2-(Piperidin-3-yl)phthalimides reduce classical markers of cellular inflammation in LPS-challenged RAW 264.7 cells and also demonstrate potentially relevant sigma and serotonin receptor affinity in membrane preparations.

Herein, we report the synthesis of new 4-amino-2-(piperidin-3-yl)isoindoline-1,3-diones and their biological evaluation in a series of in vitro experiments. The synthetic production of these materials was initiated upon the condensation of appropriate nitrophthalic acid derivatives with various 3-aminopiperidines; subsequent reduction provided the final products in moderate to good yields. Readily available chiral pool reagents facilitated entry into optically enriched samples, while the piperidine scaffold furnished a variety of amide and alkylated entries. In total, 16 candidates were produced, and their ensuing treatment in LPS-challenged RAW cells effected slight reductions in secreted TNF-α but provided more robust and dose-dependent declines in nitrite and IL-6 levels relative to basal amounts, all concurrent with maintenance of cellular viability across the concentration ranges screened. The secondary amine cohort including rac-6, (R)-7, and (S)-8 rendered the most pronounced dose-dependent reductions in nitrite and IL-6. When dosed at 30 µM, (R)-7 demonstrated the most compelling effects, with decreases of 32 % and 40 % for nitrite and IL-6, respectively. Notable reductions in the inflammatory markers were also observed for 19 which effected declines in TNF-α (14 %), nitrite (19 %), and IL-6 (11 %) when treated at 30 µM. Additionally, four representative compounds were further evaluated against numerous CNS receptors, channels, and transporters, with 6, 9, and 19 demonstrating varying degrees of nanomolar-to-low-micromolar binding to the σ-1 and σ-2 receptors and also to serotonin receptors 5HT2A, 5HT2B and 5HT3. In this regard, 6 displayed perhaps the most noteworthy affinities, with binding at σ-2 (Ki = 2.2uM), 5HT2B (Ki = 561 nM) and 5HT3 (Ki = 536 nM). Furthermore, no pronounced or dose-dependent Cereblon/DDB1 binding was observed for the screened representative compounds 6, 9, 18 and 19.

Thionated aminofluorophthalimides reduce classical markers of cellular inflammation in LPS-challenged RAW 264.7 cells.

Herein, we present the synthesis of several fluorinated pomalidomide derivatives and their thionated counterparts with subsequent biological evaluation against classical markers of cellular inflammation. Treatment in LPS-challenged cells effected varying reductions in levels of secreted TNF-α and nitrite relative to basal amounts. While arene fluorination and thioamidation had marginal and sporadic effects on TNF-α production, specific 7-position fluorination combined with subsequent increases in carbonyl thionation produced compounds 11, 14, and 15 which demonstrated corresponding and escalating anti-nitrite activities concurrent with minimal cellular toxicity. In this regard, compound 15 displayed roughly 96 % cell viability combined with a 65 % drop in nitrite production when supplied to RAW cells challenged with 60 ng/mL LPS. When a focused family of fluorinated isomers were directly compared, the analogous 5-fluorinated isomer 17 displayed comparable minimal toxicity but markedly less anti-nitrite activity versus 15 in RAW cells challenged with 70 ng/mL LPS. Compound 15 was subsequently screened in human liver microsomes for preliminary Phase 1 analysis where it demonstrated heightened stability relative to its non-fluorinated counterpart 3,6'-dithiopomalidomide 4, a result in line with the expected metabolic fortitude provided by fluorination at the sensitive pomalidomide 7-position.

Role of chronic neuroinflammation in neuroplasticity and cognitive function: A hypothesis.

