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Synthesis and evaluation of small molecule DNA-interactive compounds : total synthesis of (±)-NNN-5'-acetate, synthesis of skipped benzimidazolium aza-enediynes, and synthesis of a series of C2-aryl UK-1 analogs
textSmall-molecule DNA interactive compounds are critical as both carcinogens and therapeutic agents. In this research, a synthetic precursor to a known carcinogen, (±)-Nâ-nitrosonicotine-5â-acetate was synthesized, and its interactions with DNA were evaluated by polyacrylamide gel electrophoresis and electrospray-ionization mass spectrometry. A library of skipped benzimidazolium aza-enediynes which selectively target unmethylated cytosines in presence of unmethylated cytosines were synthesized, and their biological properties were evaluated in a nicking assay and cytotoxicity study. Finally, a series of structural analogs to a antineoplastic agent, UK-1, were synthesized via a biaryl coupling at C2 on the benzoxazole.Chemistry and Biochemistr
In Vitro and In Vivo Activities of Three Oxazolidinones against Nonreplicating Mycobacterium tuberculosis
Oxazolidinones represent a new class of antituberculosis drugs that exert their function by inhibiting protein synthesis. Here, we compared the activities of three oxazolidinones, linezolid, PNU-100480, and AZD5847, against latent tuberculosis using a simple model employing the streptomycin-starved Mycobacterium tuberculosis strain 18b. The in vitro drug susceptibility results showed that the three oxazolidinones had a bacteriostatic effect against actively growing bacilli but potent bactericidal activity against nonreplicating cells. In the murine model of latent infection with M. tuberculosis 18b, the efficacy of the three compounds varied greatly. Indeed, AZD5847 or its prodrug exhibited no activity or only modest activity, respectively, after 2 months of treatment, whereas both linezolid and PNU-100480 were effective against latent bacilli in mice and showed promising outcomes in combination therapy with rifampin. Moreover, the potency of PNU-100480 was significantly greater than that of linezolid, making it an attractive drug candidate in the development of new combination therapies for latent tuberculosis
Prediction of drug penetration in tuberculosis lesions
The
penetration of antibiotics in necrotic tuberculosis lesions is heterogeneous
and drug-specific, but the factors underlying such differential partitioning
are unknown. We hypothesized that drug binding to macromolecules in
necrotic foci (or caseum) prevents passive drug diffusion through
avascular caseum, a critical site of infection. Using a caseum binding
assay and MALDI mass spectrometry imaging of tuberculosis drugs, we
showed that binding to caseum inversely correlates with passive diffusion
into the necrotic core. We developed a high-throughput assay relying
on rapid equilibrium dialysis and a caseum surrogate designed to mimic
the composition of native caseum. A set of 279 compounds was profiled
in this assay to generate a large data set and explore the physicochemical
drivers of free diffusion into caseum. Principle component analysis
and modeling of the data set delivered an in silico signature predictive
of caseum binding, combining 69 molecular descriptors. Among the major
positive drivers of binding were high lipophilicity and poor solubility.
Determinants of molecular shape such as the number of rings, particularly
aromatic rings, number of sp<sup>2</sup> carbon counts, and volume-to-surface
ratio negatively correlated with the free fraction, indicating that
low-molecular-weight nonflat compounds are more likely to exhibit
low caseum binding properties and diffuse effectively through caseum.
To provide simple guidance in the property-based design of new compounds,
a rule of thumb was derived whereby the sum of the hydrophobicity
(clogP) and aromatic ring
count is proportional to caseum binding. These tools can be used to
ensure desirable lesion partitioning and guide the selection of optimal
regimens against tuberculosis
Correction to Absolute Quantitative MALDI Imaging Mass Spectrometry: A Case of Rifampicin in Liver Tissues
Absolute Quantitative MALDI Imaging Mass Spectrometry: A Case of Rifampicin in Liver Tissues
Absolute Quantitative MALDI Imaging Mass Spectrometry: A Case of Rifampicin in Liver Tissues
Matrix-assisted laser
desorption/ionization (MALDI) imaging mass
spectrometry (IMS) elucidates molecular distributions in thin tissue
sections. Absolute pixel-to-pixel quantitation has remained a challenge,
primarily lacking validation of the appropriate analytical methods.
In the present work, isotopically labeled internal standards are applied
to tissue sections to maximize quantitative reproducibility and yield
accurate quantitative results. We have developed a tissue model for
rifampicin (RIF), an antibiotic used to treat tuberculosis, and have
tested different methods of applying an isotopically labeled internal
standard for MALDI IMS analysis. The application of the standard and
subsequently the matrix onto tissue sections resulted in quantitation
that was not statistically significantly different from results obtained
using HPLC-MS/MS of tissue extracts. Quantitative IMS experiments
were performed on liver tissue from an animal dosed <i>in vivo</i>. Each microspot in the quantitative images measures the local concentration
of RIF in the thin tissue section. Lower concentrations were detected
from the blood vessels and around the portal tracts. The quantitative
values obtained from these measurements were comparable (>90% similarity)
to HPLC-MS/MS results obtained from extracts of the same tissue
Design and evaluation of [\ub9\u2078F]CHDI-650 as a positron emission tomography ligand to image mutant Huntingtin aggregates
Design and evaluation of [18F]CHDI-650 as a positron emission tomography ligand to image mutant huntingtin aggregates
Therapeutic interventions are being developed for Huntington's disease (HD), a hallmark of which is mutant huntingtin protein (mHTT) aggregates. Following the advancement to human testing of two [11C]-PET ligands for aggregated mHTT, attributes for further optimization were identified. We replaced the pyridazinone ring of CHDI-180 with a pyrimidine ring and minimized off-target binding using brain homogenate derived from Alzheimer's disease patients. The major in vivo metabolic pathway via aldehyde oxidase was blocked with a 2-methyl group on the pyrimidine ring. A strategically placed ring-nitrogen on the benzoxazole core ensured high free fraction in the brain without introducing efflux. Replacing a methoxy pendant with a fluoro-ethoxy group and introducing deuterium atoms suppressed oxidative defluorination and accumulation of [18F]-signal in bones. The resulting PET ligand, CHDI-650, shows a rapid brain uptake and washout profile in non-human primates and is now being advanced to human testing