Design, synthesis and biological assessment of N-adamantyl, substituted adamantyl and noradamantyl phthalimidines for nitrite, TNF-α and angiogenesis inhibitory activities

Acknowledgements SB, NV, WDF funded by a Wellcome Trust-NIH PhD Scholarship (Grant number: 098252/Z/12/Z).Peer reviewedPostprin

Nanocrystals as an effective strategy to improve Pomalidomide bioavailability in rodent

Pomalidomide (POM) is an FDA-approved immunomodulatory imide drug (IMiDs) an it is effectively used in the treatment of multiple myeloma. IMiDs are analogs of the drug thalidomide and they have been repurposed for the treatment of several diseases such as psoriatic arthritis and Kaposi Sarcoma. In recent years, IMiDs have been also evaluated as a new treatment for neurological disorders with an inflammatory and neuroinflammatory component. POM draws particular interest for its potent anti-TNF-α activity at significantly lower concentrations than the parent compound thalidomide. However, POM's low water solubility underpins its low gastrointestinal permeability resulting in irregular and poor absorption. The purpose of this work was to prepare a POM nanocrystal-based formulation that could efficiently improve POM's plasma and brain concentration after intraperitoneal injection. POM nanocrystals prepared as a nanosuspension by the media milling method showed a mean diameter of 219 nm and a polydispersity index of 0.21. POM's nanocrystal solubility value (22.97 µg/mL) in phosphate buffer was about 1.58 folds higher than the POM raw powder. Finally, in vivo studies conducted in adult Male Sprague-Dawley rats indicated that POM nanocrystal ensured higher and longer-lasting drug levels in plasma and brain when compared with POM coarse suspension

"PROTON SPONGES": A RIGID ORGANIC SCAFFOLD TO REVEAL THE QUANTUM STRUCTURE OF THE INTRAMOLECULAR PROTON BOND

Author Institution: Yale University, P. O. Box 208107, New Haven, CT, 06520; Johns Hopkins University, 3400 North Charles Street, Baltimore, MD, 21218; Brock University, St. Catherines, ON, Canada L2S 3A1Spectroscopic analysis of systems containing charged hydrogen bonds (e.g. the Zundel ion, $\mathrm{H}_{5}\mathrm{O}_{2}^{+}$) in a vibrationally cold regime is useful in decongesting numerous anharmonic features common to room temperature measurements.[Roscioli, J. R.; et. al. Science 2007] This approach has been extended to conjugate acids of the "Proton Sponge" family of organic compounds, which contain strong intramolecular hydrogen bonds between proton donor (D) and acceptor (A) groups at the 1- and 8-positions. By performing $\mathrm{H}_2/\mathrm{D}_2$ vibrational predissociation spectroscopy on cryogenically cooled ions, we explore how the proximity and spatial orientation of D and A moieties relates to the spectroscopic signature of the shared proton. In the cases studied ($\mathrm{D = Me_{2}N-H^{+}; A = OH, O(C=O)Ph}$), we observe strong anharmonic couplings between the shared proton and dark states that persist at these cryogenic temperatures. This leads to intense NH stretching features throughout the nominal CH stretching region ($2800-3000 \mathrm{cm}^{-1}$). Isotopic substitution has verified that the oscillator strength of these broad features is driven by NH stretching. Furthermore, the study of A = O(C=O)Ph has provided a spectroscopic snapshot of the shared proton at work as an active catalytic moiety fostering ester hydrolysis by first order acylium fission ($\mathrm{A_{AC}1}$). This is apparent by the high frequency carbonyl stretch at $1792\ \mathrm{cm}^{-1}$, which is a consequence of the strong hydrogen bond to the ether-ester oxygen atom. Thus, these "Proton Sponges" are useful model systems that unearth the quantum structure and reactivity of shared proton interactions in organic compounds

Interaction of a C–F Bond with the π-System of a CC Bond or “Head On” with a Proximate C–H Bond

We describe the synthesis and preliminary study of two molecules, in which a fluorine atom is positioned proximately above the π-orbitals of a CC bond or else wherein a C–F bond interacts in a “head on” fashion with a proximate C–H bond. The spectroscopic characteristics of these unusual interactions are documented, X-ray crystallographic analyses are reported, and theoretical calculations are employed to support the observed spectroscopy

Search for a Symmetrical C–F–C Fluoronium Ion in Solution: Kinetic Isotope Effects, Synthetic Labeling, and Computational, Solvent, and Rate Studies

Recently, we reported evidence for the generation of a symmetrical fluoronium ion (a [C–F–C]⁺ interaction) in solution from a cage-like precursor, relying heavily on a single isotopic-labeling experiment. Paraphrasing the axiom that a strong claim must be met by as much evidence as possible, we seek to expand upon our initial findings with comprehensive labeling studies, rate measurements, kinetic isotope effect (KIE) experiments, synthetic studies, and computations. We also chronicle the development of the system, our thought process, and how it evolved from a tantalizing indication of fluoronium ion assistance in a dibromination reaction to the final, optimized system. Our experiments show secondary KIE experiments that are fully consistent with a transition state involving fluorine participation; this is also confirmed by a significant remote isotope effect. Paired with DFT calculations, the KIE experiments are indicative of the trapping of a symmetrical intermediate. Additionally, starting with an epimeric <i>in</i>-triflate precursor that hydrolyzes through a putative frontside S_N<i>i</i> mechanism involving fluorine participation, KIE studies indicate that an identical intermediate is trapped (the fluoronium ion). Studies also show that the rate-determining step of the fluoronium forming S_N1 reaction can be changed on the basis of solvent and additives. We also report the synthesis of a nonfluorinated control substrate to measure a relative anchimeric role of the fluorine atom in hydrolysis versus μ-hydrido bridging. After extensive testing, we can make the remarkable conclusion that our system reacts solely through a “tunable” S_N1 mechanism involving a fluoronium ion intermediate. Alternative scenarios, such as S_N2 reactivity, do not occur even under forced conditions where they should be highly favored