OBJECTIVE: Evaluating the efficacy of 3,6'-dithioPomalidomide in 5xFAD Alzheimer's disease (AD) mice to test the hypothesis that neuroinflammation is directly involved in the development of synaptic/neuronal loss and cognitive decline. BACKGROUND: Amyloid-ß (Aß) or tau-focused clinical trials have proved unsuccessful in mitigating AD-associated cognitive impairment. Identification of new drug targets is needed. Neuroinflammation is a therapeutic target in neurodegenerative disorders, and TNF-α a pivotal neuroinflammatory driver. NEW HYPOTHESIS: AD-associated chronic neuroinflammation directly drives progressive synaptic/neuronal loss and cognitive decline. Pharmacologically mitigating microglial/astrocyte activation without altering Aß generation will define the role of neuroinflammation in AD progression. MAJOR CHALLENGES: Difficulty of TNF-α-lowering compounds reaching brain, and identification of a therapeutic-time window to preserve the beneficial role of neuroinflammatory processes. LINKAGE TO OTHER MAJOR THEORIES: Microglia/astroglia are heavily implicated in maintenance of synaptic plasticity/function in healthy brain and are disrupted by Aß. Mitigation of chronic gliosis can restore synaptic homeostasis/cognitive function.

Inhibition of HIV Maturation via Selective Unfolding and Cross-Linking of Gag Polyprotein by a Mercaptobenzamide Acetylator.

For HIV to become infectious, any new virion produced from an infected cell must undergo a maturation process that involves the assembly of viral polyproteins Gag and Gag-Pol at the membrane surface. The self-assembly of these viral proteins drives formation of a new viral particle as well as the activation of HIV protease, which is needed to cleave the polyproteins so that the final core structure of the virus will properly form. Molecules that interfere with HIV maturation will prevent any new virions from infecting additional cells. In this manuscript, we characterize the unique mechanism by which a mercaptobenzamide thioester small molecule (SAMT-247) interferes with HIV maturation via a series of selective acetylations at highly conserved cysteine and lysine residues in Gag and Gag-Pol polyproteins. The results provide the first insights into how acetylation can be utilized to perturb the process of HIV maturation and reveal a new strategy to limit the infectivity of HIV.

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

BACKGROUND: 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. METHODS: Three weeks after 6-hydroxydopamine infusion, rats received 10 days of treatment with l-dopa plus benserazide (6 mg/kg each) and thalidomide (70 mg/kg) or 3,6'-dithiothalidomide (56 mg/kg), and dyskinesia and contralateral turning were recorded daily. Rats were euthanized 1 hour after the last l-dopa injection, and levels of tumor necrosis factor-α, interleukin-10, OX-42, vimentin, and vascular endothelial growth factor immunoreactivity were measured in their striatum and substantia nigra reticulata to evaluate neuroinflammation and angiogenesis. Striatal levels of GLUR1 were measured as a l-dopa-induced postsynaptic change that is under tumor necrosis factor-α control. RESULTS: Thalidomide and 3,6'-dithiothalidomide significantly attenuated the severity of l-dopa-induced dyskinesia while not affecting contralateral turning. Moreover, both compounds inhibited the l-dopa-induced microgliosis and excessive tumor necrosis factor-α in the striatum and substantia nigra reticulata, while restoring physiological levels of the anti-inflammatory cytokine interleukin-10. l-Dopa-induced angiogenesis was inhibited in both basal ganglia nuclei, and l-dopa-induced GLUR1 overexpression in the dorsolateral striatum was restored to normal levels. CONCLUSIONS: These data suggest that decreasing tumor necrosis factor-α levels may be useful to reduce the appearance of dyskinesia, and thalidomide, and more potent derivatives may provide an effective therapeutic approach to dyskinesia. © 2019 International Parkinson and Movement Disorder Society.

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-α (TNF-α) is known to contribute to these processes. We have previously shown that 3,6'-dithiothalidomide (3,6'-DT), a thalidomide analog that is more potent than thalidomide with similar brain penetration, selectively inhibits the synthesis of TNF-α 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'-DT in an animal model of moderate TBI using Sprague-Dawley rats subjected to controlled cortical impact. A single dose of 3,6'-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'-DT. Notably, neuronal oxidative stress was also suppressed by 3,6'-DT. We conclude that 3,6'-DT may represent a potential therapy to ameliorate TBI-induced functional deficits.

Reaction Kinetics Direct a Rational Synthesis of an HIV-1 Inactivator of Nucleocapsid Protein 7 and Provide Mechanistic Insight into Cellular Metabolism and Antiviral Activity.

Mercaptobenzamide thioester SAMT-247 is a non-toxic, mutation-resistant HIV-1 maturation inhibitor with a unique mechanism of antiviral activity. NMR spectroscopic analyses of model reactions that mimic the cellular environment answered fundamental questions about the antiviral mechanism and inspired a high-yielding (64 % overall), scalable (75 mmol), and cost-effective ($4 mmol-1 ) three-step synthesis that will enable additional preclinical evaluation.

