Cationic Peptides and their Cu(II) and Ni(II) Complexes: Coordination and Biological Characteristics

Antimicrobial peptides are a promising group of compounds used for the treatment of infections. In some cases, metal ions are essential to activate these molecules. Examples of metalloantibiotics are, for instance, bleomycin and dermcidin. This study is focused on three new pseudopeptides with potential biological activity. The coordination behavior of all ligands with Cu(II) and Ni(II) ions has been examined. Various analytical methods such as potentiometric titration, UV-Vis and CD spectroscopies, and mass spectrometry were used. All compounds are convenient chelators for metal ion-binding. Two of the ligands tested have histidine residues. Surprisingly, imidazole nitrogen is not involved in the coordination of the metal ion. The N-terminal amino group, Dab side chains, and amide nitrogen atoms of the peptide bonds coordinated Cu(II) and Ni(II) in all the complexes formed. The cytotoxicity of three pseudopeptides and their complexes was evaluated. Moreover, their other model allowed for assessing the attenuation of LPS-induced cytotoxicity and anti-inflammatory activities were also evaluated, the results of which revealed to be very promising.

Development of Chiral N-Alkoxyamide Strategy and Application to Asymmetric Total Synthesis of Fasicularin

The asymmetric total synthesis of fasicularin by a chiral N-alkoxyamide strategy is reported. Incorporation of the chiral alkoxy group to an amide nitrogen changes the original reactivity of the amide, enabling two key transformations: aza-spirocyclization and the reductive Strecker reaction. In the aza-spirocyclization, DFT calculations indicate that pyramidalization of the alkoxyamide nitrogen is crucial to control the reactivity. The chiral alkoxy group is also used as a stereocontrol element to establish two consecutive stereocenters. The iridium-catalyzed reductive Strecker reaction of the N-alkoxylactam provides the aminonitrile with high diastereoselectivity.

Influence of N-Methylation and Conformation on Almiramide Anti-Leishmanial Activity

The almiramide N-methylated lipopeptides exhibit promising activity against trypanosomatid parasites. A structure–activity relationship study has been performed to examine the influences of N-methylation and conformation on activity against various strains of leishmaniasis protozoan and on cytotoxicity. The synthesis and biological analysis of twenty-five analogs demonstrated that derivatives with a single methyl group on either the first or fifth residue amide nitrogen exhibited greater activity than the permethylated peptides and relatively high potency against resistant strains. Replacement of amino amide residues in the peptide, by turn inducing α‑amino γ‑lactam (Agl) and N-aminoimidazalone (Nai) counterparts, reduced typically anti-parasitic activity; however, peptide amides possessing Agl residues at the second residue retained significant potency in the unmethylated and permethylated series. Systematic study of the effects of methylation and turn geometry on anti-parasitic activity indicated the relevance of an extended conformer about the central residues, and conformational mobility by tertiary amide isomerization and turn geometry at the extremities of the active peptides.

Crystal structure of atazanavir, C38H52N6O7

The crystal structure of atazanavir has been solved and refined using synchrotron X-ray powder diffraction data and optimized using density functional techniques. Atazanavir crystallizes in space group P21 (#4) with a = 15.33545(7), b = 5.90396(3), c = 21.56949(13) Å, β = 96.2923(4)°, V = 1941.134(11) Å3, and Z = 2. Despite being labeled as “atazanavir sulfate”, the commercial reagent sample consisted of atazanavir free base. The structure consists of an array of extended-conformation molecules parallel to the ac-plane. Although the atazanavir molecule contains only four classical hydrogen bond donors, hydrogen bonding is, surprisingly, important to the crystal energy. Both intra- and intermolecular hydrogen bonds are significant. The hydroxyl group forms bifurcated intramolecular hydrogen bonds to a carbonyl oxygen atom and an amide nitrogen. Several amide nitrogens act as donors to the hydroxyl group and carbonyl oxygen atoms. An amide nitrogen acts as a donor to another amide nitrogen. Several methyl, methylene, methyne, and phenyl hydrogens participate in hydrogen bonds to carbonyl oxygens, an amide nitrogen, and the pyridine nitrogen. The powder pattern is included in the Powder Diffraction File™ as entry 00-065-1426.

Studies Towards Hypoxia-Activated Prodrugs of PARP Inhibitors

Poly(ADP-ribose)polymerase (PARP) inhibitors (PARPi) have recently been approved for the treatment of breast and ovarian tumors with defects in homologous recombination repair (HRR). Although it has been demonstrated that PARPi also sensitize HRR competent tumors to cytotoxic chemotherapies or radiotherapy, normal cell toxicity has remained an obstacle to their use in this context. Hypoxia-activated prodrugs (HAPs) provide a means to limit exposure of normal cells to active drug, thus adding a layer of tumor selectivity. We have investigated potential HAPs of model PARPi in which we attach a bioreducible “trigger” to the amide nitrogen, thereby blocking key binding interactions. A representative example showed promise in abrogating PARPi enzymatic activity in a biochemical assay, with a ca. 160-fold higher potency of benzyl phthalazinone 4 than the corresponding model HAP 5, but these N-alkylated compounds did not release the PARPi upon one-electron reduction by radiolysis. Therefore, we extended our investigation to include NU1025, a PARPi that contains a phenol distal to the core binding motif. The resulting 2-nitroimidazolyl ether provided modest abrogation of PARPi activity with a ca. seven-fold decrease in potency, but released the PARPi efficiently upon reduction. This investigation of potential prodrug approaches for PARPi has identified a useful prodrug strategy for future exploration.