Synthesis and Structure-Activity Relationships of Analogs of 2'-Deoxy-2'-(3-methoxybenzamido)adenosine, a Selective Inhibitor of Trypanosomal Glycosomal Glyceraldehyde-3-phosphate Dehydrogenase

Calenbergh, Serge Van; Verlinde, Christophe L. M. J.; Soenens, J; Bruyn, André De; Callens, Mia; Blaton, N. M.; Peeters, O. M.; Rozenski, Jef; Hól, Wim G. J.; Herdewijn, Piet

doi:10.1021/jm00019a014

Cited by 49 publications

(59 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The majority of top DOCK-ranked carboxylic acids were benzoic acid derivatives. Still, we attempted to select a diverse group of ligands while, at the same time, including top DOCK-ranked substituents known to enhance adenosine affinity (Table 4; 3-methylbenzyl-, 2-methylbenzyl-, naphthylenemethyl-, and benzylamine; 4-phenylbenzoic acid, 22 3,5-dimethoxybenzoic acid, and 3,5-dichlorobenzoic acid). This led to a selection of 20 amines and 12 carboxylic acids ( Table 4) that were used to generate a 240-compound library of N 6 -(substituted)-2′-deoxy-2′-(amido)adenosine analogues via parallel solution-phase synthesis based on the common intermediate 5.…”

Section: N 6 -(Substituted)-2′-deoxy-2′-(amido)adenosine Combinatoriamentioning

confidence: 99%

“…Modifications of the C5′ of N 6 -(1-Naphthalenemethyl)adenosine and 2′-Deoxy-2′-(3,5-dimethoxy-benzamido)adenosine (Table 5) Both 5′deoxy-(5′-cyclohexylacetamido)adenosine (35) 23 and 5′deoxy-(5′-diphenylacetamido) adenosine (36) 22 inhibit L. mexicana GAPDH with IC 50 's of 250 μM. We wished to investigate if the integration of these C5′ substituents with either the N 6 -naphthalenemethyl or C2′-(3,5-dimethoxybenzamido) substituents would increase binding affinity.…”

Section: N 6 -(Substituted)-2′-deoxy-2′-(amido)adenosine Combinatoriamentioning

confidence: 99%

See 1 more Smart Citation

Adenosine Analogues as Selective Inhibitors of Glyceraldehyde-3-phosphate Dehydrogenase of Trypanosomatidae via Structure-Based Drug Design

et al. 2001

Self Cite

View full text Add to dashboard Cite

In our continuation of the structure-based design of anti-trypanosomatid drugs, parasite-selective adenosine analogues were identified as low micromolar inhibitors of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Crystal structures of Trypanosoma brucei, Trypanosoma cruzi, Leishmania mexicana, and human GAPDH's provided details of how the adenosyl moiety of NAD + interacts with the proteins, and this facilitated the understanding of the relative affinities of a series of adenosine analogues for the various GAPDH's. From exploration of modifications of the naphthalenemethyl and benzamide substituents of a lead compound, N 6 -(1-naphthalenemethyl)-2′-deoxy-2′-(3-methoxybenzamido)adenosine (6e), N 6 -(substituted-naphthalenemethyl)-2′-deoxy-2′-(substituted-benzamido)adenosine analogues were investigated. N 6 -(1-Naphthalenemethyl)-2′-deoxy-2′-(3,5-dimethoxybenzamido)adenosine (6m), N 6 -[1-(3-hydroxy-naphthalene)methyl]-2′-deoxy-2′-(3,5-dimethoxybenzamido)adenosine (7m), N 6 -[1-(3-methoxy-naphthalene)methyl]-2′-deoxy-2′-(3,5-dimethoxybenzamido)adenosine (9m), N 6 -(2-naphthalene-methyl)-2′-deoxy-2′-(3-methoxybenzamido)adenosine (11e), and N 6 -(2-naphthalenemethyl)-2′-deoxy-2′-(3,5-dimethoxybenzamido)adenosine (11m) demonstrated a 2-to 3-fold improvement over 6e and a 7100-to 25000-fold improvement over the adenosine template. IC 50 's of these compounds were in the range 2-12 μM for T. brucei, T. cruzi, and L. mexicana GAPDH's, and these compounds did not inhibit mammalian GAPDH when tested at their solubility limit. To explore more thoroughly the structure-activity relationships of this class of compounds, a library of 240 N 6 -(substituted)-2′-deoxy-2′-(amido)adenosine analogues was generated using parallel solution-phase synthesis with N 6 and C2′ substituents chosen on the basis of computational docking scores. This resulted in the identification of 40 additional compounds that inhibit parasite GAPDH's in the low micromolar range. We also explored adenosine analogues containing 5′-amido substituents and found that 2′,5′-

show abstract

Section: N 6 -(Substituted)-2′-deoxy-2′-(amido)adenosine Combinatoriamentioning

confidence: 99%

Section: N 6 -(Substituted)-2′-deoxy-2′-(amido)adenosine Combinatoriamentioning

confidence: 99%

Adenosine Analogues as Selective Inhibitors of Glyceraldehyde-3-phosphate Dehydrogenase of Trypanosomatidae via Structure-Based Drug Design

et al. 2001

Self Cite

View full text Add to dashboard Cite

show abstract

“…This possibility represents a considerable advantage over strategies reported thus far to access amide libraries by PASP synthesis making use of catch-and-release linkers. Kim and Le recently described efficient N-acylation methods mediated by activated esters of polymer-supported 4-hydroxy-3-nitrobenzophenone; Masala and Taddei introduced a 2,4,6-trichloro [1,3,5]triazine-based linker intended for the synthesis of amide libraries. 19,20 Using these PASP strategies, treatment with nucleophiles should afford amides without the option to selectively modify residues such as 4-fluoro-3-nitro-benzoic acid by aminolysis.…”