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

A library of 15 novel and heretofore uncharacterized adamantyl and noradamantyl phthalimidines was synthesized and evaluated for neuroprotective and anti-angiogenic properties. Phthalimidine treatment in LPS-challenged cells effected reductions in levels of secreted TNF-α and nitrite relative to basal amounts. The primary SAR suggests nitration of adamantyl phthalimidines has marginal effect on TNF-α activity but promotes anti-nitrite activity; thioamide congeners retain anti-nitrite activity but are less effective reducing TNF-α. Site-specific nitration and thioamidation provided phthalimidine 24, effecting an 88.5% drop in nitrite concurrent with only a 4% drop in TNF-α. Notable anti-angiogenesis activity was observed for 20, 21 and 22.

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 in-triflate precursor that hydrolyzes through a putative frontside SNi 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 SN1 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" SN1 mechanism involving a fluoronium ion intermediate. Alternative scenarios, such as SN2 reactivity, do not occur even under forced conditions where they should be highly favored.

Prodrug Strategy Extends the Use of Anti-HIV Sulfanylbenzamides for Application In Vivo.

Sulfanylbenzamide thioesters are molecules with anti-HIV activity that disrupt zinc coordination in the viral protein NCp7. These molecules are useful as topical microbicides; however, they are too unstable to be used systemically. In this article, a nitroimidazole prodrug was used to protect the sulfanylbenzamide to convey blood stability and oral bioavailability to the molecule. Studies on the molecule called nipamovir were performed to assess the rate of prodrug cleavage, antiviral activity, mechanism of metabolism, and in vivo pharmacokinetics in several different species. An efficient and inexpensive synthesis of nipamovir is also described. The results indicate that nipamovir could be further developed as a new type of drug to treat HIV infection.

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.

Characterization of highly unusual NH+-O hydrogen bonding to ester ether oxygen atoms through spectroscopic and computational studies.

We characterize a highly unusual, charged NH-O hydrogen bond formed within esters of 8-(dimethylamino)naphthalen-1-ol in which an ammonium ion serves as an intramolecular hydrogen bond donor to spatially proximate ester ether oxygen atoms. Infrared spectroscopic analysis of the ester carbonyl frequencies demonstrates significant blue-shifting when ether hydrogen bonding is possible, in stark contrast to the more commonly observed red shift that occurs upon hydrogen bonding to the ester carbonyl oxygen. The intrinsic behavior of the linkage (i.e., in which counterions and solvent effects are eliminated) is provided by vibrational predissociation spectroscopy of the isolated gas-phase cations complexed with weakly bound D(2) molecules.

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.

Activity of a Novel Anti-Inflammatory Agent F-3,6'-dithiopomalidomide as a Treatment for Traumatic Brain Injury.

Traumatic brain injury (TBI) is a major risk factor for several neurodegenerative disorders, including Parkinson's disease (PD) and Alzheimer'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-α 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'-dithiopomalidomide (F-3,6'-DP) as a novel thalidomide-like compound to ameliorate inflammation. F-3,6'-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'-DP. F-3,6'-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'-DP decreased CCI-induced neuroinflammation, neuronal loss, and behavioral deficits when administered after TBI. F-3,6'-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.

Repurposing Pomalidomide as a Neuroprotective Drug: Efficacy in an Alpha-Synuclein-Based Model of Parkinson's Disease.

