scholarly journals Synthesis, Biological Activity, and Molecular Dynamics Study of Novel Series of a Trimethoprim Analogs as Multi-Targeted Compounds: Dihydrofolate Reductase (DHFR) Inhibitors and DNA-Binding Agents

2021 ◽  
Vol 22 (7) ◽  
pp. 3685
Author(s):  
Agnieszka Wróbel ◽  
Maciej Baradyn ◽  
Artur Ratkiewicz ◽  
Danuta Drozdowska
Keyword(s):  
Dna Binding ◽  
Dihydrofolate Reductase ◽  
Solid Phase ◽  
Binding Capacity ◽  
Minor Groove ◽  
Amide Bond ◽  
Amide Bonds ◽  
Binding Agents ◽  
Pbr322 Plasmid ◽  
A Minor

Eighteen previously undescribed trimethoprim (TMP) analogs containing amide bonds (1–18) were synthesized and compared with TMP, methotrexate (MTX), and netropsin (NT). These compounds were designed as potential minor groove binding agents (MGBAs) and inhibitors of human dihydrofolate reductase (hDHFR). The all-new derivatives were obtained via solid phase synthesis using 4-nitrophenyl Wang resin. Data from the ethidium displacement test confirmed their DNA-binding capacity. Compounds 13–14 (49.89% and 43.85%) and 17–18 (41.68% and 42.99%) showed a higher binding affinity to pBR322 plasmid than NT. The possibility of binding in a minor groove as well as determination of association constants were performed using calf thymus DNA, T4 coliphage DNA, poly (dA-dT)2, and poly (dG-dC)2. With the exception of compounds 9 (IC50 = 56.05 µM) and 11 (IC50 = 55.32 µM), all of the compounds showed better inhibitory properties against hDHFR than standard, which confirms that the addition of the amide bond into the TMP structures increases affinity towards hDHFR. Derivatives 2, 6, 13, 14, and 16 were found to be the most potent hDHFR inhibitors. This molecular modelling study shows that they interact strongly with a catalytically important residue Glu-30.

scholarly journals Trimethoprim: An Old Antibacterial Drug as a Template to Search for New Targets. Synthesis, Biological Activity and Molecular Modeling Study of Novel Trimethoprim Analogs

Molecules ◽  
2019 ◽  
Vol 25 (1) ◽  
pp. 116 ◽  
Author(s):  
Agnieszka Wróbel ◽  
Dawid Maliszewski ◽  
Maciej Baradyn ◽  
Danuta Drozdowska
Keyword(s):  
Dna Binding ◽  
Dihydrofolate Reductase ◽  
Binding Capacity ◽  
Antibacterial Drug ◽  
Inhibition Assay ◽  
Amide Bonds ◽  
Calf Thymus ◽  
A Minor ◽  
New Compounds

A new series of trimethoprim (TMP) analogs containing amide bonds (1–6) have been synthesized. Molecular docking, as well as dihydrofolate reductase (DHFR) inhibition assay were used to confirm their affinity to bind dihydrofolate reductase enzyme. Data from the ethidium displacement test showed their DNA-binding capacity. Tests confirming the possibility of DNA binding in a minor groove as well as determination of the association constants were performed using calf thymus DNA, T4 coliphage DNA, poly (dA-dT)2 and poly (dG-dC)2. Additionally, the mechanism of action of the new compounds was studied. In conclusion, some of our new analogs inhibited DHFR activity more strongly than TMP did, which confirms, that the addition of amide bonds into the analogs of TMP increases their affinity towards DHFR.

scholarly journals An ab-initio study of pyrrole and imidazole arylamides

2013 ◽  
Vol 78 (11) ◽  
pp. 1789-1795
Author(s):  
Ara Abramyan ◽  
Zhiwei Liu ◽  
Vojislava Pophristic
Keyword(s):  
Dna Binding ◽  
Force Field ◽  
Dna Sequences ◽  
Density Functional ◽  
Md Simulations ◽  
Building Blocks ◽  
Amide Bond ◽  
Amide Bonds ◽  
Force Field Parameters ◽  
Arylamide Foldamers

Arylamide foldamers have been shown to have a number of biological and medicinal applications. For example, a class of pyrrole-imidazole polyamide foldamers is capable of binding specific DNA sequences and preventing development of various gene disorders, most importantly cancer. Molecular dynamics (MD) simulations can provide crucial details in understanding the atomic level events related to foldamer/DNA binding. An important first step in the accurate simulation of these foldamer/DNA systems is the reparametrization of force field parameters for torsion around the aryl-amide bonds. Here we highlight our Density Functional Theory (DFT) potential energy profiles and derived force field parameters for four aryl-amide bond types for the pyrrole and imidazole building blocks extensively used in foldamer design for the DNA-binding polyamides. These results contribute to developing of computational tools for an appropriate molecular modeling of pyrrole-imidazole polyamide/DNA binding, and provide an insight into the chemical factors that influence the flexibility of the pyrrole-imidazole polyamides, and their binding to DNA.

