Alkyl Hydrogen Phosphonate Derivatives of the anti-HIV Agent AZT may be Less Toxic than the Parent Nucleoside Analogue

Novel alkyl hydrogen phosphonate derivatives of the anti-HIV nucleoside analogue AZT have been prepared by phosphorochloridite chemistry. These materials are designed to act as labile membrane-soluble prodrugs of the bioactive free nucleotides. In vitro evaluation has revealed the compounds to have a pronounced and selective antiviral action. Short-chain (C1-C7) alkyl derivatives are more potent than the parent hydrogen phosphonate, whilst one long-chain (C18) compound is less active. In an assay that demonstrates the toxicity of the parent drug AZT, the alkyl H-phosphonates appear to be less cytotoxic, whilst retaining full antiviral activity. Lastly, the compounds are all poorly active in a cell line (JM) that is poorly responsive to AZT, indicating that they act as depot forms of the nucleoside rather than of the free nucleotide.

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Haloalkyl Phosphate Derivatives of AZT as Inhibitors of HIV: Studies in the Phosphate Region

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632029400500304 ◽

1994 ◽

Vol 5 (3) ◽

pp. 162-168 ◽

Cited By ~ 7

Author(s):

C. McGuigan ◽

S. Turner ◽

S. R. Nicholls ◽

T. J. O'Connor ◽

D. Kinchington

Keyword(s):

Biological Activity ◽

Alkyl Chain ◽

Antiviral Action ◽

Alkyl Phosphate ◽

Free Nucleotides ◽

Order Of Magnitude ◽

Derivatives Of ◽

Anti Hiv ◽

Hiv 1

Novel haloalkyl phosphate derivatives of the anti-HIV nucleoside analogue AZT were prepared by phosphorochloridate chemistry. These materials were designed to act as labile membrane-soluble prodrugs of the bio-active free nucleotides. In vitro evaluation revealed the compounds to have a pronounced and selective antiviral action, which varied greatly with the structure of the phosphate moiety. By comparison to simple dialkyl phosphates, which are inactive against HIV-1, the introduction of halogen atoms into the alkyl (phosphate) chains led to anti-HIV activity. Although halogen substitution in just one alkyl chain was sufficient for biological activity, substitution in the second alkyl chain further enhanced activity. Conversely, stabilization of the second chain, by conversion to a phosphonate, led to a reduction in activity. In one case, the diastereo-isomers resulting from mixed stereochemistry at the phosphate centre were separated, and found to differ in activity by one order of magnitude. Lastly, the bis(mono- and di-chloroethyl) phosphates were prepared and found to display moderate anti-HIV activity.

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Phosphoramidate Derivatives of AZT as Inhibitors of HIV: Studies on the Carboxyl Terminus

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632029300400204 ◽

1993 ◽

Vol 4 (2) ◽

pp. 97-101 ◽

Cited By ~ 13

Author(s):

C. McGuigan ◽

R. N. Pathirana ◽

S. S.-M. Choi ◽

D. Kinchington ◽

T. J. O'Connor

Keyword(s):

Amino Acids ◽

Biological Activity ◽

Carboxyl Terminus ◽

Amino Ester ◽

Carboxy Terminus ◽

Free Nucleotides ◽

Derivatives Of ◽

Anti Hiv ◽

Ester Lead

Novel phosphoramidate derivatives of the anti-HIV nucleoside analogue AZT have been prepared by phosphorochloridate chemistry. These materials carry carboxy-protected, amino acids, and are designed to act as membrane-soluble prodrugs of the bio-active free nucleotides. In vitro evaluation revealed the compounds to have a pronounced, selective antiviral activity. In particular, variation in the carboxy terminus region is studied. For alkyl phosphates small changes in the structure of the amino ester lead to marked changes in biological activity. However, for analogous aryl phosphates there is little dependence on the structure of the ester. This suggests a different mechanism of action for these two categories of phosphate prodrug.

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Langmuir monolayers of the long-chain alkyl derivatives of a nucleoside analogue and the formation of self-assembled nanoparticles

Colloids and Surfaces B Biointerfaces ◽

10.1016/j.colsurfb.2005.02.001 ◽

2005 ◽

Vol 42 (1) ◽

pp. 45-51 ◽

Cited By ~ 21

Author(s):

Yiguang Jin ◽

Yingxin Qiao ◽

Miao Li ◽

Ping Ai ◽

Xinpu Hou

Keyword(s):

Nucleoside Analogue ◽

Langmuir Monolayers ◽

Alkyl Derivatives ◽

Self Assembled ◽

Derivatives Of ◽

Long Chain

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Phosphoramidates as Potent Prodrugs of anti-HIV Nucleotides: Studies in the Amino Region

