Synthesis and Structure-Activity Relationships of 2,5-Dimethoxy-4-Substituted Phenethylamines and the Discovery of CYB210010: A Potent, Orally Bioavailable and Long-Acting Serotonin 5-HT2 Receptor Agonist.

Structure-activity studies of 4-substituted-2,5-dimethoxyphenethylamines led to the discovery of 2,5-dimethoxy-4-thiotrifluoromethylphenethylamines, including CYB210010, a potent and long-acting serotonin 5-HT2 receptor agonist. CYB210010 exhibited high agonist potency at 5-HT2A and 5-HT2C receptors, modest selectivity over 5-HT2B, 5-HT1A, 5-HT6, and adrenergic α2A receptors, and lacked activity at monoamine transporters and over 70 other proteins. CYB210010 (0.1-3 mg/kg) elicited a head-twitch response (HTR) and could be administered subchronically at threshold doses without behavioral tolerance. CYB210010 was orally bioavailable in three species, readily and preferentially crossed into the CNS, engaged frontal cortex 5-HT2A receptors, and increased the expression of genes involved in neuroplasticity in the frontal cortex. CYB210010 represents a new tool molecule for investigating the therapeutic potential of 5-HT2 receptor activation. In addition, several other compounds with high 5-HT2A receptor potency, yet with little or no HTR activity, were discovered, providing the groundwork for the development of nonpsychedelic 5-HT2A receptor ligands.

Isolation and biomimetic synthesis of phenylpropionyl phenylethylamines from Chloranthus henryi.

In this study, ten phenylpropionyl phenylethylamines, including five previously undescribed ones (1a/b, 2a/b, and 3), five known analogues (4-8), and two established phenylpropanoids precursors (9, 10) were isolated from the aerial parts of Chloranthus henryi Hemsl. Their structures, including absolute configurations, were determined by high-resolution mass spectrometry, enantio-separation, electronic circular dichroism calculation, and single crystal diffraction. Compounds 1a and 1b were the first examples of natural hetero-[2 + 2] cycloaddition products between phenylpropionyl phenylethylamine and phenylpropene. The plausible hetero-[2 + 2] biosynthesis pathway was confirmed by a photocatalytic biomimetic synthesis in eight steps, which also led to the production of three other potential natural homo-[2 + 2] adducts (1'a/b, 2', and 3'). Bioactivity screening indicated that these adducts bear medium inhibitory activity on nitric oxide generation, with IC50 values of 6-35 µM in RAW 264.7 macrophages.

25X-NBOMe compounds - chemistry, pharmacology and toxicology. A comprehensive review.

Recently, a growing number of reports have indicated a positive effect of hallucinogenic-based therapies in different neuropsychiatric disorders. However, hallucinogens belonging to the group of new psychoactive substances (NPS) may produce high toxicity. NPS, due to their multi-receptors affinity, are extremely dangerous for the human body and mental health. An example of hallucinogens that have been lately responsible for many severe intoxications and deaths are 25X-NBOMes - N-(2-methoxybenzyl)-2,5-dimethoxy-4-substituted phenethylamines, synthetic compounds with strong hallucinogenic properties. 25X-NBOMes exhibit a high binding affinity to serotonin receptors but also to dopamine, adrenergic and histamine receptors. Apart from their influence on perception, many case reports point out systemic and neurological poisoning with these compounds. In humans, the most frequent side effects are tachycardia, anxiety, hypertension and seizures. Moreover, preclinical studies confirm that 25X-NBOMes cause developmental impairments, cytotoxicity, cardiovascular toxicity and changes in behavior of animals. Metabolism of NBOMes seems to be very complex and involves many metabolic pathways. This fact may explain the observed high toxicity. In addition, many analytical methods have been applied in order to identify these compounds and their metabolites. The presented review summarized the current knowledge about 25X-NBOMes, especially in the context of toxicity.

2-Phenethylamines in Medicinal Chemistry: A Review.

A concise review covering updated presence and role of 2-phenethylamines in medicinal chemistry is presented. Open-chain, flexible alicyclic amine derivatives of this motif are enumerated in key therapeutic targets, listing medicinal chemistry hits and appealing screening compounds. Latest reports in discovering new bioactive 2-phenethylamines by research groups are covered too.

Significantly improved detection performances of immunoassay for ractopamine in urine based on highly urea-tolerant rabbit monoclonal antibody.