Marketed drugs for Parkinson's disease (PD) treat disease motor symptoms but are ineffective in stopping or slowing disease progression. In the quest of novel pharmacological approaches that may target disease progression, drug-repurposing provides a strategy to accelerate the preclinical and clinical testing of drugs already approved for other medical indications. Here, we targeted the inflammatory component of PD pathology, by testing for the first time the disease-modifying properties of the immunomodulatory imide drug (IMiD) pomalidomide in a translational rat model of PD neuropathology based on the intranigral bilateral infusion of toxic preformed oligomers of human α-synuclein (H-αSynOs). The neuroprotective effect of pomalidomide (20 mg/kg; i.p. three times/week 48 h apart) was tested in the first stage of disease progression by means of a chronic two-month administration, starting 1 month after H-αSynOs infusion, when an already ongoing neuroinflammation is observed. The intracerebral infusion of H-αSynOs induced an impairment in motor and coordination performance that was fully rescued by pomalidomide, as assessed via a battery of motor tests three months after infusion. Moreover, H-αSynOs-infused rats displayed a 40-45% cell loss within the bilateral substantia nigra, as measured by stereological counting of TH + and Nissl-stained neurons, that was largely abolished by pomalidomide. The inflammatory response to H-αSynOs infusion and the pomalidomide treatment was evaluated both in CNS affected areas and peripherally in the serum. A reactive microgliosis, measured as the volume occupied by the microglial marker Iba-1, was present in the substantia nigra three months after H-αSynOs infusion as well as after H-αSynOs plus pomalidomide treatment. However, microglia differed for their phenotype among experimental groups. After H-αSynOs infusion, microglia displayed a proinflammatory profile, producing a large amount of the proinflammatory cytokine TNF-α. In contrast, pomalidomide inhibited the TNF-α overproduction and elevated the anti-inflammatory cytokine IL-10. Moreover, the H-αSynOs infusion induced a systemic inflammation with overproduction of serum proinflammatory cytokines and chemokines, that was largely mitigated by pomalidomide. Results provide evidence of the disease modifying potential of pomalidomide in a neuropathological rodent model of PD and support the repurposing of this drug for clinical testing in PD patients.

3,6'- and 1,6'-Dithiopomalidomide Mitigate Ischemic Stroke in Rats and Blunt Inflammation.

(1) Background: An important concomitant of stroke is neuroinflammation. Pomalidomide, a clinically available immunomodulatory imide drug (IMiD) used in cancer therapy, lowers TNF-α generation and thus has potent anti-inflammatory actions. Well-tolerated analogs may provide a stroke treatment and allow evaluation of the role of neuroinflammation in the ischemic brain. (2) Methods: Two novel pomalidomide derivatives, 3,6'-dithiopomalidomide (3,6'-DP) and 1,6'-dithiopomalidomide (1,6'-DP), were evaluated alongside pomalidomide in a rat middle cerebral artery occlusion (MCAo) stroke model, and their anti-inflammatory actions were characterized. (3) Results: Post-MCAo administration of all drugs lowered pro-inflammatory TNF-α and IL1-ß levels, and reduced stroke-induced postural asymmetry and infarct size. Whereas 3,6'- and 1,6'-DP, like pomalidomide, potently bound to cereblon in cellular studies, 3,6'-DP did not lower Ikaros, Aiolos or SALL4 levels-critical intermediates mediating the anticancer/teratogenic actions of pomalidomide and IMiDs. 3,6'-DP and 1,6'-DP lacked activity in mammalian chromosome aberration, AMES and hERG channel assays -critical FDA regulatory tests. Finally, 3,6'- and 1,6'-DP mitigated inflammation across rat primary dopaminergic neuron and microglia mixed cultures challenged with α-synuclein and mouse LPS-challenged RAW 264.7 cells. (4) Conclusion: Neuroinflammation mediated via TNF-α plays a key role in stroke outcome, and 3,6'-DP and 1,6'-DP may prove valuable as stroke therapies and thus warrant further preclinical development.

NH+-F hydrogen bonding in a fluorinated "proton sponge" derivative: integration of solution, solid-state, gas-phase, and computational studies.

