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4 results on '"Stephan Ohnmacht"'

1. Xanthene and Xanthone Derivatives as G-Quadruplex Stabilizing Ligands

Author

Alessandro Altieri, Antonello Alvino, Stephan Ohnmacht, Giancarlo Ortaggi, Stephen Neidle, Daniele Nocioni, Marco Franceschin, and Armandodoriano Bianco

Subjects
G-quadruplex, xanthene, xanthone, ESI-MS, FRET, telomere, c-myc, bcl-2, Organic chemistry, QD241-441
Abstract

Following previous studies on anthraquinone and acridine-based G-quadruplex ligands, here we present a study of similar aromatic cores, with the specific aim of increasing G-quadruplex binding and selectivity with respect to duplex DNA. Synthesized compounds include two and three-side chain xanthone and xanthene derivatives, as well as a dimeric “bridged” form. ESI and FRET measurements suggest that all the studied molecules are good G-quadruplex ligands, both at telomeres and on G-quadruplex forming sequences of oncogene promoters. The dimeric compound and the three-side chain xanthone derivative have been shown to represent the best compounds emerging from the different series of ligands presented here, having also high selectivity for G-quadruplex structures with respect to duplex DNA. Molecular modeling simulations are in broad agreement with the experimental data.

Published
2013
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4. Inhibition of oxidative metabolism of tocopherols with ω-N-heterocyclic derivatives of vitamin E

Author

Ryan West, Phillip Nava, Jeffrey Atkinson, Stephan Ohnmacht, and Robert S. Parker

Subjects
Magnetic Resonance Spectroscopy, medicine.medical_treatment, Clinical Biochemistry, Pharmaceutical Science, Tocopherols, Biochemistry, Article, Mass Spectrometry, Cell Line, Mixed Function Oxygenases, chemistry.chemical_compound, Mice, Non-competitive inhibition, Cytochrome P-450 Enzyme System, Drug Discovery, medicine, Animals, Bile, Cytochrome P-450 Enzyme Inhibitors, Humans, Vitamin E, heterocyclic compounds, Tocopherol, Molecular Biology, Unspecific monooxygenase, biology, Tocotrienols, Organic Chemistry, Cytochrome P450, food and beverages, Metabolism, Monooxygenase, Triazoles, chemistry, Liver, biology.protein, Molecular Medicine, lipids (amino acids, peptides, and proteins), Benzimidazoles, Tocotrienol
Abstract

The oxidative metabolism of tocopherols and tocotrienols by monooxygenases is a key factor in the plasma and tissue clearance of forms of vitamin E other than alpha-tocopherol. It is well known that a commonly ingested form of vitamin E, gamma-tocopherol, has greatly reduced plasma half-life (faster clearance) than alpha-tocopherol. The tocotrienols are metabolized even faster than gamma-tocopherol. Both gamma-tocopherol and alpha- and delta-tocotrienol possess intriguing biological activities that are different from alpha-tocopherol, making them potentially of interest for therapeutic use. Unfortunately, the fast clearance of non-alpha-tocopherols from animal tissues is a significant hurdle to maximizing their effect(s) as dietary supplements. We report here the design and synthesis of N-heterocycle-containing analogues of alpha-tocopherol that act as inhibitors of Cyp4F2, the key monooxygenase responsible for omega-hydroxylation of the side chain of tocols. In particular, an omega-imidazole containing compound, 1, [(R)-2-(9-(1H-imidazol-1-yl)nonyl)-2,5,7,8-tetramethylchroman-6-ol] had an ED(50) for inhibition of gamma-CEHC production from gamma-tocopherol of approximately 1 nM when tested in HepG2 cells in culture. Furthermore, feeding of 1 to mice along with rapidly metabolized delta-tocopherol, resulted in a doubling of the delta-tocopherol/alpha-tocopherol ratio in liver (P

Published
2008

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