Gregory R J Thatcher

University of Illinois at Chicago, Chicago, Illinois, United States

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Publications (144)636.93 Total impact

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    ABSTRACT: Schistosomiasis affects millions of people in developing countries and is responsible for more than 200,000 deaths annually. Because of toxicity and limited spectrum of activity of alternatives, there is effectively only one drug, praziquantel, available for its treatment. Recent data suggest that drug resistance could soon be a problem. There is therefore the need to identify new drug targets and develop drugs for the treatment of schistosomiasis. Analysis of the Schistosoma mansoni genome sequence for proteins involved in detoxification processes found that it encodes a single cytochrome P450 (CYP450) gene. Here we report that the 1452 bp open reading frame has a characteristic heme-binding region in its catalytic domain with a conserved heme ligating cysteine, a hydrophobic leader sequence present as the membrane interacting region, and overall structural conservation. The highest sequence identity to human CYP450s is 22%. Double stranded RNA (dsRNA) silencing of S. mansoni (Sm)CYP450 in schistosomula results in worm death. Treating larval or adult worms with antifungal azole CYP450 inhibitors results in worm death at low micromolar concentrations. In addition, combinations of SmCYP450-specific dsRNA and miconazole show additive schistosomicidal effects supporting the hypothesis that SmCYP450 is the target of miconazole. Treatment of developing S. mansoni eggs with miconazole results in a dose dependent arrest in embryonic development. Our results indicate that SmCYP450 is essential for worm survival and egg development and validates it as a novel drug target. Preliminary structure-activity relationship suggests that the 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethan-1-ol moiety of miconazole is necessary for activity and that miconazole activity and selectivity could be improved by rational drug design.
    Full-text · Article · Dec 2015 · PLoS Neglected Tropical Diseases
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    ABSTRACT: In breast tumors, activation of the nuclear factor kappaB (NFkB) pathway promotes survival, migration, invasion, angiogenesis, stem cell-like properties, and resistance to therapy; all phenotypes of aggressive disease where therapy options remain limited. Adding an anti-inflammatory/anti-NFkB agent to breast cancer treatment would be beneficial, but no such drug is approved as either a mono- or adjuvant therapy. To address this need, we examined whether dimethyl fumarate (DMF), an anti-inflammatory drug already in clinical use for multiple sclerosis, can inhibit the NFkB pathway. We find that DMF effectively blocks NFkB activity in multiple breast cancer cell lines and abrogates NFkB-dependent mammosphere formation, indicating that DMF has anti-cancer stem cells properties. In addition, DMF inhibits cell proliferation and significantly impairs xenograft tumor growth. Mechanistically, DMF prevents p65 nuclear translocation and attenuates its DNA binding activity, but has no effect on upstream proteins in the NFkB pathway. Dimethyl succinate (DMS), the inactive analog of DMF that lacks the electrophilic double bond of fumarate, is unable to inhibit NFkB activity. Also, the cell permeable thiol, N-acetyl L-cysteine, reverses DMF inhibition of the NFkB pathway, supporting the notion that the electrophile, DMF, acts via covalent modification. To determine whether DMF directly interacts with p65, we synthesized and used a novel chemical probe of DMF by incorporating an alkyne functionality, and found that DMF covalently modifies p65 with cysteine 38 being essential for DMF activity. These results establish DMF as an NFkB inhibitor with anti-tumor activity that may add therapeutic value in treating aggressive breast cancers.
    Full-text · Article · Dec 2015 · Journal of Biological Chemistry
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    ABSTRACT: Background Synaptic dysfunction is a key event in pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD) where synapse loss pathologically correlates with cognitive decline and dementia. Although evidence suggests that aberrant protein production and aggregation are the causative factors in familial subsets of such diseases, drugs singularly targeting these hallmark proteins, such as amyloid-β, have failed in late stage clinical trials. Therefore, to provide a successful disease-modifying compound and address synaptic dysfunction and memory loss in AD and mixed pathology dementia, we repurposed a clinically proven drug, CMZ, with neuroprotective and anti-inflammatory properties via addition of nitric oxide (NO) and cGMP signaling property. Results The novel compound, NMZ, was shown to retain the GABAA potentiating actions of CMZ in vitro and sedative activity in vivo. Importantly, NMZ restored LTP in hippocampal slices from AD transgenic mice, whereas CMZ was without effect. NMZ reversed amnestic blockade of acetylcholine receptors by scopolamine as well as NMDA receptor blockade by a benzodiazepine and a NO synthase inhibitor in the step-through passive avoidance (STPA) test of learning and working memory. A PK/PD relationship was developed based on STPA analysis coupled with pharmacokinetic measures of drug levels in the brain: at 1 nM concentration in brain and plasma, NMZ was able to restore memory consolidation in mice. Conclusion Our findings show that NMZ embodies a promising pharmacological approach targeting synaptic dysfunction and opens new avenues for neuroprotective intervention strategies in mixed pathology AD, neurodegeneration, and dementia. Electronic supplementary material The online version of this article (doi:10.1186/s12868-015-0208-9) contains supplementary material, which is available to authorized users.