We report detailed studies on the characterization of an intramolecular NH-F hydrogen bond formed within a fluorinated "proton sponge" derivative. An ammonium ion, generated from 8-fluoro-N,N-dimethylnaphthalen-1-amine, serves as a charged hydrogen bond donor to a covalently bound fluorine appropriately positioned on the naphthalene skeleton. Potentiometric titrations of various N,N-dimethylnaphthalen-1-amines demonstrate a significant increase in basicity when hydrogen bonding is possible. X-ray crystallography reveals that NH-F hydrogen bonding in protonated 8-fluoro-N,N-dimethylnaphthalen-1-amine is heavily influenced by ion pairing in the solid state; bifurcated and trifurcated hydrogen bonds are formed depending on the counterion utilized. Compelling evidence of hydrogen bonding in the 8-fluoro-N,N-dimethylnaphthyl-1-ammonium cation is provided by gas-phase cryogenic vibrational photodissociation spectroscopy. Solution-phase infrared spectroscopy provides complementary results, and the frequencies of the N-H stretching mode in both phases are in excellent agreement with the computed vibrational spectra. NMR analysis of protonated 8-fluoro-N,N-dimethylnaphthalen-1-amine demonstrates significant H-F coupling between the N-H hydrogen and fluorine that cannot be attributed to long-range, through-bond interactions; the couplings correlate favorably with calculated values. The results obtained from these experiments are congruent with the formation of an NH-F hydrogen bond upon protonation of 8-fluoro-N,N-dimethylnaphthalen-1-amine.

Repurposing Immunomodulatory Imide Drugs (IMiDs) in Neuropsychiatric and Neurodegenerative Disorders.

Neuroinflammation represents a common trait in the pathology and progression of the major psychiatric and neurodegenerative disorders. Neuropsychiatric disorders have emerged as a global crisis, affecting 1 in 4 people, while neurological disorders are the second leading cause of death in the elderly population worldwide (WHO, 2001; GBD 2016 Neurology Collaborators, 2019). However, there remains an immense deficit in availability of effective drug treatments for most neurological disorders. In fact, for disorders such as depression, placebos and behavioral therapies have equal effectiveness as antidepressants. For neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, drugs that can prevent, slow, or cure the disease have yet to be found. Several non-traditional avenues of drug target identification have emerged with ongoing neurological disease research to meet the need for novel and efficacious treatments. Of these novel avenues is that of neuroinflammation, which has been found to be involved in the progression and pathology of many of the leading neurological disorders. Neuroinflammation is characterized by glial inflammatory factors in certain stages of neurological disorders. Although the meta-analyses have provided evidence of genetic/proteomic upregulation of inflammatory factors in certain stages of neurological disorders. Although the mechanisms underpinning the connections between neuroinflammation and neurological disorders are unclear, and meta-analysis results have shown high sensitivity to factors such as disorder severity and sample type, there is significant evidence of neuroinflammation associations across neurological disorders. In this review, we summarize the role of neuroinflammation in psychiatric disorders such as major depressive disorder, generalized anxiety disorder, post-traumatic stress disorder, and bipolar disorder, as well as in neurodegenerative disorders, such as Parkinson's disease and Alzheimer's disease, and introduce current research on the potential of immunomodulatory imide drugs (IMiDs) as a new treatment strategy for these disorders.

Combining asymmetric catalysis with natural product functionalization through enantioselective alpha-fluorination.

An examination into the derivatization of various natural products using newly developed alpha-fluorination methodology is disclosed. An activated ketene enolate, generated from an acid chloride, is allowed to react with an electrophilic fluorine source (NFSi). Quenching the reaction with a nucleophilic natural product produces biologically relevant alpha-fluorinated carbonyl derivatives of select chemotherapeutics, antibiotics, and other pharmaceuticals.

3,6'-dithiopomalidomide reduces neural loss, inflammation, behavioral deficits in brain injury and microglial activation.

Traumatic brain injury (TBI) causes mortality and disability worldwide. It can initiate acute cell death followed by secondary injury induced by microglial activation, oxidative stress, inflammation and autophagy in brain tissue, resulting in cognitive and behavioral deficits. We evaluated a new pomalidomide (Pom) analog, 3,6'-dithioPom (DP), and Pom as immunomodulatory agents to mitigate TBI-induced cell death, neuroinflammation, astrogliosis and behavioral impairments in rats challenged with controlled cortical impact TBI. Both agents significantly reduced the injury contusion volume and degenerating neuron number evaluated histochemically and by MRI at 24 hr and 7 days, with a therapeutic window of 5 hr post-injury. TBI-induced upregulated markers of microglial activation, astrogliosis and the expression of pro-inflammatory cytokines, iNOS, COX-2, and autophagy-associated proteins were suppressed, leading to an amelioration of behavioral deficits with DP providing greater efficacy. Complementary animal and cellular studies demonstrated DP and Pom mediated reductions in markers of neuroinflammation and α-synuclein-induced toxicity.