Orally Active MMP-1 Sparing α-tetrahydropyranyl and α-piperidinyl Sulfone Matrix Metalloproteinase (MMP) Inhibitors with Efficacy in Cancer, Arthritis, and Cardiovascular Disease

α-Sulfone-α-piperidine and α-tetrahydropyranyl hydroxamates were explored that are potent inhibitors of MMP’s-2, -9, and -13 that spare MMP-1, with oral efficacy in inhibiting tumor growth in mice and left-ventricular hypertrophy in rats and in the bovine cartilage degradation ex vivo explant system. α-Piperidine 19v (SC-78080/SD-2590) was selected for development toward the initial indication of cancer, while α-piperidine and α-tetrahydropyranyl hydroxamates 19w (SC-77964) and 9i (SC-77774), respectively, were identified as backup compounds

MMP-13 Selective α-sulfone Hydroxamates: a Survey of P1\u27 Heterocyclic Amide Isosteres

Seeking compounds preferentially potent and selective for MMP-13, we reported in the preceding Letter on a series of hydroxamic acids with a flexible benzamide tail groups.(1a) Here, we replace the amide moiety with non-hydrolyzable heterocycles in an effort to improve half-life. We identify a hydroxamate tetrazole 4e that spares MMP-1 and -14, shows \u3e400-fold selectivity versus MMP-8 and \u3e600-fold selectivity versus MMP-2, and has a 4.8 h half-life in rats. X-ray data (1.9 Å) for tetrazole 4c is presented

MMP-13 Selective Alpha-sulfone Hydroxamates: Identification of Selective P1\u27 Amides

Continuing our interest in designing compounds preferentially potent and selective for MMP-13, we report on a series of hydroxamic acids with a flexible amide P1\u27 substituents. We identify an amide which spares both MMP-1 and -14, and shows \u3e500 fold selectivity for MMP-13 versus MMP-2 and -8

Quantitative diffusion tensor MR imaging of the brain: field strength related variance of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) scalars

The objectives were to study the "impact” of the magnetic field strength on diffusion tensor imaging (DTI) metrics and also to determine whether magnetic-field-related differences in T2-relaxation times of brain tissue influence DTI measurements. DTI was performed on 12 healthy volunteers at 1.5 and 3.0 Tesla (within 2 h) using identical DTI scan parameters. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values were measured at multiple gray and white matter locations. ADC and FA values were compared and analyzed for statistically significant differences. In addition, DTI measurements were performed at different echo times (TE) for both field strengths. ADC values for gray and white matter were statistically significantly lower at 3.0 Tesla compared with 1.5 Tesla (% change between −1.94% and −9.79%). FA values were statistically significantly higher at 3.0 Tesla compared with 1.5 Tesla (% change between +4.04 and 11.15%). ADC and FA values are not significantly different for TE=91ms and TE=125ms. Thus, ADC and FA values vary with the used field strength. Comparative clinical studies using ADC or FA values should consequently compare ADC or FA results with normative ADC or FA values that have been determined for the field strength use

A molecular motor from lignocellulose

Lignin is the largest natural source of functionalized aromatics on the planet, therefore exploiting its inherent structural features for the synthesis of aromatic products is a timely and ambitious goal. While the recently developed lignin depolymerization strategies gave rise to well-defined aromatic platform chemicals, the diversification of these structures, especially toward high-end applications is still poorly addressed. Molecular motors and switches have found widespread application in many important areas such as targeted drug delivery systems, responsive coatings for self-healing surfaces, paints and resins or muscles for soft robotics. They typically comprise a functionalized aromatic backbone, yet their synthesis from lignin has not been considered before. In this contribution, we showcase the synthesis of a novel light-driven unidirectional molecular motor from the specific aromatic platform chemical 4-(3-hydroxypropyl)-2,6-dimethoxyphenol (dihydrosynapyl alcohol) that can be directly obtained from lignocellulose via a reductive catalytic fractionation strategy. The synthetic path takes into account the principles of green chemistry and aims to maintain the intrinsic functionality of the lignin-derived platform molecule

Structural and Biochemical Characterization of Chlamydia trachomatis Hypothetical Protein CT263 Supports That Menaquinone Synthesis Occurs through the Futalosine Pathway

BACKGROUND: Specific pathways and components for respiration in Chlamydia are poorly understood. RESULTS: The C. trachomatis hypothetical protein CT263 crystal structure displays strong structural similarity with 5′-methylthioadenosine nucleosidase enzymes. CONCLUSION: Bioinformatic analyses and enzymatic characterization of CT263 suggest menaquinone biosynthesis proceeds through the futalosine pathway in Chlamydiaceae. SIGNIFICANCE: Unique structural aspects of the CT263 active site can be leveraged to modify existing transition state inhibitors

The Forum: Fall 2006/Spring 2007

Fall 2006 / Spring 2007 journal of the Honors Program at the University of North Dakota. The issue includes stories, poems, essays and art by undergraduate students.https://commons.und.edu/und-books/1060/thumbnail.jp

α-Amino-β-sulphone hydroxamates as potent MMP-13 inhibitors that spare MMP-1

A series of α-amino-β-sulphone hydroxamates was prepared and evaluated for potency versus MMP-13 and selectivity versus MMP-1. Various substituents were employed on the α-amino group (P1 position), as well as different groups attached to the sulphone group extending into P1′. Low nanomolar potency was obtained for MMP-13 with selectivity versus MMP-1 of \u3e1000× for a number of analogues. α-Amino-β-sulphone hydroxamates were prepared, which are potent MMP-13 inhibitors with selectivity versus MMP-1 of \u3e1000× for a number of analogues. Selected compounds exhibited oral bioavailability