Observation of Ɛ-AlKeggin-oligonucleotide complexes in analytical sample solutions.

Complexes formed between aluminum cluster molecules that adopt a Ɛ-Al-Keggin structure and antisense oligonucleotides were observed as new impurity peaks during drug product stability testing. The Ɛ-Al-Keggin molecules were determined to be artifacts of the analysis, originating from contact between antisense oligonucleotide drug product solution and aluminum weigh boats used to prepare the analytical sample solutions. The presence of the Ɛ-Al-Keggin molecules was confirmed through synthesis of the Keggin molecule through an established route and subsequent spiking studies.

Extemporaneous preparation strategy for early phase clinical studies.

Extemporaneous preparations (EPs) of investigational drugs, which are compounded at the clinical study site by a pharmacist, are being increasingly used in early phase clinical studies to accelerate the development of new medicines. The successful application of EP strategies in clinical studies requires 'fit-for-purpose' formulation design and preparation processes, as well as administration procedures that are safe, flexible, cost-effective, and simple to adapt by a compounding pharmacist at the clinical site. DNS-7801 is a weakly basic investigational compound that exhibits a higher aqueous solubility at lower pH with its solubility dropping off precipitously with increase in pH.

Gelatin and Non-Gelatin Capsule Dosage Forms.

Capsules offer an alternate to tablets for oral delivery of therapeutic compounds. One advantage of capsules over tablets is their amenability to deliver not only solids but also nonaqueous liquids and semisolids as a unit dose solid dosage form. Shell component is an essential part of capsule dosage forms.

Polyethylene glycols in oral and parenteral formulations--A critical review.

Polyethylene glycols (PEGs) are frequently employed as vehicles in oral and parenteral dosage forms. PEGs have low toxicity, are miscible with aqueous fluids in all proportions, and dissolve many poorly aqueous soluble compounds. Compounds with poor aqueous solubility and resulting poor bioavailability and considerable individual variability in the absorption were shown to provide exceptionally high bioavailability and reduced inter-subject variability in plasma concentrations when dosed as solutions or suspensions in PEGs.

A systematic method for the targeted discovery of chemical attribution signatures: application to isopropyl bicyclophosphate production.

Potential attribution signatures for the synthesis of a highly toxic bicyclophosphate, 4-isopropyl-2,6,7-trioxa-1-phosphabicyclo[2.2.2]octane 1-oxide (Isopropyl Bicyclophosphate or IPBCP) were discovered using a trilateral synthetic, analytical, and statistical approach.

Gas-phase stability of G-quadruplex DNA determined by electrospray ionization tandem mass spectrometry and molecular dynamics simulations.

The relative gas-phase stabilities of seven quadruplex DNA structures, [d(TG(4)T)](4), [d(T(2)G(3)T)](4), [d(G(4)T(4)G(4))](2), [d(T(2)AG(3))(2)](2), d(T(2)AG(3))(4), d(T(2)G(4))(4), and d(G(2)T(4))(4), were investigated using molecular dynamics simulations and electrospray ionization mass spectrometry (ESI-MS). MD simulations revealed that the G-quadruplexes maintained their structures in the gas phase although the G-quartets were distorted to some degree and ammonium ions, retained by [d(TG(4)T)](4) and [d(T(2)G(3)T)](4), played a key role in stabilizing the tetrad structure. Energy-variable collisional activated dissociation was used to assess the relative stabilities of each quadruplex based on E(1/2) values, and the resulting order of relative stabilities was found to be [d(TG(4)T)](4) >> d(T(2)AG(3))(4) approximately d(T(2)G(4))(4) > [d(T(2)G(3)T)](4) > [d(T(2)AG(3))(2)](2) approximately d(G(2)T(4))(4) approximately [d(G(4)T(4)G(4))](2.

Evaluation of metal-mediated DNA binding of benzoxazole ligands by electrospray ionization mass spectrometry.

The binding of a series of benzoxazole analogs with different amide- and ester-linked side chains to duplex DNA in the absence and presence of divalent metal cations is examined. All ligands were found to form complexes with Ni2+, Cu2+, and Zn2+, with 2:1 ligand/metal cation binding stoichiometries dominating for ligands containing shorter side chains (2, 6, 7, and 8), while 1:1 complexes were the most abundant for ligands with long side chains (9, 10, and 11). Ligand binding with duplex DNA in the absence of metal cations was assessed, and the long side-chain ligands were found to form low abundance complexes with 1:1 ligand/DNA binding stoichiometries.

Probing ligand binding to duplex DNA using KMnO4 reactions and electrospray ionization tandem mass spectrometry.

