HFIP in Organic Synthesis.

1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) is a polar, strongly hydrogen bond-donating solvent that has found numerous uses in organic synthesis due to its ability to stabilize ionic species, transfer protons, and engage in a range of other intermolecular interactions. The use of this solvent has exponentially increased in the past decade and has become a solvent of choice in some areas, such as C-H functionalization chemistry. In this review, following a brief history of HFIP in organic synthesis and an overview of its physical properties, literature examples of organic reactions using HFIP as a solvent or an additive are presented, emphasizing the effect of solvent of each reaction.

Tunable Heteroaromatic Sulfones Enhance in-Cell Cysteine Profiling.

Heteroaromatic sulfones react with cysteine via nucleophilic aromatic substitution, providing a mechanistically selective and irreversible scaffold for cysteine conjugation. Here we evaluate a library of heteroaromatic sulfides with different oxidation states, heteroatom substitutions, and a series of electron-donating and electron-withdrawing substituents. Select substitutions profoundly influence reactivity and stability compared to conventional cysteine conjugation reagents, increasing the reaction rate by >3 orders of magnitude. The findings establish a series of synthetically accessible electrophilic scaffolds tunable across multiple centers. New electrophiles and their corresponding alkyne conjugates were profiled directly in cultured cells, achieving thiol saturation in a few minutes at submillimolar concentrations. Direct addition of desthiobiotin-functionalized probes to cultured cells simplified enrichment and elution to enable the mass spectrometry discovery of >3000 reactive and/or accessible thiols labeled in their native cellular environments in a fraction of the standard analysis time. Surprisingly, only half of the annotated cysteines were identified by both iodoacetamide-desthiobiotin and methylsulfonylbenzothiazole-desthiobiotin in replicate experiments, demonstrating complementary detection by mass spectrometry analysis. These probes offer advantages over existing cysteine alkylation reagents, including accelerated reaction rates, improved stability, and robust ionization for mass spectrometry applications. Overall, heteroaromatic sulfones provide modular tunability, shifted chromatographic elution times, and superior in-cell cysteine profiling for in-depth proteome-wide analysis and covalent ligand discovery.

An Interrupted Schmidt Reaction: C-C Bond Formation Arising from Nitrilium Ion Capture.

The rerouting of the nitrilium ion formed in the Schmidt reaction of ketones and TMSN3 to encompass C-C bond formation with an electron-rich aromatic group is reported. Thus, when the reaction is carried out in HFIP using AlCl3 or AlBr3 as the promoter, imines, iminium ions, or enamide derivatives are obtained through one-pot procedures. The scope and possible mechanisms of these new transformations are considered.

Detection of Leukocortical Lesions in Multiple Sclerosis and Their Association with Physical and Cognitive Impairment: A Comparison of Conventional and Synthetic Phase-Sensitive Inversion Recovery MRI.

BACKGROUND AND PURPOSE: Cortical lesions are common in multiple sclerosis and are included in the latest diagnostic criteria. The limited sensitivity of cortical MS lesions on conventional MR imaging can be improved by phase-sensitive inversion recovery. Synthetic MR imaging could provide phase-sensitive inversion recovery without additional scanning, but the use of synthetic phase-sensitive inversion recovery remains to be validated. We aimed to compare the ability and clinical value of detecting leukocortical lesions with conventional and synthetic phase-sensitive inversion recovery in MS. MATERIALS AND METHODS: Twenty-one patients with MS prospectively underwent conventional and synthetic phase-sensitive inversion recovery, 3D T1-weighted, and T2 FLAIR imaging. Two neuroradiologists independently performed blinded phase-sensitive inversion recovery lesion assessments; a consensus rating with all sequences was considered the criterion standard. Lesion volumes were segmented. All participants underwent standardized cognitive and physical examinations and Fatigue Severity Scale assessment. Results were analyzed with multiple linear regressions. RESULTS: Interrater and criterion standard agreement for leukocortical lesions was excellent for both conventional and synthetic phase-sensitive inversion recovery (intraclass correlation coefficient = 0.79-0.97). Leukocortical lesion volumes for both sequences were associated with lower information-processing speed (P ≤ .01) and verbal fluency (P ≤ .02). Both phase-sensitive inversion recovery sequences showed a positive effect on the association when combining volumes of leukocortical lesions and white matter lesions with information-processing speed (P ≤ .005) and verbal fluency (P ≤ .03). No associations were found between leukocortical lesion volumes and physical disability or fatigue. CONCLUSIONS: Synthetic and conventional phase-sensitive inversion recovery have a sensitivity similar to that of leukocortical MS lesions. The detected leukocortical lesions are associated with cognitive dysfunction and thus provide clinically relevant information, which encourages assessment of cortical MS involvement at conventional field strengths.