Interaction of a C–F Bond with the π-System of a CC Bond or “Head On” with a Proximate C–H Bond

We describe the synthesis and preliminary study of two molecules, in which a fluorine atom is positioned proximately above the π-orbitals of a CC bond or else wherein a C–F bond interacts in a “head on” fashion with a proximate C–H bond. The spectroscopic characteristics of these unusual interactions are documented, X-ray crystallographic analyses are reported, and theoretical calculations are employed to support the observed spectroscopy

Interaction of a C–F Bond with the π-System of a CC Bond or “Head On” with a Proximate C–H Bond

We describe the synthesis and preliminary study of two molecules, in which a fluorine atom is positioned proximately above the π-orbitals of a CC bond or else wherein a C–F bond interacts in a “head on” fashion with a proximate C–H bond. The spectroscopic characteristics of these unusual interactions are documented, X-ray crystallographic analyses are reported, and theoretical calculations are employed to support the observed spectroscopy

Post-Injury Neuroprotective Effects of the Thalidomide Analog 3,6′-Dithiothalidomide on Traumatic Brain Injury

Traumatic brain injury (TBI) is a major cause of mortality and disability worldwide. Long-term deficits after TBI arise not only from the direct effects of the injury but also from ongoing processes such as neuronal excitotoxicity, inflammation, oxidative stress and apoptosis. Tumor necrosis factor-&#945; (TNF-&#945;) is known to contribute to these processes. We have previously shown that 3,6&#8242;-dithiothalidomide (3,6&#8242;-DT), a thalidomide analog that is more potent than thalidomide with similar brain penetration, selectively inhibits the synthesis of TNF-&#945; in cultured cells and reverses behavioral impairments induced by mild TBI in mice. In the present study, we further explored the therapeutic potential of 3,6&#8242;-DT in an animal model of moderate TBI using Sprague-Dawley rats subjected to controlled cortical impact. A single dose of 3,6&#8242;-DT (28 mg/kg, i.p.) at 5 h after TBI significantly reduced contusion volume, neuronal degeneration, neuronal apoptosis and neurological deficits at 24 h post-injury. Expression of pro-inflammatory cytokines in the contusion regions were also suppressed at the transcription and translation level by 3,6&#8242;-DT. Notably, neuronal oxidative stress was also suppressed by 3,6&#8242;-DT. We conclude that 3,6&#8242;-DT may represent a potential therapy to ameliorate TBI-induced functional deficits

Immunomodulatory drugs alleviate l-dopa-induced dyskinesia in a rat model of Parkinson's disease

Thalidomide and closely related analogues are used clinically for their immunomodulatory and antiangiogenic properties mediated by the inhibition of the proinflammatory cytokine tumor necrosis factor α. Neuroinflammation and angiogenesis contribute to classical neuronal mechanisms underpinning the pathophysiology of l-dopa-induced dyskinesia, a motor complication associated with l-dopa therapy in Parkinson's disease. The efficacy of thalidomide and the more potent derivative 3,6'-dithiothalidomide on dyskinesia was tested in the 6-hydroxydopamine Parkinson's disease model

Activity of a Novel Anti-Inflammatory Agent F-3,6&prime;-dithiopomalidomide as a Treatment for Traumatic Brain Injury

Traumatic brain injury (TBI) is a major risk factor for several neurodegenerative disorders, including Parkinson&rsquo;s disease (PD) and Alzheimer&rsquo;s disease (AD). Neuroinflammation is a cause of later secondary cell death following TBI, has the potential to aggravate the initial impact, and provides a therapeutic target, albeit that has failed to translate into clinical trial success. Thalidomide-like compounds have neuroinflammation reduction properties across cellular and animal models of TBI and neurodegenerative disorders. They lower the generation of proinflammatory cytokines, particularly TNF-&alpha; which is pivotal in microglial cell activation. Unfortunately, thalidomide-like drugs possess adverse effects in humans before achieving anti-inflammatory drug levels. We developed F-3,6&prime;-dithiopomalidomide (F-3,6&prime;-DP) as a novel thalidomide-like compound to ameliorate inflammation. F-3,6&prime;-DP binds to cereblon but does not efficiently trigger the degradation of the transcription factors (SALL4, Ikaros, and Aiolos) associated with the teratogenic and anti-proliferative responses of thalidomide-like drugs. We utilized a phenotypic drug discovery approach that employed cellular and animal models in the selection and development of F-3,6&rsquo;-DP. F-3,6&prime;-DP significantly mitigated LPS-induced inflammatory markers in RAW 264.7 cells, and lowered proinflammatory cytokine/chemokine levels in the plasma and brain of rats challenged with systemic LPS. We subsequently examined immunohistochemical, biochemical, and behavioral measures following controlled cortical impact (CCI) in mice, a model of moderate TBI known to induce inflammation. F-3,6&prime;-DP decreased CCI-induced neuroinflammation, neuronal loss, and behavioral deficits when administered after TBI. F-3,6&prime;-DP represents a novel class of thalidomide-like drugs that do not lower classical cereblon-associated transcription factors but retain anti-inflammatory actions and possess efficacy in the treatment of TBI and potentially longer-term neurodegenerative disorders