An electrospray ionization tandem mass spectrometry (ESI-MS/MS) strategy employing the thymine-selective KMnO4 oxidation reaction to detect conformational changes and ligand binding sites in noncovalent DNA/drug complexes is reported. ESI-MS/MS is used to detect specific mass shifts of the DNA ions that are associated with the oxidation of thymines. This KMnO4 oxidation/ESI-MS/MS approach is an alternative to conventional gel-based oxidation methods and affords excellent sensitivity while eliminating the reliance on radiolabeled DNA.

Screening of threading bis-intercalators binding to duplex DNA by electrospray ionization tandem mass spectrometry.

The DNA binding of novel threading bis-intercalators V1, trans-D1, and cis-C1, which contain two naphthalene diimide (NDI) intercalation units connected by a scaffold, was evaluated using electrospray ionization mass spectrometry (ESI-MS) and DNAse footprinting techniques. ESI-MS experiments confirmed that V1, the ligand containing the -Gly3-Lys- peptide scaffold, binds to a DNA duplex containing the 5'-GGTACC-3' specific binding site identified in previous NMR-based studies. The ligand formed complexes with a ligand/DNA binding stoichiometry of 1:1, even when there was excess ligand in solution.

Investigation of silver binding to polyamidoamine (PAMAM) dendrimers by ESI tandem mass spectrometry.

Electrospray ionization tandem mass spectrometry (ESI-MS/MS) was used to probe the binding of silver ions and reduced silver species with polyamidoamine generation 1 amine-terminated (PAMAMG1NH2) and generation 2 hydroxyl-terminated (PAMAMG2OH) dendrimers. At Ag(+)/PAMAMG2OH molar ratios of 1, 2:1 and low abundance 3:1 complexes emerge. Similar results were observed for PAMAMG1NH2.

Evaluation of binding of perylene diimide and benzannulated perylene diimide ligands to DNA by electrospray ionization mass spectrometry.

Electrospray ionization mass spectrometry (ESI-MS) and spectroscopic studies in solution were used to evaluate the self-association, G-quadruplex DNA binding, and selectivity of a series of perylene diimides (PDIs) (PIPER, Tel01, Tel11, Tel12, and Tel18) or benzannulated perylene diimide ligands (Tel34 and Tel32). Fluorescence and resonance light scattering spectra of Tel01, Tel12, Tel32, and Tel34 reveal that these analogs undergo self-association in solution. UV-Vis and fluorescence titrations with G-quadruplex, duplex, or single-stranded DNA demonstrate that all the analogs, with the exception of Tel32, bind to G-quadruplex DNA, with those PDIs that are self-associated in solution showing the highest degree of selectivity for binding G-quadruplex DNA.

Electrochemical, spectroscopic, and mass spectrometric studies of the interaction of silver species with polyamidoamine dendrimers.

Electrochemical, spectroscopic, and mass spectrometric (MS) methods were used to probe the interaction (complexation) of silver ions and zerovalent silver species with polyamidoamine generation 1 amine-terminated (PAMAMG1NH2) and generation 2 hydroxy-terminated (PAMAMG2OH) dendrimers (DDMs). Stability constants (Kq+) and stoichiometries (q) (i.e.

Duplex and quadruplex DNA binding and photocleavage by trioxatriangulenium ion.

The stable trioxatriangulenium ion (TOTA) has previously been shown to bind to and photooxidize duplex DNA, leading to cleavage at G residues, particularly 5'-GG-3' repeats. Telomeric DNA consists of G-rich sequences that may exist in either duplex or G-quadruplex forms. We have employed electrospray ionization mass spectrometry (ESI-MS) to investigate the interactions between TOTA and duplex DNA or G-quadruplex DNA.

Evaluation of complexes of DNA duplexes and novel benzoxazoles or benzimidazoles by electrospray ionization mass spectrometry.

Electrospray ionization mass spectrometry is used to compare the metal ion binding and metal-mediated DNA binding of benzoxazole (1, 2, 3, 4) and benzimidazole (5) compounds and to elucidate the putative binding modes and stoichiometries. The observed metal versus non-metal-mediated DNA binding, as well as the specificity of DNA binding, is correlated with the biological activities of the analogs. The ESI-MS spectra for the antibacterial benzoxazole and benzimidazole analogs 4 and 5 demonstrated non-specific and non-metal-mediated binding to DNA, with the appearance of DNA complexes containing multiple ligands.

HPLC of monolayer-protected gold nanoclusters.

Polydisperse samples of Au nanoparticles protected with monolayers of hexanethiolate ligands (C6 MPCs) and with mixed monolayers of hexanethiolate and mercaptoundecanoic acid (C6/MUA MPCs) have been chromatographically separated using C8 120-A columns and acetone/ toluene mobile phase. The spectral details of eluted peaks and of quantized double-layer charging features in the differential pulse voltammetry of collected fractions were used to show that the elution orders of C6 MPC mixtures and of C6/MUA MPC mixtures were different. For C6 MPCs, the smallest MPCs were eluted first, whereas the smallest C6/MUA MPCs were eluted last.