Chemoselective ratiometric imaging of protein S-sulfenylation.

Here we report a ratiometric fluorescent probe for chemoselective conjugation to sulfenic acids in living cells. Our approach couples an α-fluoro-substituted dimedone to an aminonaphthalene fluorophore (F-DiNap), which upon sulfenic acid conjugation is locked as the 1,3-diketone, changing the fluorophore excitation. F-DiNap reacts with S-sulfenylated proteins at equivalent rates to current probes, but the α-fluorine substitution blocks side-reactions with biological aldehydes.

Retention of Gadolinium-Based Contrast Agents in Multiple Sclerosis: Retrospective Analysis of an 18-Year Longitudinal Study.

BACKGROUND AND PURPOSE: Gadolinium-based contrast agents have been associated with lasting high T1-weighted signal intensity in the dentate nucleus and globus pallidus, with histopathologically confirmed gadolinium retention. We aimed to longitudinally investigate the relationship of multiple gadolinium-based contrast agent administrations to the Signal Intensity Index in the dentate nucleus and globus pallidus and any associations with cognitive function in multiple sclerosis. MATERIALS AND METHODS: The Signal Intensity Index in the dentate nucleus and globus pallidus was retrospectively evaluated on T1-weighted MR imaging in an 18-year longitudinal cohort study of 23 patients with MS receiving multiple gadolinium-based contrast agent administrations and 23 healthy age- and sex-matched controls. Participants also underwent comprehensive neuropsychological testing. RESULTS: Patients with MS had a higher Signal Intensity Index in the dentate nucleus (P < .001), but not in the globus pallidus (P = .19), compared with non-gadolinium-based contrast agent-exposed healthy controls by an unpaired t test. Increasing numbers of gadolinium-based contrast agent administrations were associated with an increased Signal Intensity Index in the dentate nucleus (ß = 0.45, P < .001) and globus pallidus (ß = 0.60, P < .001). This association remained stable with corrections for the age, disease duration, and physical disability for both the dentate nucleus (ß = 0.43, P = .001) and globus pallidus (ß = 0.58, P < .001). An increased Signal Intensity Index in the dentate nucleus among patients with MS was associated with lower verbal fluency scores, which remained significant after correction for several aspects of disease severity (ß = -0.40 P = .013). CONCLUSIONS: Our data corroborate previous reports of lasting gadolinium retention in brain tissues. An increased Signal Intensity Index in the dentate nucleus and globus pallidus was associated with lower verbal fluency, which does not prove causality but encourages further studies on cognition and gadolinium-based contrast agent administration.

Natural Withanolides in the Treatment of Chronic Diseases.

Withanolides, and in particular extracts from Withania somnifera, have been used for over 3,000 years in traditional Ayurvedic and Unani Indian medical systems as well as within several other Asian countries. Traditionally, the extracts were ascribed a wide range of pharmacologic properties with corresponding medical uses, including adaptogenic, diuretic, anti-inflammatory, sedative/anxiolytic, cytotoxic, antitussive, and immunomodulatory. Since the discovery of the archetype withaferin A in 1965, approximately 900 of these naturally occurring, polyoxygenated steroidal lactones with 28-carbon ergostane skeletons have been discovered across 24 diverse structural types. Subsequently, extensive pharmacologic research has identified multiple mechanisms of action across key inflammatory pathways. In this chapter we identify and describe the major withanolides with anti-inflammatory properties, illustrate their role within essential and supportive inflammatory pathways (including NF-κB, JAK/STAT, AP-1, PPARγ, Hsp90 Nrf2, and HIF-1), and then discuss the clinical application of these withanolides in inflammation-mediated chronic diseases (including arthritis, autoimmune, cancer, neurodegenerative, and neurobehavioral). These naturally derived compounds exhibit remarkable biologic activity across these complex disease processes, while showing minimal adverse effects. As novel compounds and analogs continue to be discovered, characterized, and clinically evaluated, the interest in withanolides as a novel therapeutic only continues to grow.

Synthesis and Biological Evaluation of Novobiocin Core Analogues as Hsp90 Inhibitors.