Highly sensitive and accurate screening of ractopamine (RAC) residue in animal urine is greatly needed to ensure food security. The detection performance of immunoassay for RAC was always seriously harmed by the antibody inactivation derived from urea. Here, we first discovered one rabbit monoclonal antibody (RmAb) to RAC with a high affinity of 0.007 ng mL-1 and a surprising urea tolerance of 3 M urea, which is beneficial for developing robustly developed immunoassay in urine without sample pretreatment. The limits of detection of developed indirect competitive enzyme-linked immunosorbent assay based on RmAb1 for RAC were 0.0042-0.014 µg L-1 with the coefficient of variation below 11.7% in swine, sheep, and cow urine, significantly improved 10-100-fold in sensitivity. Moreover, the urea-tolerant mechanism of RmAb1 showed that more non-polar amino acids, more hydrogen bond donors on the surface, and preponderant Pi interaction of antibody-RAC all contributed to the stability of the RmAb1 in a high concentration of urea.

Acute behavioral and Neurochemical Effects of Novel N-Benzyl-2-Phenylethylamine Derivatives in Adult Zebrafish.

Hallucinogenic drugs potently affect brain and behavior and have also recently emerged as potentially promising agents in pharmacotherapy. Complementing laboratory rodents, the zebrafish (Danio rerio) is a powerful animal model organism for screening neuroactive drugs, including hallucinogens. Here, we test a battery of ten novel N-benzyl-2-phenylethylamine (NBPEA) derivatives with the 2,4- and 3,4-dimethoxy substitutions in the phenethylamine moiety and the -OCH3, -OCF3, -F, -Cl, and -Br substitutions in the ortho position of the phenyl ring of the N-benzyl moiety, assessing their acute behavioral and neurochemical effects in the adult zebrafish. Overall, substitutions in the Overall, substitutions in the N-benzyl moiety modulate locomotion, and substitutions in the phenethylamine moiety alter zebrafish anxiety-like behavior, also affecting the brain serotonin and/or dopamine turnover. The 24H-NBOMe(F) and 34H-NBOMe(F) treatment also reduced zebrafish despair-like behavior. Computational analyses of zebrafish behavioral data by artificial intelligence identified several distinct clusters for these agents, including anxiogenic/hypolocomotor (24H-NBF, 24H-NBOMe, and 34H-NBF), behaviorally inert (34H-NBBr, 34H-NBCl, and 34H-NBOMe), anxiogenic/hallucinogenic-like (24H-NBBr, 24H-NBCl, and 24H-NBOMe(F)), and anxiolytic/hallucinogenic-like (34H-NBOMe(F)) drugs. Our computational analyses also revealed phenotypic similarity of the behavioral activity of some NBPEAs to that of selected conventional serotonergic and antiglutamatergic hallucinogens. In silico functional molecular activity modeling further supported the overlap of the drug targets for NBPEAs tested here and the conventional serotonergic and antiglutamatergic hallucinogens. Overall, these findings suggest potent neuroactive properties of several novel synthetic NBPEAs, detected in a sensitive in vivo vertebrate model system, the zebrafish, raising the possibility of their potential clinical use and abuse.

Synthesis of DPIE [2-(1,2-Diphenyl-1H-indol-3-yl)ethanamine] Derivatives and Their Regulatory Effects on Pro-Inflammatory Cytokine Production in IL-1ß-Stimulated Primary Human Oral Cells.

Interleukin-1 beta (IL-1ß) has diverse physiological functions and plays important roles in health and disease. In this report, we focus on its function in the production of pro-inflammatory cytokines, including IL-6 and IL-8, which are implicated in several autoimmune diseases and host defense against infection. IL-1ß activity is markedly dependent on the binding affinity toward IL-1 receptors (IL-1Rs). Several studies have been conducted to identify suitable small molecules that can modulate the interactions between 1L-1ß and 1L-1R1. Based on our previous report, where DPIE [2-(1,2-Diphenyl-1H-indol-3-yl)ethanamine] exhibited such modulatory activity, three types of DPIE derivatives were synthesized by introducing various substituents at the 1, 2, and 3 positions of the indole group in DPIE. To predict a possible binding pose in complex with IL-1R1, a docking simulation was performed. The effect of the chemicals was determined in human gingival fibroblasts (GFs) following IL-1ß induction. The DPIE derivatives affected different aspects of cytokine production. Further, a group of the derivatives enabled synergistic pro-inflammatory cytokine production, while another group caused diminished cytokine production compared to DPIE stimulation. Some groups displayed no significant difference after stimulation. These findings indicate that the modification of the indole site could modulate IL-1ß:IL1R1 binding affinity to reduce or enhance pro-inflammatory cytokine production.