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632029600700106 ◽

1996 ◽

Vol 7 (1) ◽

pp. 31-36 ◽

Cited By ~ 7

Author(s):

C. McGuigan ◽

D. Cahard ◽

A. Salgado ◽

E. De Clercq ◽

J. Balzarini

Keyword(s):

Amino Acid ◽

Vital Role ◽

Nucleoside Analogues ◽

Acid Moiety ◽

Hiv Replication ◽

Amino Acid Moiety ◽

Free Nucleotides ◽

Derivatives Of ◽

Anti Hiv

Novel phosphoramidate derivatives of the anti-HIV nucleoside analogues AZT and d4T have been prepared by phosphorochloridate chemistry. These materials are designed to act as labile membrane-soluble prodrugs of the bio-active free nucleotides. All compounds were fully characterised by a range of methods and were subjected to evaluation in vitro of their anti-HIV efficacy. A notable feature of the current study was that any attempt to replace the amino acid moiety of the phosphoramidate with a simple amine lead to a marked, virtually total loss of activity. Such simple phenyl alkylamino phosphate derivatives of either d4T or AZT inhibit HIV replication at cytotoxic concentrations and have no detectable antiviral selectivity. This clearly highlights the vital role played by the amino acid in the antiviral efficacy of the blocked phosphoramidates.

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Phosphate Derivatives of 3-Carboxyacylbetulin: SynThesis, In Vitro Anti-HIV and Molecular Docking Study

Biomolecules ◽

10.3390/biom10081148 ◽

2020 ◽

Vol 10 (8) ◽

pp. 1148

Author(s):

Krzysztof Marciniec ◽

Elwira Chrobak ◽

Aleksandra Dąbrowska ◽

Ewa Bębenek ◽

Monika Kadela-Tomanek ◽

...

Keyword(s):

Molecular Docking ◽

Betulinic Acid ◽

Strong Interactions ◽

Molecular Docking Study ◽

Gag Protein ◽

Terminal Domain ◽

Derivatives Of ◽

Anti Hiv ◽

Hiv 1

Lupane-type pentacyclic triterpenes such as betulin and betulinic acid play an important role in the search for new therapies that would be effective in controlling viral infections. The aim of this study was the synthesis and evaluation of in vitro anti-HIV-1 activity for phosphate derivatives of 3-carboxyacylbetulin 3–5 as well as an in silico study of new compounds as potential ligands of the C-terminal domain of the HIV-1 capsid–spacer peptide 1 (CA-CTD-SP1) as a molecular target of HIV-1 maturation inhibitors. In vitro studies showed that 28-diethoxyphosphoryl-3-O-(3′,3′-dimethylsuccinyl)betulin (compound 3), the phosphate analog of bevirimat (betulinic acid derivative, HIV-1 maturation inhibitor), has IC50 (half maximal inhibitory concentration) equal to 0.02 μM. Compound 3 inhibits viral replication at a level comparable to bevirimat and is also more selective (selectivity indices = 1250 and 967, respectively). Molecular docking was used to examine the probable interaction between the phosphate derivatives of 3-carboxyacylbetulin and C-terminal domain (CTD) of the HIV-1 capsid (CA)–spacer peptide 1 (SP1) fragment of Gag protein, designated as CTD-SP1. Compared with interactions between bevirimat (BVM) and the protein, an increased number of strong interactions between ligand 3 and the protein, generated by the phosphate group, were observed. These compounds might have the potential to also inhibit SARS-CoV2 proteins, in as far as the intrinsically imprecise docking scores suggest.

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Phenyl phosphoramidate derivatives of stavudine as anti-HIV agents with potent and selective in-vitro antiviral activity against Adenovirus

European Journal of Medicinal Chemistry ◽

10.1016/j.ejmech.2003.12.002 ◽

2004 ◽

Vol 39 (3) ◽

pp. 225-234 ◽

Cited By ~ 10

Author(s):

Fatih M. Uckun ◽

Sharon Pendergrass ◽

Sanjive Qazi ◽

P. Samuel ◽

T.K. Venkatachalam

Keyword(s):

Antiviral Activity ◽

Anti Hiv Agents ◽

Derivatives Of ◽

Anti Hiv

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

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632029600700606 ◽

1996 ◽

Vol 7 (6) ◽

pp. 330-337 ◽

Cited By ~ 2

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.

