Biomedical subjects

Paul W Baures

Publications and source records attributed to Paul W Baures.

7 recordsLinked to original sources

PubMed2005

Imidazole-4,5-dicarboxamide derivatives with antiproliferative activity against HL-60 cells.

A series of N,N'-disubstituted imidazole-4,5-dicarboxamides (I45DCs) were prepared and tested in order to determine their antiproliferative activity against HL-60 cells. The design of the I45DCs was based in part on the structures of trisubstituted purines complexed with cyclin dependent kinase 2 (cdk2), a protein important in regulating the G1/S transition in the cell cycle, and the intramolecular hydrogen bond in I45DCs that predisposes the conformation to one that mimics substituted adenosines. A majority of the I45DCs in this study inhibit proliferation of HL-60 cells as measured by an MTS mitochondrial functional assay with IC50's in the 2.5-25 microM range. The SAR of the I45DCs is consistent with anticipated hydrogen bonding interactions in the ATP-binding site of cdk2. Thus, the I45DCs represent a useful scaffold for anticancer lead discovery that is both readily accessible and easily diversified.

Adenosine Triphosphate↗

PubMed2005

Intramolecular hydrogen bond strength and pK(a) determination of N,N'-disubstituted imidazole-4,5-dicarboxamides.

N,N'-Disubstituted imidazole-4,5-dicarboxamides (I45DCs) form an intramolecular hydrogen bond worth an estimated 14 +/- 1 kcal/mol, as measured with a model structure in DMSO-d6 at 3 mM, thereby predisposing the molecular conformation to a folded rather than extended form. The I45DCs also show evidence of aggregation in both CDCl3 (>1 mM) and DMSO-d6 (>10 mM) solutions. These compounds are uncharacteristically weak bases in comparison with imidazoles bearing similar electron-withdrawing groups.

Hydrogen Bonding↗

PubMed2004

Synthesis of symmetric bis(imidazole-4,5-dicarboxamides) substituted with amino acids.

A series of symmetric bis(imidazole-4,5-dicarboxamides) (bis-I45DCs) were prepared with amino acid esters and a variety of linker groups. The critical pyrazine intermediates, substituted with amino acid esters, were synthesized by stoichiometric control of the amino acid ester, even though primary alkanamines, in comparison, generally offer less selectivity for this reaction. Diamines are added to subsequently react with and open the remaining acyl imidazole bonds in the pyrazine intermediates and thereby yield the bis-I45DCs.

Amides↗

PubMed2004

Expected and unexpected results from combined beta-hairpin design elements.

A model beta-hairpin dodecapeptide [EFGWVpGKWTIK] was designed by including a favorable D-ProGly Type II' beta-turn sequence and a Trp-zip interaction, while also incorporating a beta-strand unfavorable glycine residue in the N-terminal strand. This peptide is highly folded and monomeric in aqueous solution as determined by combined analysis with circular dichroism and 1H NMR spectroscopy. A peptide representing the folded conformation of the model beta-hairpin [cyclic(EFGWVpGKWTIKpG)] and a linear peptide representing the unfolded conformation [EFGWVPGKWTIK] yield unexpected relative deviations between the CD and 1H NMR spectroscopic results that are attributed to variations in the packing interactions of the aromatic side chains. Mutational analysis of the model beta-hairpin indicates that the Trp-zip interaction favors folding and stability relative to an alternate hydrophobic cluster between Trp and Tyr residues [EFGYVpGKWTIK]. The significance of select diagonal interactions in the model beta-hairpin was tested by rearranging the cross-strand hydrophobic interactions to provide a folded peptide [EWFGIpGKTYWK] displaying evidence of an unusual backbone conformation at the hydrophobic cluster. This unusual conformation does not appear to be a result of the glycine residue in the beta-strand, as replacement with a serine results in a peptide [EWFSIpGKTYWK] with a similar and seemingly characteristic CD spectrum. However, an alternate arrangement of hydrophobic residues with a Trp-zip interaction in a similar position to the parent beta-hairpin [EGFWVpGKWITK] results in a folded beta-hairpin conformation. The differences between side chain packing of these peptides precludes meaningful thermodynamic analysis and illustrates the caution necessary when interpreting beta-hairpin folding thermodynamics that are driven, at least in part, by aromatic cross strand interactions.

Circular Dichroism↗

PubMed2003

Small molecule inhibition of hepatitis C virus E2 binding to CD81.

The hepatitis C virus (HCV) is a causal agent of chronic liver infection, cirrhosis, and hepatocellular carcinoma infecting more than 170 million people. CD81 is a receptor for HCV envelope glycoprotein E2. Although the binding of HCV-E2 with CD81 is well documented the role of this interaction in the viral life cycle remains unclear. Host specificity and mutagenesis studies suggest that the helix D region of CD81 mediates binding to HCV-E2. Structural analysis of CD81 has enabled the synthesis of small molecules designed to mimic the space and hydrophobic features of the solvent-exposed face on helix D. Utilizing a novel bis-imidazole scaffold a series of over 100 compounds has been synthesized. Seven related, imidazole-based compounds were identified that inhibit binding of HCV-E2 to CD81. The inhibitory compounds have no short-term effect on cellular expression of CD81 or other tetraspanins, do not disrupt CD81 associations with other cell surface proteins, and bind reversibly to HCV-E2. These results provide an important proof of concept that CD81-based mimics can disrupt binding of HCV-E2 to CD81.

Aminoimidazole Carboxamide↗

PubMed2002

An improved method for the synthesis of dissymmetric N,N'-disubstituted imidazole-4,5-dicarboxamides.

Symmetrically and dissymmetrically disubstituted imidazole-4,5-dicarboxamides (I45DCs) have diverse bioactivities and therefore represent useful small molecules for lead structure identification in drug discovery. For this reason, an improved synthesis was developed as a first step in the preparation of greater numbers of analogues. The method involves the transformation of imidazole-4,5-dicarboxylic acid into dissymmetrically disubstituted I45DCs in four steps and in a minimum yield of 51%. This reflects an overall reduction of one synthetic step and a greater than 30% improvement in yield over the known method.

Amides↗

PubMed2002

Solution and solid-state models of peptide CH...O hydrogen bonds.

Fumaramide derivatives were analyzed in solution by (1)H NMR spectroscopy and in the solid state by X-ray crystallography in order to characterize the formation of CH...O interactions under each condition and to thereby serve as models for these interactions in peptide and protein structure. Solutions of fumaramides at 10 mM in CDCl(3) were titrated with DMSO-d(6), resulting in chemical shifts that moved downfield for the CH groups thought to participate in CH...O=S(CD(3))(2) hydrogen bonds concurrent with NH...O=S(CD(3))(2) hydrogen bonding. In this model, nonparticipating CH groups under the same conditions showed no significant change in chemical shifts between 0.0 and 1.0 M DMSO-d(6) and then moved upfield at higher DMSO-d(6) concentrations. At concentrations above 1.0 M DMSO-d(6), the directed CH...O=S(CD(3))(2) hydrogen bonds provide protection from random DMSO-d(6) contact and prevent the chemical shifts for participating CH groups from moving upfield beyond the original value observed in CDCl(3). X-ray crystal structures identified CH...O=C hydrogen bonds alongside intermolecular NH...O=C hydrogen bonding, a result that supports the solution (1)H NMR spectroscopy results. The solution and solid-state data therefore both provide evidence for the presence of CH...O hydrogen bonds formed concurrent with NH...O hydrogen bonding in these structures. The CH...O=C hydrogen bonds in the X-ray crystal structures are similar to those described for antiparallel beta-sheet structure observed in protein X-ray crystal structures.

Amides↗