    Preview · Article · Dec 2015 · BMC Neuroscience
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    ABSTRACT: Introduction Activation of cyclooxygenase (COX)/prostaglandin and nuclear factor κB (NFκB) pathways can promote breast tumor initiation, growth, and progression to drug resistance and metastasis. Thus, anti-inflammatory drugs have been widely explored as chemopreventive and antineoplastic agents. Aspirin (ASA), in particular, is associated with reduced breast cancer incidence but gastrointestinal toxicity has limited its usefulness. To improve potency and minimize toxicity, ASA ester prodrugs have been developed, in which the carboxylic acid of ASA is masked and ancillary pharmacophores can be incorporated. To date, the effects of ASA and ASA prodrugs have been largely attributed to COX inhibition and reduced prostaglandin production. However, ASA has also been reported to inhibit the NFκB pathway at very high doses. Whether ASA prodrugs can inhibit NFκB signaling remains relatively unexplored. Methods A library of ASA prodrugs was synthesized and screened for inhibition of NFκB activity and cancer stem-like cell (CSC) properties, an important PGE2-and NFκB-dependent phenotype of aggressive breast cancers. Inhibition of NFκB activity was determined by dual luciferase assay, RT-QPCR, p65 DNA binding activity and Western blots. Inhibition of CSC properties was determined by mammosphere growth, CD44+CD24−immunophenotype and tumorigenicity at limiting dilution. Results While we identified multiple ASA prodrugs that are capable of inhibiting the NFκB pathway, several were associated with cytotoxicity. Of particular interest was GTCpFE, an ASA prodrug with fumarate as the ancillary pharmacophore. This prodrug potently inhibits NFκB activity without innate cytotoxicity. In addition, GTCpFE exhibited selective anti-CSC activity by reducing mammosphere growth and the CD44+CD24−immunophenotype. Moreover, GTCpFE pre-treated cells were less tumorigenic and, when tumors did form, latency was increased and growth rate was reduced. Structure-activity relationships for GTCpFE indicate that fumarate, within the context of an ASA prodrug, is essential for anti-NFκB activity, whereas both the ASA and fumarate moieties contributed to attenuated mammosphere growth. Conclusions These results establish GTCpFE as a prototype for novel ASA-and fumarate-based anti-inflammatory drugs that: (i) are capable of targeting CSCs, and (ii) may be developed as chemopreventive or therapeutic agents in breast cancer. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1868-7) contains supplementary material, which is available to authorized users.
    Full-text · Article · Nov 2015 · BMC Cancer
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    ABSTRACT: Alzheimer's disease, one of the most important brain pathologies associated with neurodegenerative processes, is related to overactivation of calpain-mediated proteolysis. Previous data showed a compelling efficacy of calpain inhibition against abnormal synaptic plasticity and memory produced by the excess of amyloid-β, a distinctive marker of the disease. Moreover, a beneficial effect of calpain inhibitors in Alzheimer's disease is predictable by the occurrence of calpain hyperactivation leading to impairment of memory-related pathways following abnormal calcium influxes that might ensue independently of amyloid-β elevation. However, molecules currently available as effective calpain inhibitors lack adequate selectivity. This work is aimed at characterizing the efficacy of a novel class of epoxide-based inhibitors, synthesized to display improved selectivity and potency towards calpain 1 compared to the prototype epoxide-based generic calpain inhibitor E64. Both functional and preliminary toxicological investigations proved the efficacy, potency, and safety of the novel and selective calpain inhibitors NYC438 and NYC488 as possible therapeutics against the disease.
    No preview · Article · Oct 2015 · Journal of Alzheimer's disease: JAD
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    Marton Siklos · Manel BenAissa · Gregory R.J. Thatcher
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    ABSTRACT: Cysteine proteases continue to provide validated targets for treatment of human diseases. In neurodegenerative disorders, multiple cysteine proteases provide targets for enzyme inhibitors, notably caspases, calpains, and cathepsins. The reactive, active-site cysteine provides specificity for many inhibitor designs over other families of proteases, such as aspartate and serine; however, a) inhibitor strategies often use covalent enzyme modification, and b) obtaining selectivity within families of cysteine proteases and their isozymes is problematic. This review provides a general update on strategies for cysteine protease inhibitor design and a focus on cathepsin B and calpain 1 as drug targets for neurodegenerative disorders; the latter focus providing an interesting query for the contemporary assumptions that irreversible, covalent protein modification and low selectivity are anathema to therapeutic safety and efficacy.
    Preview · Article · Sep 2015

