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

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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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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Novel Nucleoside Phosphoramidates as Inhibitors of HIV: Studies on the Stereochemical Requirements of the Phosphoramidate Amino Acid

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632029600700402 ◽

1996 ◽

Vol 7 (4) ◽

pp. 184-188 ◽

Cited By ~ 14

Author(s):

C. McGuigan ◽

A. Salgado ◽

C. Yarnold ◽

T.Y. Harries ◽

E. De Clercq ◽

...

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Antiviral Activity ◽

Antiviral Effect ◽

Amino Acid Derivatives ◽

Free Nucleotides ◽

Nucleoside Phosphoramidates ◽

Derivatives Of ◽

Anti Hiv ◽

Marked Dependence

Novel phosphoramidate derivatives of the anti-HIV nucleoside analogue d4T were designed to act as labile membrane-soluble prodrugs of the bio-active free nucleotide d4TMP. We herein reveal the very marked dependence of the antiviral activity of these phosphoramidates upon the stereochemistry of the amino acid attached to the phosphate centre; with a strong preference for the L-stereochemistry. These phosphate triesters were shown to liberate amino acid derivatives of the nucleotide intracellularly. These novel analogues, typified by alaninyl d4T monophosphate, may act as intracellular sources of the free nucleotides. The alaninyl d4T adducts themselves exert an antiviral effect when administered extracellularly, but again with clear distinctions between the L- and D-series. This evidence indicates that extracellularly administered blocked triesters derived from L-amino acids can generate d4TMP intracellularly, by a new pathway which is highly dependent on the amino acid stereochemistry.

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

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632029400500409 ◽

1994 ◽

Vol 5 (4) ◽

pp. 271-277 ◽

Cited By ~ 9

Author(s):

C. McGuigan ◽

P. Bellevergue ◽

B. C. N. M. Jones ◽

N. Mahmood ◽

A. J. Hay ◽

...

Keyword(s):

Nucleoside Analogue ◽

Parent Drug ◽

Antiviral Action ◽

Alkyl Derivatives ◽

Free Nucleotides ◽

A Cell ◽

Derivatives Of ◽

Anti Hiv ◽

Long Chain

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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Translational and Structural Requirements of the Early Nodulin Gene enod40, a Short-Open Reading Frame-Containing RNA, for Elicitation of a Cell-Specific Growth Response in the Alfalfa Root Cortex

Molecular and Cellular Biology ◽

10.1128/mcb.21.1.354-366.2001 ◽

2001 ◽

Vol 21 (1) ◽

pp. 354-366 ◽

Cited By ~ 66

Author(s):

Carolina Sousa ◽

Christina Johansson ◽

Celine Charon ◽

Hamid Manyani ◽

Christof Sautter ◽

...

Keyword(s):

Amino Acids ◽

Biological Activity ◽

Rna Structure ◽

Open Reading Frames ◽

In Vitro Translation ◽

Cortical Cells ◽

Root Cortex ◽

Reading Frame ◽

Early Nodulin

ABSTRACT A diversity of mRNAs containing only short open reading frames (sORF-RNAs; encoding less than 30 amino acids) have been shown to be induced in growth and differentiation processes. The early nodulin geneenod40, coding for a 0.7-kb sORF-RNA, is expressed in the nodule primordium developing in the root cortex of leguminous plants after infection by symbiotic bacteria. Ballistic microtargeting of this gene into Medicago roots induced division of cortical cells. Translation of two sORFs (I and II, 13 and 27 amino acids, respectively) present in the conserved 5′ and 3′ regions ofenod40 was required for this biological activity. These sORFs may be translated in roots via a reinitiation mechanism. In vitro translation products starting from the ATG of sORF I were detectable by mutating enod40 to yield peptides larger than 38 amino acids. Deletion of a Medicago truncatula enod40 region between the sORFs, spanning a predicted RNA structure, did not affect their translation but resulted in significantly decreased biological activity. Our data reveal a complex regulation of enod40action, pointing to a role of sORF-encoded peptides and structured RNA signals in developmental processes involving sORF-RNAs.

