A5058327282- Cancer Treatment and Pharmacology
- Synthetic Organic Chemistry Methods
- Microbial Natural Products and Biosynthesis
- Chemical Synthesis and Analysis
- Microtubule and mitosis dynamics
- DNA and Nucleic Acid Chemistry
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Advanced Synthetic Organic Chemistry
- Marine Sponges and Natural Products
- Advanced biosensing and bioanalysis techniques
- Chemical synthesis and alkaloids
- Carbohydrate Chemistry and Synthesis
- RNA and protein synthesis mechanisms
- 14-3-3 protein interactions
- Phytochemistry and Bioactive Compounds
- Cancer therapeutics and mechanisms
- Drug Transport and Resistance Mechanisms
- Click Chemistry and Applications
- HIV/AIDS drug development and treatment
- HER2/EGFR in Cancer Research
- Cannabis and Cannabinoid Research
- Mycobacterium research and diagnosis
- Supramolecular Self-Assembly in Materials
- Crystallography and molecular interactions
ETH Zurich
2016-2025
University of Bern
2010-2020
HCL Technologies (India)
2020
Board of the Swiss Federal Institutes of Technology
2011-2015
École Polytechnique Fédérale de Lausanne
2005-2015
University of Lausanne
1990-2009
Novartis (Switzerland)
1999-2009
Bayer (Germany)
2009
Granta Design (United Kingdom)
2009
University of Geneva
2009
The psychoactive cannabinoids from Cannabis sativa L. and the arachidonic acid-derived endocannabinoids are nonselective natural ligands for cannabinoid receptor type 1 (CB(1)) CB(2) receptors. Although CB(1) is responsible psychomodulatory effects, activation of a potential therapeutic strategy treatment inflammation, pain, atherosclerosis, osteoporosis. Here, we report that widespread plant volatile (E)-beta-caryophyllene [(E)-BCP] selectively binds to (K(i) = 155 +/- 4 nM) it functional...
Microtubule-stabilizing agents (MSAs) are efficacious chemotherapeutic drugs widely used for the treatment of cancer. Despite importance MSAs medical applications and basic research, their molecular mechanisms action on tubulin microtubules remain elusive. We determined high-resolution crystal structures αβ-tubulin in complex with two unrelated MSAs, zampanolide epothilone A. Both compounds were bound to taxane pocket β-tubulin respective side chains induce structuring M-loop into a short...
Significance Microtubules are dynamic protein filaments assembled from tubulin subunits, which play a key role for cell division. Ligands that target microtubules and affect their dynamics belong to the most successful classes of chemotherapeutic drugs against cancer by inhibiting proliferation. Here we have analyzed three structurally unrelated destabilize microtubules, using X-ray crystallography. The data reveal new tubulin-binding site these drugs, renders mechanism action distinct other...
Alkylamides (alkamides) from Echinacea modulate tumor necrosis factor α mRNA expression in human monocytes/macrophages via the cannabinoid type 2 (CB2) receptor (Gertsch, J., Schoop, R., Kuenzle, U., and Suter, A. (2004) FEBS Lett. 577, 563–569). Here we show that alkylamides dodeca-2E,4E,8Z,10Z-tetraenoic acid isobutylamide (A1) dodeca-2E,4E-dienoic (A2) bind to CB2 more strongly than endogenous cannabinoids. The Ki values of A1 A2 (CB2 ∼60 nm;CB1 >1500 nm) were determined by displacement...
The sprouting of new blood vessels, or angiogenesis, is necessary for any solid tumor to grow large enough cause life-threatening disease. Vascular endothelial growth factor (VEGF) one the key promoters induced angiogenesis. VEGF receptors, tyrosine kinases Flt-1 and KDR, are expressed on vascular cells initiate angiogenesis upon activation by VEGF. 1-Anilino-(4-pyridylmethyl)-phthalazines, such as CGP 79787D (or PTK787 / ZK222584), reversibly inhibit KDR with IC(50) values < 0.1 microM....