Inhibition Profiles of Some Symmetric Sulfamides Derived from Phenethylamines on Human Carbonic Anhydrase I, and II Isoenzymes.

In this work, the inhibitory effect of some symmetric sulfamides derived from phenethylamines were determined against human carbonic anhydrase (hCA) I, and II isoenzymes, and compared with standard compound acetazolamide. IC50 values were obtained from the Enzyme activity (%)-[Symmetric sulfamides] graphs. Also, Ki values were calculated from the Lineweaver-Burk graphs. Some symmetric sulfamides compounds (11-18) demonstrated excellent inhibition effects against hCA I, and II isoenzymes. These compounds demonstrated effective inhibitory profiles with IC50 values in ranging from 21.66-28.88 nM against hCA I, 14.44-30.13 nM against hCA II. Among these compounds, the best Ki value for hCA I (Ki : 8.34±1.60 nM) and hCA II (Ki : 16.40±1.00 nM) is compound number 11. Besides, the IC50 value of acetazolamide used as a standard was determined as hCA I, hCA II 57.75 nM, 49.50 nM, respectively. Moreover, in silico ADME-Tox study showed that all synthesized compounds (11-18) had good oral bioavailability in light of Jorgensen's rule of three, and of Lipinski's rule of five.

Stable Crystalline Organic-Inorganic Hybrid Indium Phosphate with Dye Removal and Ractopamine Detection Applications.

A highly stable framework of an organic-inorganic hybrid indium phosphate (NTOU-7) was synthesized under hydro(solvo)thermal conditions and structurally characterized by single-crystal X-ray diffraction and solid-state NMR spectroscopy. This is the first example of a post-transition-metal phosphate incorporating tetradentate organic molecules. The In atoms in the inorganic layers are coordinated by imidazole rings of the 1,2,4,5-tetrakis(imidazol-1-ylmethyl)benzene linkers to generate a new solid-state material. NTOU-7 showed high chemical stability and displayed excellent performance for both dye removal and ractopamine (RAC) detection, which are interesting environmental and biosensing applications. The sensitivity and ultralow limit of detection were 607.9 µA·µM·cm-2 and 2.74 × 10-10 mol·L-1 (0.08 ppb), which meet the requirements stated by the Codex Alimentarius Commission (10 ppb RAC residue in beef and pork). The detection performance was confirmed by sensing spiked-in RAC in real pork samples. We also reported the synthesis, characterization, structural stability, dye removal, and sensing properties of NTOU-7.

Study of Substituted Phenethylamine Fragmentation Induced by Electrospray Ionization Mass Spectrometry and Its Application for Highly Sensitive Analysis of Neurotransmitters in Biological Samples.

Although liquid chromatography-tandem mass spectrometry (LC-MS/MS) equipped with electrospray ionization (ESI) is widely employed for metabolite analysis, substituted phenethylamines commonly undergo fragmentation during ESI in-source collision-induced dissociation (CID). Unexpected fragmentation hampers not only unambiguous identification but also accurate metabolite quantification. ESI in-source CID induces N-Cα bond dissociation in substituted phenethylamines lacking a ß-hydroxy group to produce fragment ions with a spiro[2.5]octadienylium motif. In contrast, phenethylamines with a ß-hydroxy group generate substituted 2-phenylaziridium through ESI in-source CID-induced H2O loss. The fragment ion yield produced by ESI in-source CID can be estimated by the dissociation rate constant and internal energy of the analyte ion, determined by employing density functional theory calculations and the survival yield method using a thermometer ion, respectively. Fragmentation is strongly enhanced by the presence of an ß-hydroxy group, whereas N-methylation suppresses fragmentation. In particular, octopamine and noradrenaline, which contain an ß-hydroxy and primary amine groups, produce more intense fragment ion signals than protonated molecules. Regarding the quantitative analysis of phenethylamines present in the mouse brain, the noradrenaline fragment ion used as the precursor in multiple reaction monitoring (MRM) provided a higher signal-to-noise ratio in the resulting spectra than protonated noradrenaline. The present method allows for the quantitative analysis of substituted phenethylamines with high sensitivity.