Development of heat shock protein 90 (Hsp90) C-terminal inhibitors has emerged as an exciting strategy for the treatment of cancer. Previous efforts have focused on modifications to the natural products novobiocin and coumermycin. Moreover, variations in both the sugar and amide moieties have been extensively studied, whereas replacements for the coumarin core have received less attention. Herein, 24 cores were synthesized with varying distances and angles between the sugar and amide moieties. Compounds that exhibited good anti-proliferative activity against multiple cancer cell lines and Hsp90 inhibitory activity, were those that placed the sugar and amide moieties between 7.7 and 12.1 Šapart along with angles of 180°.

Hereditary diffuse leukoencephalopathy with spheroids - a volumetric and radiological comparison with multiple sclerosis patients and healthy controls.

BACKGROUND AND PURPOSE: Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant disorder caused by colony-stimulating factor 1 receptor (CSF1R) gene mutations, resulting in demyelination and axonal degeneration with spheroids. The clinical expression is variable, including behavioral changes, cognitive impairment, motor symptoms and parkinsonism. Magnetic resonance imaging (MRI) reveals white matter (WM) changes and atrophy. The indistinct phenotype has led to misdiagnoses. This study's aim was to compare brain volumetry and radiological ratings in HDLS with multiple sclerosis (MS) patients and controls. METHODS: Five HDLS patients with c.2562T>A p.Asn854Lys CSF1R mutation, five age- and gender-matched MS patients and five healthy controls were cross-sectionally studied. All patients were examined neurologically. HDLS patients underwent Mini-Mental State Examination (MMSE). Brain MRI scans were analyzed volumetrically with FreeSurfer and Lesion Segmentation Toolbox and neuroradiologically with the brain MRI scoring system for HDLS. RESULTS: Patients with HDLS had lower brain, grey matter and WM fractions (66.3%; 37.9%; 27.6%) compared with controls (78.5%, P = 0.008; 44.4%, P = 0.008; 32.0%, P = 0.008), but not compared with MS patients (65.7%, P = 0.7; 36.8%, P = 0.4; 27.3%, P = 0.7). Cerebellar WM changes and atrophy were not seen in the HDLS group. The HDLS lesion volume fraction correlated with MMSE scores (r = -0.90, P = 0.04). CONCLUSIONS: Brain volume fractions in HDLS were lower than in controls and similar to those seen in MS. The cerebellum was relatively spared in HDLS, which may help in differentiating HDLS WM changes from MS. The strong relationship of HDLS lesions with MMSE scores indicates that accumulating WM pathology in HDLS is associated with cognitive decline.

Clinical Feasibility of Synthetic MRI in Multiple Sclerosis: A Diagnostic and Volumetric Validation Study.

BACKGROUND AND PURPOSE: Quantitative MR imaging techniques are gaining interest as methods of reducing acquisition times while additionally providing robust measurements. This study aimed to implement a synthetic MR imaging method on a new scanner type and to compare its diagnostic accuracy and volumetry with conventional MR imaging in patients with MS and controls. MATERIALS AND METHODS: Twenty patients with MS and 20 healthy controls were enrolled after ethics approval and written informed consent. Synthetic MR imaging was implemented on a Siemens 3T scanner. Comparable conventional and synthetic proton-density-, T1-, and T2-weighted, and FLAIR images were acquired. Diagnostic accuracy, lesion detection, and artifacts were assessed by blinded neuroradiologic evaluation, and contrast-to-noise ratios, by manual tracing. Volumetry was performed with synthetic MR imaging, FreeSurfer, FMRIB Software Library, and Statistical Parametric Mapping. Repeatability was quantified by using the coefficient of variance. RESULTS: Synthetic proton-density-, T1-, and T2-weighted images were of sufficient or good quality and were acquired in 7% less time than with conventional MR imaging. Synthetic FLAIR images were degraded by artifacts. Lesion counts and volumes were higher in synthetic MR imaging due to differences in the contrast of dirty-appearing WM but did not affect the radiologic diagnostic classification or lesion topography (P = .50-.77). Synthetic MR imaging provided segmentations with the shortest processing time (16 seconds) and the lowest repeatability error for brain volume (0.14%), intracranial volume (0.12%), brain parenchymal fraction (0.14%), and GM fraction (0.56%). CONCLUSIONS: Synthetic MR imaging can be an alternative to conventional MR imaging for generating diagnostic proton-density-, T1-, and T2-weighted images in patients with MS and controls while additionally delivering fast and robust volumetric measurements suitable for MS studies.

Remodeling and Enhancing Schmidt Reaction Pathways in Hexafluoroisopropanol.