Abstract Laulimalide and peloruside A are microtubule‐stabilizing agents (MSAs), the mechanism of action on microtubules which is poorly defined. Here, using X‐ray crystallography it shown that laulimalide bind to a unique non‐taxane site β‐tubulin use their respective macrolide core structures interact with second tubulin dimer across protofilaments. At same time, they allosterically stabilize taxane‐site M‐loop establishes lateral contacts in microtubules. Structures ternary complexes...
All cellular RNA polymerases (RNAPs), from those of bacteria to man, possess a clamp that can open and close, it has been assumed the RNAP separates promoter DNA strands then closes establish tight grip on template. Here, we resolve successive motions initiating bacterial by studying real-time signatures fluorescent reporters placed in presence ligands locking distinct conformations. We report evidence for an unexpected obligatory step early initiation involving transient closure as...
Significance Suitable chemical tools have been instrumental in the discovery and characterization of endocannabinoid system. However, lack potent selective inhibitors for transport has prevented molecular this process. Current uptake are poorly bioavailable to central nervous system (CNS) weakly because they also inhibit fatty acid amide hydrolase (FAAH), major anandamide-degrading enzyme. Few studies addressed inhibition 2-arachidonoyl glycerol (2-AG), which is endocannabinoid. Here, we...
The L-type amino acid transporter 1 (LAT1/SLC7A5) transports essential acids across the plasma membrane. While LAT1 is overexpressed in a variety of human neoplasms, its expression and role thyroid cancer currently unknown. Anaplastic carcinoma (ATC) highly aggressive malignancy for which no effective therapy exists. purpose this study was to explore whether inhibition ATC would affect tumor growth both vitro vivo. pharmacologically blocked by JPH203 papillary (PTC) cell lines. effects on...
Abstract LAT1 (SLC7A5) is one of the representative light chain proteins heteromeric amino acid transporters, forming a heterodimer with its heavy partner 4F2hc (SLC3A2). overexpressed in many types tumors and mediates transfer drugs hormones across blood-brain barrier. Thus, considered as drug target for cancer treatment may be exploited delivery into brain. Here, we synthesized three potent inhibitors human LAT1, which inhibit transport leucine IC 50 values between 100 250 nM, solved...
Paclitaxel (Taxol) is a taxane and chemotherapeutic drug that stabilizes microtubules. While the interaction of paclitaxel with microtubules well described, lack high-resolution structural information on tubulin-taxane complex precludes comprehensive description binding determinants affect its mechanism action. Here, we solved crystal structure baccatin III core moiety paclitaxel-tubulin at 1.9 Å resolution. Based this information, engineered taxanes modified C13 side chains, their...
The design, chemical synthesis, and biological evaluation of a series cyclopropyl cyclobutyl epothilone analogues (3−12, Figure 1) are described. synthetic strategies toward these epothilones involved Nozaki−Hiyama−Kishi coupling to form the C15−C16 carbon−carbon bond, an aldol reaction construct C6−C7 Yamaguchi macrolactonization complete required skeletal framework. Biological studies with synthesized compounds led identification 3, 4, 7, 8, 9, 11 as potent tubulin polymerization promoters...
From efforts to improve the biophysical properties of antisense oligonucleotides by incorporating backbone- or sugar-modified nucleoside analogs, 2'-O-methoxyethyl ribonucleosides 8b were identified as building blocks for a second generation oligonucleotides. Compounds containing these modifications demonstrated combine benefit high binding affinity RNA complement with large increase in nuclease resistance, allowing use regular phosphodiester linkages. Chimeric ribonucleosides, 8b, wings and...
To determine the mechanism of action responsible for in vivo antitumor activity a phosphorothioate antisense inhibitor targeted against human C- raf kinase (ISIS 5132, also known as CGP69846A), series mismatched analogs ISIS 5132 or CGP69846A were synthesized and characterized with respect to hybridization affinity, inhibitory effects on gene expression vitro , . Incorporation single mismatch into sequence resulted reduced affinity toward RNA sequences tumor growth Moreover, incorporation...
A focused collection of organic synthesis reactions for computer-based molecule construction is presented. It inspired by real-world chemistry and has been compiled in close collaboration with medicinal chemists to achieve high practical relevance. Virtual molecules assembled from existing starting material connected these are supposed have an enhanced chance be amenable real chemical synthesis. About 50% the dataset ring-forming reactions, which fosters assembly novel ring systems...