Enantioseparation of phenethylamines by using high-performance liquid chromatography column permanently coated with methylated ß-cyclodextrin.

Cyclodextrins and their derivatives have been used for chiral high-performance liquid chromatography selectors, while they are costly to use as mobile phase additives in high-performance liquid chromatography. Here, we report application of phenyl column coated permanently with methylated ß-cyclodextrin for chiral high-performance liquid chromatography. A 0.1% (v/v) phosphoric acid solution containing 1 M NaCl and 0.5% (w/v) methylated ß-cyclodextrin was subjected to a phenyl column at a flow rate of 0.5 mL/min at 30°C for 2 h. Using the precoating phenyl column, all the enantiomers of the four phenethylamines (norepinephrine, epinephrine, octopamine, and synephrine) were successfully separated simultaneously by high-performance liquid chromatography with a mobile phase without methylated ß-cyclodextrin at a flow rate of 0.2 mL/min at 30°C. The enantioseparation ability was retained for successive analyses during 1 week. It is suggested that inclusion complex of methylated ß-cyclodextrin with a phenyl group on the surface of the stationary phase could be formed and that the inclusion complex could form the ternary complex with the injected analytes. The longer retention time of (S)-enantiomers of analytes than corresponding (R)-enantiomers for high-performance liquid chromatography could be explained from the higher stability of the methylated ß-cyclodextrin complexes with (S)-enantiomers, which were confirmed by capillary electrophoresis and 1 H NMR spectroscopy experiments.

Desorption Electrospray Ionization Mass Spectrometry Imaging of Cimbi-36, a 5-HT2A Receptor Agonist, with Direct Comparison to Autoradiography and Positron Emission Tomography.

PURPOSE: The study demonstrates the use of Desorption Electrospray Ionization mass spectrometry imaging (DESI-MSI) for imaging of the PET tracer compound Cimbi-36 in brain tissue and compares imaging by DESI-MSI to imaging by autoradiography and PET. PROCEDURES: Rats were dosed intraperitoneally with 3 mg/kg of Cimbi-36 and euthanized at t = 5, 10, 15, 30, 60 and 120 min post-injection. The brains were removed, frozen and sectioned, and sagittal sections were imaged by DESI-MSI in positive ion mode. Additionally, brain sections from a non-dosed animal were incubated with 14C-labelled Cimbi-36 and imaged by autoradiography. Finally, PET images were acquired from an animal dosed with 11C-labelled Cimbi-36. RESULTS: DESI-MSI and autoradiography images of a sagittal brain sections showed similar distributions of Cimbi-36, with increased abundance in the frontal cortex and choroid plexus, regions which are high in 5-HT2A and 5-HT2C receptors. The PET image also showed increased abundance in cortex, but the spatial resolution was clearly inferior to DESI-MSI and autoradiography. The DESI-MSI results showed increased abundance of Cimbi-36 in brain tissue until 15 min, after which the abundance was declining. The PET-tracer was still clearly detectable at t = 120 min. Similar imaging of the kidneys showed the abundance of Cimbi-36 peaking at 30 min. Cimbi-36 was quantified in a t = 15 min brain section by quantitative DESI-MSI, resulting in tissue concentrations of 19.8 µg/g in cortex, 15.4 µg/g in cerebellum and 12.5 µg/g in whole brain. CONCLUSIONS: DESI imaging from an in vivo dosing experiment showed distribution of the PET tracer remarkably similar to what was obtained by autoradiography of an in vitro incubation experiment, indicating that the obtained results represent actual binding to certain receptors in the brain. DESI-MSI is suggested as a cost-effective screening tool, which does not rely on labelling of compounds.

Anti-rheumatic activity of pseudoephedrine (a substituted phenethylamine) in complete Freund's adjuvant-induced arthritic rats by down regulating IL-1ß, IL-6 and TNF-α as well as upregulating IL-4 and IL-10.

