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

1996 ◽  
Vol 7 (4) ◽  
pp. 184-188 ◽  
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.

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

1993 ◽  
Vol 4 (2) ◽  
pp. 97-101 ◽  
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.

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.

ChemInform Abstract: AMINO ACID DERIVATIVES OF PHENYLALKYLAMINE PART 3, ACYLATION OF BETA-PHENYLETHYLAMINE DERIVATIVES WITH ALPHA-AMINO ACIDS

1975 ◽  
Vol 6 (26) ◽  
pp. no-no
Author(s):  
I. D. KISELEVA ◽  
N. S. VOLODARSKAYA ◽  
D. N. MASLIN ◽  
YU. A. DAVIDOVICH ◽  
S. V. ROGOZHIN ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Amino Acid Derivatives ◽  
Derivatives Of

Some N-acyl-D-amino acid derivatives having antibotulinal properties

1987 ◽  
Vol 33 (7) ◽  
pp. 577-582 ◽  
Author(s):  
A. Paquet ◽  
K. Rayman
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Aspartic Acid ◽  
Sodium Nitrite ◽  
Amino Acid Derivatives ◽  
Ester Method ◽  
Succinimidyl Ester ◽  
High Yields ◽  
Derivatives Of ◽  
Acyl Derivatives

Several N-acyl derivatives of D-tryptophan, D-alanine, D-methionine, D-valine, and D-aspartic acid were synthesized in high yields using the succinimidyl ester method and examined for their antibotulinal properties. In conjunction with 60 ppm of sodium nitrite, sorbyl-D-tryptophan, sorbyl-D-alanine, myristoyl-D-aspartic acid, and glycyl-D-alanine were highly inhibitory. In the absence of sodium nitrite, the N-acyl derivatives of the D-amino acids were not inhibitory. On its own, 60 ppm of sodium nitrite was only slightly inhibitory. Sorbyl-L-tryptophan and sorbyl-L-alanine had no effect in the presence or absence of 60 ppm of sodium nitrite.

scholarly journals N4-amino-acid derivatives of 6-azacytidine: structure-activity relationship.

2000 ◽  
Vol 47 (1) ◽  
pp. 95-101 ◽  
Author(s):  
I Alexeeva ◽  
L Palchikovskaya ◽  
A Shalamay ◽  
L Nosach ◽  
V Zhovnovataya ◽  
...  
Keyword(s):  
Amino Acid ◽  
Antiviral Activity ◽  
Chemical Structure ◽  
Specific Activity ◽  
Biological Properties ◽  
Activity Relationship ◽  
Amino Acid Derivatives ◽  
Condensation Method ◽  
Structure Activity ◽  
Derivatives Of

Several N4-derivatives of 6-azacytidine were synthesized using of Vorbrüggen's condensation method. Their antiviral activity with respect to the adenovirus serotypes 2 and 5 in Hep-2 cells culture was studied and primary specific activity was determined. Correlation between chemical structure of new 6-azacytidine derivatives and their biological properties is discussed.

Piezoactive amino acid derivatives containing fragments of planar-chiral ortho-carboranes

2018 ◽  
Vol 6 (32) ◽  
pp. 8638-8645 ◽  
Author(s):  
Dmitry A. Gruzdev ◽  
Alla S. Nuraeva ◽  
Pavel A. Slepukhin ◽  
Galina L. Levit ◽  
Pavel S. Zelenovskiy ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Amino Acid Derivatives ◽  
Piezoelectric Activity ◽  
Derivatives Of

Compounds possessing a high piezoelectric activity have been found among enantio pure ortho-carboranyl derivatives of amino acids.

Synthesis of amino acid derivatives of 5-alkoxy-3,4-dihalo-2(5H)-furanones and their preliminary bioactivity investigation as linkers

2019 ◽  
Vol 17 (20) ◽  
pp. 5138-5147 ◽  
Author(s):  
Shi-He Luo ◽  
Kai Yang ◽  
Jian-Yun Lin ◽  
Juan-Juan Gao ◽  
Xin-Yan Wu ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Toxic Effect ◽  
Amino Acid Derivatives ◽  
Metal Free ◽  
Mtt Tests ◽  
Derivatives Of

MTT tests of 2(5H)-furanone derivatives obtained via metal-free C–N coupling show that amino acids as linkers have no toxic effect.

LIPOPHILIC CHARACTER OF NOVEL AMINO ACID DERIVATIVES OF ZIDOVUDINE WITH ANTI HIV ACTIVITY

2002 ◽  
Vol 25 (9) ◽  
pp. 1345-1365 ◽  
Author(s):  
Guillermo N. Moroni ◽  
Mario A. Quevedo ◽  
Soledad Ravetti ◽  
Margarita C. Briñón
Keyword(s):  
Amino Acid ◽  
Amino Acid Derivatives ◽  
Derivatives Of ◽  
Anti Hiv ◽  
Lipophilic Character

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

1996 ◽  
Vol 7 (1) ◽  
pp. 31-36 ◽  
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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