxicity and higher activity.

scholarly journals Structural and Functional Characterization of Membrane Fusion Inhibitors with Extremely Potent Activity against Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Simian Immunodeficiency Virus

2018 ◽  
Vol 92 (20) ◽  
Author(s):  
Huihui Chong ◽  
Yuanmei Zhu ◽  
Danwei Yu ◽  
Yuxian He
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Membrane Fusion ◽  
Simian Immunodeficiency Virus ◽  
Genetic Barrier ◽  
Fusion Inhibitors ◽  
Structure Activity ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACTT-20 (enfuvirtide) is the only membrane fusion inhibitor available for the treatment of viral infection; however, it has low anti-human immunodeficiency virus (anti-HIV) activity and a low genetic barrier for drug resistance. We recently reported that T-20 sequence-based lipopeptides possess extremely potentin vitroandin vivoefficacies (X. Ding, Z. Zhang, H. Chong, Y. Zhu, H. Wei, X. Wu, J. He, X. Wang, Y. He, 2017, J Virol 91:e00831-17, https://doi.org/10.1128/JVI.00831-17; H. Chong, J. Xue, Y. Zhu, Z. Cong, T. Chen, Y. Guo, Q. Wei, Y. Zhou, C. Qin, Y. He, 2018, J Virol 92:e00775-18, https://doi.org/10.1128/JVI.00775-18). Here, we focused on characterizing the structure-activity relationships of the T-20 derivatives. First, a novel lipopeptide termed LP-52 was generated with improved target-binding stability and anti-HIV activity. Second, a large panel of truncated lipopeptides was characterized, revealing a 21-amino-acid sequence core structure. Third, it was surprisingly found that the addition of the gp41 pocket-binding residues in the N terminus of the new inhibitors resulted in increased binding but decreased antiviral activities. Fourth, while LP-52 showed the most potent activity in inhibiting divergent HIV-1 subtypes, its truncated versions, such as LP-55 (25-mer) and LP-65 (24-mer), still maintained their potencies at very low picomolar concentrations; however, both the N- and C-terminal motifs of LP-52 played crucial roles in the inhibition of T-20-resistant HIV-1 mutants, HIV-2, and simian immunodeficiency virus (SIV) isolates. Fifth, we verified that LP-52 can bind to target cell membranes and human serum albumin and has low cytotoxicity and a high genetic barrier to inducing drug resistance.IMPORTANCEDevelopment of novel membrane fusion inhibitors against HIV and other enveloped viruses is highly important in terms of the peptide drug T-20, which remains the only one for clinical use, even if it is limited by large dosages and resistance. Here, we report a novel T-20 sequence-based lipopeptide showing extremely potent and broad activities against HIV-1, HIV-2, SIV, and T-20-resistant mutants, as well as an extremely high therapeutic selectivity index and genetic resistance barrier. The structure-activity relationship (SAR) of the T-20 derivatives has been comprehensively characterized, revealing a critical sequence core structure and the target sites of viral vulnerability that do not include the gp41 pocket. The results also suggest that membrane-anchored inhibitors possess unique modes of action relative to unconjugated peptides. Combined, our series studies have not only provided drug candidates for clinical development but also offered important tools to elucidate the mechanisms of viral fusion and inhibition.

scholarly journals Sensitivity of human immunodeficiency virus to bicyclam derivatives is influenced by the three-dimensional structure of gp120.

1997 ◽  
Vol 41 (12) ◽  
pp. 2616-2620 ◽  
Author(s):  
K De Vreese ◽  
I Van Nerum ◽  
K Vermeire ◽  
J Anné ◽  
E De Clercq
Keyword(s):  
Human Immunodeficiency Virus ◽  
Amino Acid ◽  
Single Amino Acid ◽  
Resistance Pattern ◽  
V3 Loop ◽  
Resistant Virus ◽  
Wild Type ◽  
Immunodeficiency Virus ◽  
Resistant Strains ◽  
Anti Hiv

The bicyclams are a new class of anti-human immunodeficiency virus (anti-HIV) compounds targeted at viral entry. From marker rescue experiments, it appears that the envelope gp120 glycoprotein plays an important role in the anti-HIV activity of the bicyclams. Bicyclam-resistant strains contain a number of amino acid changes scattered over the V2 to V5 region of gp120. Experiments aimed at estimating the relative importance of particular amino acid changes with regard to the overall resistance pattern are described. The sequences of some partially bicyclam-resistant virus strains, obtained during the resistance development process, were analyzed, and the corresponding 50% effective concentrations were determined. Selected mutations observed in bicyclam-resistant strains were introduced in the wild-type background by site-directed mutagenesis. In addition, some amino acids were back-mutated to their wild-type counterparts in an otherwise JM3100-resistant strain. The sensitivities of these mutant viruses to bicyclams were determined. Construction of chimeric viruses, carrying the V3 loop of JM3100-resistant virus in a wild-type HIV type 1 HXB2 background, enabled us to investigate the importance of the mutations in the V3 loop of JM3100-resistant virus. From the results described in the report, it can be concluded that single amino acid substitutions do not influence the observed resistance to JM3100. Also, the mutations in the V3 loop are not sufficient to engender even a partially resistant phenotype. We postulate that the overall conformation of gp120 determines the degree of sensitivity or resistance of HIV strains to bicyclams.

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