1H and 13C NMR assignments and molecular modelling of a minor groove DNA-binding peptide from the HMG-I protein

2009 ◽  
Vol 45 (6) ◽  
pp. 554-560 ◽  
Author(s):  
JEREMY N.S. EVANS ◽  
JAROSLAV ZAJICEK ◽  
MARK S. NISSEN ◽  
GERHARD MUNSKE ◽  
VIRGINIA SMITH ◽  
...  
Keyword(s):  
Dna Binding ◽  
13C Nmr ◽  
Molecular Modelling ◽  
Nmr Assignments ◽  
Minor Groove ◽  
1H And 13C Nmr ◽  
Binding Peptide ◽  
A Minor

DNA Binding Compounds. VII. Synthesis, Characterization and DNA Binding Capacity of 1,2-Dicarba-closo-dodecaborane Bibenzimidazoles Related to the DNA Minor Groove Binder Hoechst 33258

1999 ◽  
Vol 52 (4) ◽  
pp. 291 ◽  
Author(s):  
Stuart A. Bateman ◽  
David P. Kelly ◽  
Jonathan M. White ◽  
Roger F. Martin
Keyword(s):  
Dna Binding ◽  
Binding Capacity ◽  
Minor Groove ◽  
Minor Groove Binder ◽  
Hoechst 33258 ◽  
Binding Studies ◽  
Dna Minor Groove ◽  
Dna Binding Studies ◽  
Carborane Ligand ◽  
Dna Minor Groove Binder

A series of bibenzimidazole derivatives based on the known DNA minor groove binder Hoechst 33258 have been prepared to include a 1,2-dicarba-closo-dodecaborane cage for potential use in boron neutron capture therapy (BNCT). The carborane derivatives (5){(7) were chosen to reduce the steric inhibition of minor groove DNA binding displayed by the previously prepared carborane ligand (4). The synthesis and preliminary DNA binding studies of these bibenzimidazole derivatives are presented herein.

scholarly journals 1,2,3-Triazoles as Biomimetics in Peptide Science

Molecules ◽  
2021 ◽  
Vol 26 (10) ◽  
pp. 2937
Author(s):  
Naima Agouram ◽  
El Mestafa El Hadrami ◽  
Abdeslem Bentama
Keyword(s):  
Enzymatic Degradation ◽  
Triazole Ring ◽  
Biologically Active ◽  
Amide Bond ◽  
Biologically Relevant ◽  
Amide Bonds ◽  
Natural Peptides ◽  
Mimicking Peptides ◽  
Chemical Mediators

Natural peptides are an important class of chemical mediators, essential for most vital processes. What limits the potential of the use of peptides as drugs is their low bioavailability and enzymatic degradation in vivo. To overcome this limitation, the development of new molecules mimicking peptides is of great importance for the development of new biologically active molecules. Therefore, replacing the amide bond in a peptide with a heterocyclic bioisostere, such as the 1,2,3-triazole ring, can be considered an effective solution for the synthesis of biologically relevant peptidomimetics. These 1,2,3-triazoles may have an interesting biological activity, because they behave as rigid link units, which can mimic the electronic properties of amide bonds and show bioisosteric effects. Additionally, triazole can be used as a linker moiety to link peptides to other functional groups.

scholarly journals Structure-Acid Lability Relationship of N-alkylated α,α-dialkylglycine Obtained via a Ugi Multicomponent Reaction

Molecules ◽  
2021 ◽  
Vol 26 (1) ◽  
pp. 197
Author(s):  
Iván Ramos-Tomillero ◽  
Marisa K. Sánchez ◽  
Hortensia Rodríguez ◽  
Fernando Albericio
Keyword(s):  
Solid Phase Synthesis ◽  
Solid Phase ◽  
Structural Features ◽  
Amide Bond ◽  
Acidic Media ◽  
Phase Synthesis ◽  
Acyl Chains ◽  
Cyclic Compounds ◽  
Relationship Of ◽  
Fine Tune

Using the classical Ugi four-component reaction to fuse an amine, ketone, carboxylic acid, and isocyanide, here we prepared a short library of N-alkylated α,α-dialkylglycine derivatives. Due to the polyfunctionality of the dipeptidic scaffold, this highly steric hindered system shows an interesting acidolytic cleavage of the C-terminal amide. In this regard, we studied the structure-acid lability relationship of the C-terminal amide bond (cyclohexylamide) of N-alkylated α,α-dialkylglycine amides 1a–n in acidic media and, afterward, it was established that the most important structural features related to its cleavage. Then, it was demonstrated that electron-donating effects in the aromatic amines, flexible acyl chains (Gly) at the N-terminal and the introduction of cyclic compounds into dipeptide scaffolds, increased the rate of acidolysis. All these effects are related to the ease with which the oxazolonium ion intermediate forms and they promote the proximity of the central carbonyl group to the C-terminal amide, resulting in C-terminal amide cleavage. Consequently, these findings could be applied for the design of new protecting groups, handles for solid-phase synthesis, and linkers for conjugation, due to its easily modulable and the fact that it allows to fine tune its acid-lability.

Binding mode and affinity studies of DNA-binding agents using topoisomerase I DNA unwinding assay

2007 ◽  
Vol 17 (4) ◽  
pp. 1013-1017 ◽  
Author(s):  
Ruel E. McKnight ◽  
Aaron B. Gleason ◽  
James A. Keyes ◽  
Sadia Sahabi
Keyword(s):  
Dna Binding ◽  
Topoisomerase I ◽  
Binding Mode ◽  
Dna Unwinding ◽  
Binding Agents ◽  
Dna Binding Agents
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