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Synthesis, Degradation Kinetics and in vitro Antimicrobial Activity of Tetrahydro-2H-1,3,5-thiadiazine-2-thione Derivatives of Some β-Amino Acids

Arzneimittelforschung ◽

10.1055/s-0031-1297144 ◽

2011 ◽

Vol 53 (07) ◽

pp. 526-531

Author(s):

Aboul-Fadl Tarek ◽

Abdel-Raouf Khallil

Keyword(s):

Amino Acids ◽

Antimicrobial Activity ◽

Degradation Kinetics ◽

In Vitro Antimicrobial Activity ◽

Derivatives Of

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Alkylation of γ-(4-nitrobenzyl)pyridine by four N-diazoacetyl derivatives of amino acids. Lack of fine correlation with the unscheduled DNA synthesis induced in mouse cells “In vitro”

Pharmacological Research Communications ◽

10.1016/s0031-6989(77)80092-1 ◽

1977 ◽

Vol 9 (7) ◽

pp. 621-631 ◽

Cited By ~ 6

Author(s):

S. Parodi ◽

M. Picca ◽

C. Bolognesi ◽

M. Cavanna ◽

P. Carlo ◽

...

Keyword(s):

Amino Acids ◽

Dna Synthesis ◽

Unscheduled Dna Synthesis ◽

Mouse Cells ◽

Derivatives Of

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The Presence of Novel Amino Acids in the Cytoplasmic Domain of Stem Cell Factor Results in Hematopoietic Defects inSteel17H Mice

Blood ◽

10.1182/blood.v94.6.1915 ◽

1999 ◽

Vol 94 (6) ◽

pp. 1915-1925 ◽

Cited By ~ 20

Author(s):

Reuben Kapur ◽

Ryan Cooper ◽

Xingli Xiao ◽

Mitchell J. Weiss ◽

Peter Donovan ◽

...

Keyword(s):

Amino Acids ◽

Bone Marrow ◽

Biological Activity ◽

Stem Cell ◽

Blood Cell ◽

Red Blood Cell ◽

Stem Cell Factor ◽

Cytoplasmic Domain

Abstract Stem cell factor (SCF) is expressed as an integral membrane growth factor that may be differentially processed to produce predominantly soluble (S) (SCF248) or membrane-associated (MA) (SCF220) protein. A critical role for membrane presentation of SCF in the hematopoietic microenvironment (HM) has been suggested from the phenotype of the Steel-dickie(Sld) mice, which lack MA SCF, and by studies performed in our laboratory (and by others) using long-term bone marrow cultures and transgenic mice expressing different SCF isoforms.Steel17H (Sl17H) is an SCF mutant that demonstrates melanocyte defects and sterility in males but not in females. The Sl17H allele contains a intronic mutation resulting in the substitution of 36 amino acids (aa’s) in the SCF cytoplasmic domain with 28 novel aa’s. This mutation, which affects virtually the entire cytoplasmic domain of SCF, could be expected to alter membrane SCF presentation. To investigate this possibility, we examined the biochemical and biologic properties of the Sl17H-encoded protein and its impact in vivo and in vitro on hematopoiesis and on c-Kit signaling. We demonstrate that compound heterozygous Sl/Sl17H mice manifest multiple hematopoietic abnormalities in vivo, including red blood cell deficiency, bone marrow hypoplasia, and defective thymopoiesis. In vitro, both S and MA Sl17H isoforms of SCF exhibit reduced cell surface expression on stromal cells and diminished biological activity in comparison to wild-type (wt) SCF isoforms. These alterations in presentation and biological activity are associated with a significant reduction in the proliferation of an SCF-responsive erythroid progenitor cell line and in the activation of phosphatidylinositol 3-Kinase/Akt and mitogen-activated protein-Kinase signaling pathways. In vivo, transgene expression of the membrane-restricted (MR) (SCFX9/D3) SCF in Sl/Sl17H mutants results in a significant improvement in peripheral red blood cell counts in comparison toSl/Sl17H mice.

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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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