Exploration of imatinib and nilotinib-derived templates as the P2-Ligand for HIV-1 protease inhibitors: Design, synthesis, protein X-ray structural studies, and biological evaluation.

Structure-based design, synthesis, X-ray structural studies, and biological evaluation of a new series of potent HIV-1 protease inhibitors are described. These inhibitors contain various pyridyl-pyrimidine, aryl thiazole or alkylthiazole derivatives as the P2 ligands in combination with darunavir-like hydroxyethylamine sulfonamide isosteres. These heterocyclic ligands are inherent to kinase inhibitor drugs, such as nilotinib and imatinib. These ligands are designed to make hydrogen bonding interactions with the backbone atoms in the S2 subsite of HIV-1 protease. Various benzoic acid derivatives have been synthesized and incorporation of these ligands provided potent inhibitors that exhibited subnanomolar level protease inhibitory activity and low nanomolar level antiviral activity. Two high resolution X-ray structures of inhibitor-bound HIV-1 protease were determined. These structures provided important ligand-binding site interactions for further optimization of this class of protease inhibitors.

Synthesis and Stereochemical Assignment of Conioidine A: DNA- and HSA-Binding Studies of the Four Diastereomers.

Conioidine A (1), isolated in 1993 with unknown relative and absolute configuration, was suggested to be a DNA-binding compound by an indirect technique. Four stereoisomers of conioidine A have been synthesized from d- and l-proline, and the natural product has been identified as possessing (4R,6R) absolute configuration. Binding of the conioidine diastereomers to calf thymus DNA (CT DNA) and human serum albumin (HSA) has been investigated by fluorescence spectroscopy and isothermal titration calorimetry (ITC). All stereoisomers display at least an order of magnitude weaker binding to DNA than the control compound netropsin; however, a strong association with HSA was observed for the (4R,6S) stereoisomer.

Total Synthesis of Alvaradoins E and F, Uveoside, and 10-epi-Uveoside.

Concise total syntheses of the anthracenone C-glycosides alvaradoins E and F, uveoside, and 10-epi-uveoside (1-4) have been accomplished from chrysophanic acid 8 and bromosugar 9. Key steps in the syntheses include the DBU-induced coupling of 8 and 9 to produce ß-C-glycoside 11, and a Pb(OAc)4-mediated Kochi reaction to introduce the C-1' oxygen atom of the natural products. Isothermal titration calorimetry and fluorescence binding studies reveal that compounds 1 and 2 have good affinity for the plasma protein HSA.

Synthesis and DNA binding profile of monomeric, dimeric, and trimeric derivatives of crystal violet.

Monomeric, dimeric, and trimeric derivatives of the triphenylmethane dye crystal violet (1a-1f) have been synthesized for the purpose of evaluating their affinity and sequence selectivity for duplex DNA. Competitive ethidum displacement assays indicate that 1a-1f have apparent association constants for CT DNA in the range of 1.80-16.2 × 107 M-1 and binding site sizes of 10-14 bp. Viscosity experiments performed on ligand 1f confirmed that these dyes associate with duplex DNA by a non-intercalative mode of binding. Circular dichroism and competition binding studies of the tightest binding ligand 1e with known major and minor groove binding molecules suggest that these dye derivatives likely occupy the major groove of DNA. Data from the binding of 1e to polynucleotides indicate close to an order of magnitude preference for associating with AT rich homopolymers over GC rich homopolymers, suggesting a shape-selective match of the sterically bulky ligand with DNA containing a wider major groove.