Section: Resultsmentioning

confidence: 99%

“…1 (ppm) ) 8.69 (d, 1H, 2′NH, J ) 8.65), 8.27 (s, 1H, 8H), 8.14 (s, 1H, 2H), 7.88 (d, 1H, aromat., J ) 19 (m, 1H, 2′H), 4.33-4.26 (m, 1H, 3′H), 3.69-3.55 (m, 3H, 4′H, 5′H 2 ).…”

Section: ′-Deoxy-2′-(3-fluorobenzamido)adenosine (6a)mentioning

confidence: 99%

See 1 more Smart Citation

Polymer-Assisted Solution-Phase Synthesis of 2‘-Amido-2‘-deoxyadenosine Derivatives Targeted at the NAD⁺-Binding Sites of Parasite Enzymes

et al. 2000

Self Cite

View full text Add to dashboard Cite

A polymer-assisted solution-phase (PASP) synthesis of lead structure analogues ready for biological testing without the demand for chromatographic purification is described. Carboxylic acids are coupled to the Kenner or Ellman safety catch linker, respectively, activated by methylation or cyanomethylation and subsequently transferred to the 2′-amino group of the 2′-amino-2′-deoxyadenosine scaffold (5). The chemoselective attack of weakly nucleophilic amino groups on the N-alkylated N-acyl sulfonamide linker allows for the synthesis of amides 6 in high yields without the need for protection of primary and secondary hydroxyl functions. Thus, the use of 4-sulfamylbenzoylaminomethyl polystyrene is reported for the construction of chemoselective polymer-supported acylating reagents instead of its known use as linker in solid-phase peptide or organic synthesis. This approach is demonstrated to be well suited to obtain 2′-amido-2′-deoxyadenosine derivatives 6 in parallel format. Biological evaluation of all compounds reported revealed no improvement over known lead structures.

show abstract

Conformations of nicotinamide adenine dinucleotide (NAD+) in various environments

Smith

Tanner

2000

J. Mol. Recognit.

View full text Add to dashboard Cite

Enzymes bind NAD(+) in extended conformations and yet NAD(+) exists in aqueous solution as a compact, folded molecule. Thus, NAD(+) conformation is environment dependent. In an attempt to investigate the effects of environmental changes on the conformation of NAD(+), a series of molecular dynamics simulations in different solvents was performed. The solvents investigated (water, DMSO, methanol and chloroform) represented changes in relative permittivity and hydrophobic character. The simulations predicted folded conformations of NAD(+) to be more stable in water, DMSO and methanol. In contrast, extended conformations of NAD(+) were observed to be more stable in chloroform. Furthermore, the extended conformations observed in chloroform were similar to conformations of NAD(+) bound to enzymes. In particular, a large separation between the aromatic rings and a strong interaction between the pyrophosphate and nicotinamide groups were observed. The implications of these observations for the recognition of NAD(+) by enzymes is discussed. It is argued that a hydrophobic environment is important for stabilizing unfolded conformations of NAD(+).

show abstract

Synthesis and Structure-Activity Relationships of Analogs of 2'-Deoxy-2'-(3-methoxybenzamido)adenosine, a Selective Inhibitor of Trypanosomal Glycosomal Glyceraldehyde-3-phosphate Dehydrogenase

Cited by 49 publications

References 12 publications

Adenosine Analogues as Selective Inhibitors of Glyceraldehyde-3-phosphate Dehydrogenase of Trypanosomatidae via Structure-Based Drug Design

Adenosine Analogues as Selective Inhibitors of Glyceraldehyde-3-phosphate Dehydrogenase of Trypanosomatidae via Structure-Based Drug Design

Polymer-Assisted Solution-Phase Synthesis of 2‘-Amido-2‘-deoxyadenosine Derivatives Targeted at the NAD⁺-Binding Sites of Parasite Enzymes

Conformations of nicotinamide adenine dinucleotide (NAD+) in various environments

Contact Info

Product

Resources

About

Synthesis and Structure-Activity Relationships of Analogs of 2'-Deoxy-2'-(3-methoxybenzamido)adenosine, a Selective Inhibitor of Trypanosomal Glycosomal Glyceraldehyde-3-phosphate Dehydrogenase

Cited by 49 publications

References 12 publications

Adenosine Analogues as Selective Inhibitors of Glyceraldehyde-3-phosphate Dehydrogenase of Trypanosomatidae via Structure-Based Drug Design

Adenosine Analogues as Selective Inhibitors of Glyceraldehyde-3-phosphate Dehydrogenase of Trypanosomatidae via Structure-Based Drug Design

Polymer-Assisted Solution-Phase Synthesis of 2‘-Amido-2‘-deoxyadenosine Derivatives Targeted at the NAD+-Binding Sites of Parasite Enzymes

Conformations of nicotinamide adenine dinucleotide (NAD+) in various environments

Contact Info

Product

Resources

About

Polymer-Assisted Solution-Phase Synthesis of 2‘-Amido-2‘-deoxyadenosine Derivatives Targeted at the NAD⁺-Binding Sites of Parasite Enzymes