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Synthesis and Cytostatic Activity of N-[2-(Phosphonomethoxy)alkyl] Derivatives of N6-Substituted Adenines, 2,6-Diaminopurines and Related Compounds

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc20011545 ◽

2001 ◽

Vol 66 (10) ◽

pp. 1545-1592 ◽

Cited By ~ 55

Author(s):

Antonín Holý ◽

Ivan Votruba ◽

Eva Tloušťová ◽

Milena Masojídková

Keyword(s):

Cytostatic Activity ◽

Secondary Amines ◽

Dimethylformamide Dimethylacetal ◽

Alkyl Derivatives ◽

Derivatives Of ◽

Related Compounds ◽

Substituted Adenines

N6-Substituted adenine and 2,6-diaminopurine derivatives of 9-[2-(phosphonomethoxy)- ethyl] (PME), 9-[(R)-2-(phosphonomethoxy)propyl] [(R)-PMP] and enantiomeric (S)-PMP series were synthesized by reactions of primary or secondary amines with 6-chloro-9-{[2-(diisopropoxyphosphoryl)methoxy]alkyl}purines (26-28) or 2-amino-6-chloro-9-{[2-(diisopropoxy- phosphoryl)methoxy]alkyl}purines (29-31) followed by treatment of the diester intermediates32with bromo(trimethyl)silane and hydrolysis. Diesters32were also obtained by reaction ofN6-substituted purines with synthons23-25bearing diisopropoxyphosphoryl group. Alkylation of 2-amino-6-chloropurine (9) with diethyl [2-(2-chloroethoxy)ethyl]phosphonate (148) gave the diester149which was analogously converted toN6-substituted 2,6-diamino- 9-[2-(2-phosphonoethoxy)ethyl]purines151-153. Alkylation ofN6-substituted 2,6-diaminopurines with (R)-[(trityloxy)methyl]oxirane (155) followed by reaction of thus-obtained intermediates156with dimethylformamide dimethylacetal and condensation with diisopropyl [(tosyloxy)methyl]phosphonate (158) followed by deprotection of the intermediates159gaveN6-substituted 2,6-diamino-9-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]purines160-163. The highest cytostatic activityin vitrowas exhibited by the followingN6-derivatives of 2,6-diamino-9-[2-(phosphonomethoxy)ethyl]purine (PMEDAP): 2,2,2-trifluoroethyl (53), allyl (54), [(2-dimethylamino)ethyl] (68), cyclopropyl (75) and dimethyl (91). In CCRF-CEM cells, the cyclopropyl derivative75is deaminated to the guanine derivative PMEG (3) which is then converted to its diphosphate.

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A N-propionylsulfonamide prodrug of K-5a2 provided improved aqueous solubility and hERG inhibition

10.21203/rs.3.rs-20505/v1 ◽

2020 ◽

Author(s):

Xiaofang Zuo ◽

Zhipeng Huo ◽

Dongwei Kang ◽

Tong Zhao ◽

Erik De Clercq ◽

...

Keyword(s):

Water Solubility ◽

Parent Drug ◽

Aqueous Solubility ◽

Drug Candidate ◽

Log P ◽

Vitro Assay ◽

Subacute Toxicity ◽

Anti Hiv ◽

Hiv 1

Abstract Background Having the potential disadvantages and safety risk of the use of anti-HIV-1 drug candidate K-5a2 in the longterm treatment of HIV patients in mind, we set out with the goal of finding a second-generation backup compound of K-5a2 with the appropriate anti-HIV potency, significantly reduced hERG activity, decreased induction of the CYP enzyme, and improved aqueous solubility. Herein, using a N-propionylsulfonamide prodrug strategy, we report the discovery of compound HM-1Methods In vitro assay of anti-HIV activities in TZM-bl and MT-4 cells, metabolic stability in HLM and human plasma, measurements of water solubility and Log P, assay procedures for hERG activity, acute and subacute toxicity experiment and cytochrome P450 inhibition assay were carried out for HM-1.Results HM-1 can be rapidly hydrolyzed to parent drug K-5a2 and exhibited high potency against HIV-1NL4 − 3 strain (EC50 = 7.99 nM) in TZM-bl cells, HIV-1IIIB strain (EC50 = 2.9 nM) and HIV-1Y181C strain (EC50 = 5.5 nM) in MT-4 cells. And it also showed a > 70-fold improvement in aqueous solubility and presented a low acute toxicity in mice (LD50 > 2 g•kg− 1); no obvious organ damage was detected in the assessment of subacute toxicity. Meanwhile, HM-1 also showed 50 times lower hERG inhibition (IC50 = 6.39 µM) than K-5a2 (IC50 = 0.13 µM).Conclusions It was HM-1 appeared to be free of most of the drawbacks associated with K-5a2 and has been selected for further development as an oral anti-HIV-infection agent.

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