Pseudoephedrine (substituted phenethylamine) is well known as psychotic and bronchodilator. Numerous studies on phenethylamine derivatives indicated that these agents have the potential to abolish inflammatory responses in the non-biological and biological systems. These facts provided the basis to conduct a study on pseudoephedrine to explore its therapeutics in Complete Freund's Adjuvant (CFA)-induced arthritis. Furthermore, existing treatment approaches for RA associated with limited effect on chronic immunological models. Real-time polymerase chain reaction (q-PCR) was performed to execute the expression of pro and anti-inflammatory cytokines in treated and non-treated arthritic rats. These findings were further co investigate by histological observations. The paw volume, paw diameter, weight variations and arthritic score were determined at specific days throughout the experiment of 28 days. Pseudoephedrine at all doses significantly (p < 0.001) suppressed the expression of PGE2, TNF-α, IL-1ß and IL-6. Moreover, pseudoephedrine (20 and 40 mg/kg) caused significant augmentation of IL-4 and IL-10. Similarly, the drug expressed a significant anti-arthritic effect by reducing the paw volume, paw diameter and arthritic score. Similarly, it also reverts the reduction in body weight of arthritic rats at all above-mentioned doses. These findings supported the anti-arthritic potential of pseudoephedrine and recommended it for clinical trials.

Effective Removal of Clenbuterol and Ractopamine from Water with a Stable Al(III)-Based Metal-Organic Framework.

Clenbuterol (CLE) and ractopamine (RAC) are two kinds of typical ß2-adrenergic agonists which pose a serious threat to the health of human beings. In this work, 10 kinds of metal-organic frameworks (MOFs) with high stability and various pore features are screened to assess adsorption performance for CLE and RAC. An Al(III)-MOF (BUT-19) with abundant ethyl groups exhibits exceptional performance in removing CLE and RAC from water. The maximum adsorption capacity for CLE and RAC are up to 294.1 and 366.3 mg/g under the optimum adsorption conditions, respectively. Meanwhile, the adsorption mechanism effects of pH, temperature, and coexisted ions are investigated systematically. It is found that the MOF pore size and weak hydrogen-bond interactions between CLE/RAC molecules and the MOF are the main causes leading to the extraordinary adsorption. This study provides a new idea for the purposeful design and synthesis of MOFs for removing environmental pollutants and sheds light on the depuration of contaminated water.

Bioactive edible film based on Konjac glucomannan and probiotic Lactobacillus plantarum strains: Physicochemical properties and shelf life of fresh-cut kiwis.

This study investigates the efficacy of Lactobacillus plantarum strains (L. plantarum LP3, L. plantarum AF1, and L. plantarum LU5) incorporated into a Konjac-based edible coating in order to prevent fungi growth and retain physicochemical characteristics of fresh-cut kiwis kept at 4 °C for 5 days. For this purpose, probiotic survivability, fungi counts, decay percentage, color changes, titratable acidity (TA), total soluble solids (TSS), ascorbic acid content, chlorophyll amount, total phenolics, and DPPH radical scavenging of fresh-cut kiwis were evaluated. Results indicated that the population of L. plantarum strains in all treated groups retained at sufficient amounts of probiotic consumption (above 6 and 7 log CFU/g) at the end of the storage period and L. plantarum LP3 had the highest viability in comparison to other strains. The incorporation of L. plantarum in Konjac coatings markedly reduced the amount of decay and color changes and maintained the chlorophyll and ascorbic acid contents of fresh-cut kiwis compared to control samples. After 5 days of storage, total phenol content and the DPPH antiradical activities of coated kiwi slices treated with probiotics were observed about 1.2 and 10.23 g/kg compared to the pure Konjac-coated (0.84 and 7.6 g/kg) and Konjac-uncoated samples (0.44 and 4.1 g/kg), respectively. No significant difference in TSS and TA of various treatments was detected. Coated kiwi slices loaded with probiotics had higher overall acceptability compared to Konjac-coated and control samples. In addition, probiotic treatment significantly reduced mold and yeast counts compared to the control group. PRACTICAL APPLICATIONS: Recently, edible films have received more consideration as a promising method to enhance the shelf life of fresh-cut fruit. The presence of probiotics in edible films reduces the growth of spoilage microorganisms and improves consumer health. Our findings encourage the application of edible coating incorporated with L. plantarum to design multifunctional foods and preserve the qualities of fresh-cut kiwifruit.

Biochar-Supported Cu2+/Cu+ Composite as an Electrochemical Ultrasensitive Interface for Ractopamine Detection.