The effect of carrying out two variations of the Schmidt reaction with ketone electrophiles in hexafluoroisopropanol (HFIP) solvent has been studied. When TMSN3 is reacted with ketones in the presence of triflic acid (TfOH) promoter, tetrazoles are obtained as the major products. This observation is in contrast to established methods, which usually lead to amides or lactams arising from formal NH insertion as the major products. The full product profiles of several examples of this reaction are also reported and found to include mechanistically interesting products (e.g., double ring expansion). Application of TfOH promoter in HFIP was also found to promote the reaction of a hydroxyalkyl azide with a ketone, which affords lactams following nucleophilic opening of initially formed iminium ether more efficiently than previously reported methods.

Intramolecular Friedel-Crafts Acylation Reaction Promoted by 1,1,1,3,3,3-Hexafluoro-2-propanol.

Simple dissolution of an arylalkyl acid chloride in 1,1,1,3,3,3-hexafluoro-2-propanol promotes an intramolecular Friedel-Crafts acylation without additional catalysts or reagents. This reaction is operationally trivial in both execution and product isolation (only requiring concentration followed by purification) and accommodates a broad range of substrates. Preliminary studies that bear upon potential reaction mechanisms are reported.

Improved Schmidt Conversion of Aldehydes to Nitriles Using Azidotrimethylsilane in 1,1,1,3,3,3-Hexafluoro-2-propanol.

The Schmidt reaction of aromatic aldehydes using a substoichiometric amount (40 mol %) of triflic acid is described. Low catalyst loading was enabled by a strong hydrogen-bond-donating solvent hexafluoro-2-propanol (HFIP). This improved protocol tolerates a broad scope of aldehydes with diverse functional groups and the corresponding nitriles were obtained in good to high yields without the need for aqueous work up.

Synthesis and Cytotoxicity of Semisynthetic Withalongolide A Analogues.

The natural product withaferin A exhibits potent antitumor activity and other diverse pharmacological activities. The recently discovered withalongolide A, a C-19 hydroxylated congener of withaferin A, was recently reported to possess cytotoxic activity against head and neck squamous cell carcinomas. Semisynthetic acetylated analogues of withalongolide A were shown to be considerably more cytotoxic than the parent compound. To further explore the structure-activity relationships, 20 new semisynthetic analogues of withalongolide A were synthesized and evaluated for cytotoxic activity against four different cancer cell lines. A number of derivatives were found to be more potent than the parent compound and withaferin A.

Overcoming product inhibition in catalysis of the intramolecular Schmidt reaction.

A method for carrying out the intramolecular Schmidt reaction of alkyl azides and ketones using a substoichiometric amount of catalyst is reported. Following extensive screening, the use of the strong hydrogen-bond-donating solvent hexafluoro-2-propanol was found to be consistent with low catalyst loadings, which ranged from 2.5 mol % for favorable substrates to 25 mol % for more difficult cases. Reaction optimization, broad substrate scope, and preliminary mechanistic studies of this improved version of the reaction are described.

The A1 chieve study - an observational non-interventional study of patients with type 2 diabetes mellitus initiating or switched to insulin analogue therapy: subgroup analysis of the Gulf population.

AIM: To evaluate the safety and effectiveness of insulin analogues (insulin aspart, insulin detemir and biphasic insulin aspart 30, alone or in combination) in type 2 diabetes mellitus (T2DM) patients in routine clinical practice in the Gulf as a subgroup of the A(1) chieve multi-national study. METHODS: A total of 10,704 T2DM Gulf patients with uncontrolled T2DM on oral antidiabetics ± insulins other than insulin aspart, insulin detemir or biphasic insulin aspart 30, who initiated or switched to study insulins were included and followed up for 24 weeks in the context of the A(1) chieve study. RESULTS: Baseline HbA(1c) (± SD) was poor: 9.7 ± 1.7%. At Week 24, an improvement in HbA(1c) of -2.3 ± 1.6% was observed in the entire cohort, and -2.4 ± 1.5% and -2.1 ± 1.7% for insulin-naïve patients and prior insulin users respectively. Overall, rates of hypoglycaemia increased in those new to insulin therapy, whereas a reduction was observed in those switching from other insulins. A marginal reduction in body weight (-0.8 ± 4.4 kg) was noted in the entire cohort, whereas the overall lipid profile and systolic blood pressure (-6.2 ± 15.3 mmHg) improved. CONCLUSIONS: Initiating or switching to insulin analogues was well tolerated and resulted in significant improvements in glycaemic control in T2DM patients in the Gulf.