Ractopamine as an important ß-agonist is frequently found in pork to enhance food quality, which is harmful to human health. Thus, it is extremely important to develop an efficient analytical method to detect ractopamine for food safety control. Herein, we develop a kind of electrochemical biosensor using a biochar-supported Cu2+/Cu+ composite as an electrochemical sensing interface for detecting ractopamine. The electrochemical sensor combines the collective advantages of Nafion (enriches ractopamine and effectively shields the interference of negatively charged compounds), biochar (unique three-dimensional porous network structure to increase the contact area), and Cu2+/Cu+ (excellent electrical conductivity to speed up the charge transfer rate), which are beneficial to the accumulation and electrochemical sensing of targets on a Nafion-biochar-supported Cu2+/Cu+ electrode (NBC-GCE). The as-prepared sensor shows a good electrochemical sensing ability, with an ultralow detection limit and high sensitivity (0.041 µM and 416 µA·mM-1·cm-2, respectively), in the 0.1-1.75 µM range. In addition, the stability, repeatability, and anti-interference performance of the modified electrode are also satisfying. Last, its practicability is shown for assaying ractopamine in pork sausages. This research provides an environmentally friendly method to simultaneously treat food waste and achieve ultrasensitive detection of ractopamine in food.

Fabrication of an electrochemical biodevice for ractopamine detection under a strategy of a double recognition of the aptamer/molecular imprinting polymer.

The importance of RAC tracking in human biofluids has boosted many demands for designing an ultrasensitive tool to determine the trace value of the RAC from clinical, judicial, and forensic centers. In this study, an electrochemical biodevice has developed for the highly selective detection of this illegal feed additive under a double recognition strategy of the aptamer (Apt) and molecular imprinting polymer (MIP) on a glassy carbon electrode (GCE). The sensing relies on this fact that both the MIP and Apt act synergistically to trap the RAC molecules. The sensing surface fabrication steps have been monitored by some electrochemical techniques such as electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV(. The charge transfer resistance (Rct) value of the redox probe as a representative of the biodevice response has increased linearly with the RAC concentration increasing in a dynamic range of 1 fM to 1.90 µM. The detection limit (LOD) value has been estimated to be 330 aM, lower than all of the reported methods in the RAC sensing. Furthermore, the practical feasibility of biodevice has been evaluated in some human blood serum and urine samples. This strategy offers some useful advantages in reliable detection of the RAC, which may help in the routine analysis, as mandated by regulatory agencies.

New Advances in the Synthetic Application of Enantiomeric 1-Phenylethylamine (α-PEA): Privileged Chiral Inducer and Auxiliary.

New developments in the synthesis, resolution, and synthetic applications of chiral 1-phenylethylamine (α-PEA) reported in the last decade have been reviewed. In particular, improvements in the synthesis of α-PEA and its derivatives and chiral resolution, as well as their applications in the resolution of other compounds, were discussed. α-PEA was used as a chiral auxiliary in the diastereoselective synthesis of medicinal substances and natural products. Chiral ligands with α-PEA moieties were applied in asymmetric reactions, and effective modular chiral organocatalysts were constructed with α-PEA fragments and used in important synthetic reactions.

Match-mismatch effects in two-fold transfer of chirality within a Möbius metallo-receptor.

Two-fold transfer of chirality has been investigated in a Möbius Zn(ii) hexaphyrin metallo-receptor able to bind simultaneously two different chiral molecules. Match/mismatch effects influence the dynamic stereoselective twisting of the π-system, and allow tuning of the induced chiroptical activity. Such allosteric control is attractive for building chirality sensing systems.

Synthesis of paramagnetic ligands that target the C-terminal binding site of Hsp90.

Identification of a ligand binding site represents the starting point for a structure-based drug development program. Lack of a binding site hampers the development of improved ligands that modulate the protein of interest. In this letter, we describe the development of chemical tools that will allow for elucidation of the Hsp90 C-terminal ligand binding site. Our strategy is based on the preparation of paramagnetic analogs of KU-596, an investigational new drug that is currently undergoing clinical trials for the treatment of neuropathy and interacts with the Hsp90 C-terminal domain. In particular, we report the design and synthesis of three novel paramagnetic analogs of KU-596, which will be used to obtain long range distances for NMR structural studies of Hsp90 in complex with C-terminal ligands.