Copper-catalyzed oxaziridine-mediated oxidation of C-H bonds.

The highly regio- and chemoselective oxidation of activated C-H bonds has been observed via copper-catalyzed reactions of oxaziridines. The oxidation proceeded with a variety of substrates, primarily comprising allylic and benzylic examples, as well as one example of an otherwise unactivated tertiary C-H bond. The mechanism of the reaction is proposed to involve single-electron transfer to the oxaziridines to generate a copper-bound radical anion, followed by hydrogen atom abstraction and collapse to products, with regeneration of the catalyst by a final single-electron transfer event. The involvement of allylic radical intermediates was supported by a radical-trapping experiment with TEMPO.

Progress in COX-2 inhibitors: a journey so far.

The non-steroidal anti-inflammatory drugs (NSAIDs) are diverse group of compounds used for the treatment of inflammation, since the introduction of acetylsalicylic acid in 1899. Traditional (first generation) NSAIDs exert antiinflammatory, analgesic, and antipyretic effects through the blockade of prostaglandin synthesis via non-selective inhibition of cyclooxygenase (COX-1 and COX-2) isozymes. Their use is associated with side effects such as gastrointestinal and renal toxicity. A number of selective (second generation) COX-2 inhibitors (rofecoxib, celecoxib, valdecoxib etc.) were developed as safer NSAIDs with improved gastric safety profile. Observation of increased cardiovascular risks in APPROVe (Adenomatous Polyp Prevention on Vioxx) study sent tremors and led to voluntary withdrawn of Vioxx (rofecoxib) by Merck from the market in September 2004 followed by Bextra (valdecoxib) in 2005 raising a question on the safety of selective COX-2 inhibitors. This leads to the belief that these effects are mechanism based and may be class effect. However, some studies suggested association of traditional NSAIDs with similar effects requiring a relook into the whole class of NSAIDs rather than simply victimizing the selective COX-2 inhibitors. Recognition of new avenues for selective COX-2 inhibitors such as cancer, Alzheimer's disease, Parkinson's disease, schizophrenia, major depression, ischemic brain injury and diabetic peripheral nephropathy has kindled the interest in these compounds. This review highlights the various structural classes of selective COX-2 inhibitors developed during past seven years (2003-2009) with special emphasis on diaryl-hetero/carbo-cyclic class of compounds. Molecular modeling aspects are also briefly discussed.

Acute administration of GPR40 receptor agonist potentiates glucose-stimulated insulin secretion in vivo in the rat.

Recently, several in vitro studies have shown that GPR40 receptor activation by free fatty acids (FFAs) results in glucose-dependent insulin secretion. However, whether GPR40 receptor activation results in glucose-dependent insulin secretion in vivo in rats is not known. Therefore, we evaluated the effect of synthetic GPR40 receptor agonist (compound 1) on glucose tolerance test (GTT) in fed, fasted, and insulin-resistant rats. In oral GTT, intraperitoneal GTT, and intravenous GTT, GPR40 receptor agonist improved glucose tolerance, which was associated with increase in plasma insulin level. Interestingly, in GTTs, the rise in insulin levels in agonist-treated group was directly proportional to the rate of rise and peak levels of glucose in control group. Although glibenclamide, a widely used insulin secretagogue, improved glucose tolerance in all GTTs, it did not display insulin release in intraperitoneal GTT or intravenous GTT. In the absence of glucose load, GPR40 receptor agonist did not significantly change the plasma insulin concentration, but did decrease the plasma glucose concentration. Fasted rats exhibited impaired glucose-stimulated insulin secretion (GSIS) as compared with fed rats. Compound 1 potentiated GSIS in fasted state but failed to do so in fed state. Suspecting differential pharmacokinetics, a detailed pharmacokinetic evaluation was performed, which revealed the low plasma concentration of compound 1 in fed state. Consequently, we examined the absorption profile of compound 1 at higher doses in fed state; and at a dose at which its absorption was comparable with that in fasted state, we observed significant potentiation of GSIS. Chronic high-fructose (60%) diet feeding resulted in impaired glucose tolerance, which was improved by GPR40 receptor agonist. Therefore, our results demonstrate for the first time that acute GPR40 receptor activation leads to potentiation of GSIS in vivo and improves glucose tolerance even in insulin-resistant condition in rats. Taken together, these results suggest that GPR40 receptor agonists could be potential therapeutic alternatives to sulfonylureas.