  • No preview · Article · Aug 2015 · Cancer Research

  • No preview · Article · Nov 2014 · European Journal of Cancer
  • Hitisha Patel · Rui Xiong · Jiong Zhao · Mary Ellen Molloy · Debra Tonetti · Gregory R.J Thatcher

    No preview · Article · Oct 2014 · Cancer Research
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    ABSTRACT: Previous data demonstrate that Bexarotene (Bex), an RXR agonist, reduces soluble and insoluble amyloid-β (Aβ) in Alzheimer's disease (AD)-transgenic (Tg) mice either via increasing the levels of mouse apolipoprotein E (apoE) or increasing ABCA1/ABCG1-induced apoE lipoprotein-association/lipidation. However, while the mechanism of action of RXR agonists remains unclear, a major concern for their use is human (h)-APOE4, the greatest AD genetic-risk factor. If APOE4 imparts a toxic gain-of-function, then increasing apoE4 may increase soluble Aβ, likely the proximal AD neurotoxin. If APOE4 imparts a loss-of-function, then ABCA1/ABCG1-induced lipidation of apoE4 may be beneficial. In novel EFAD-Tg mice (overexpressing h-Aβ42 with h-APOE), levels of soluble Aβ (Aβ42 and oligomeric Aβ (oAβ)) are highest in E4FAD-hippocampus (HP) > E3FAD-HP > E4FAD-cortex (CX) > E3FAD-CX, while levels of lipoprotein-associated/lipidated apoE have the opposite pattern (6-months, M). In E4FAD-HP, short-term RXR agonist treatment (Bex or LG100268; 5.75-6M) increased ABCA1, apoE4 lipoprotein-association/lipidation and apoE4/Aβ complex, decreased soluble Aβ and increased PSD95. In addition, hydrogel delivery, which mimics low sustained release, was equally effective as gavage for Bex and LG in lowering soluble Aβ with APOE4. RXR agonists induced no beneficial effects in the E4FAD-HP in a prevention protocol (5-6M), and increased soluble Aβ levels in E3FAD-CX and E4FAD-CX (5.75-6M), likely the result of systemic hepatomegaly. Thus, RXR agonists address the loss-of-function associated with APOE4 and exacerbated by Aβ pathology--low levels of apoE4 lipoprotein-association/lipidation. Further studies are vital to address whether RXR agonists are an APOE4-specific AD therapeutic and the systemic side effects that limit translational application.
    Full-text · Article · Sep 2014 · Journal of Biological Chemistry
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    ABSTRACT: Endocrine-resistant breast cancer is a major clinical obstacle. The use of 17beta-estradiol (E2) has re-emerged as a potential treatment option following exhaustive use of tamoxifen (TAM) or aromatase inhibitors although side effects have hindered its clinical usage. Protein kinase C alpha (PKCalpha) expression was shown to be a predictor of disease outcome for patients receiving endocrine therapy and may predict a positive response to an estrogenic treatment. Here, we have investigated the use of novel benzothiophene selective estrogen mimics (SEMs) as an alternative to E2 for the treatment of TAM-resistant breast cancer. Following in vitro characterization of SEMs, a panel of clinically relevant PKCalpha-expressing, TAM-resistant models were used to investigate the antitumor effects of these compounds. SEM treatment resulted in growth inhibition and apoptosis of TAM-resistant cell lines in vitro. In vivo SEM treatment induced tumor regression of TAM-resistant T47D:A18/PKCalpha and T47D:A18-TAM1 tumor models. T47D:A18/PKCalpha tumor regression was accompanied by translocation of ERalpha to extranuclear sites, possibly defining a mechanism through which these SEMs initiate tumor regression. SEM treatment did not stimulate growth of E2-dependent T47D:A18/neo tumors. Additionally, unlike E2 or TAM, treatment with SEMs did not stimulate uterine weight gain. These findings suggest the further development of SEMs as a feasible therapeutic strategy for the treatment of endocrine-resistant breast cancer without the side effects associated with E2.
    Full-text · Article · Sep 2014 · Molecular Cancer Therapeutics
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    Kevin Koster · Mary Jo LaDu · Jia Luo · Gregory Thatcher · Leon Tai

    Full-text · Article · Jul 2014 · Alzheimer's and Dementia
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    ABSTRACT: The risk of developing hormone-dependent cancers with long-term exposure to estrogens is attributed both to proliferative, hormonal actions at the estrogen receptor (ER), and chemical carcinogenesis elicited by genotoxic, oxidative estrogen metabolites. Non-tumorigenic MCF-10A human breast epithelial cells are classified as ER(-) and undergo estrogen-induced malignant transformation. Selective estrogen receptor modulators (SERMs), in use for breast cancer chemoprevention and for post-menopausal osteoporosis, were observed to inhibit malignant transformation, as measured by anchorage-independent colony growth. This chemopreventive activity was observed to correlate with reduced levels of oxidative estrogen metabolites, cellular ROS, and DNA oxidation. The ability of raloxifene, desmethylarzoxifene (DMA), and bazedoxifene to inhibit this chemical carcinogenesis pathway was not shared by 4-hydroxytamoxifen. Regulation of Phase 2 rather than Phase 1 metabolic enzymes was implicated mechanistically: raloxifene and DMA were observed to upregulate sulfotransferase (SULT 1E1) and glucuronidase (UGT 1A1). The results support upregulation of Phase 2 metabolism in detoxification of catechol estrogen metabolites leading to attenuated ROS formation as a mechanism for inhibition of malignant transformation by a subset of clinically important SERMs.
    Full-text · Article · Mar 2014 · Cancer Prevention Research
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    ABSTRACT: Breast cancer remains a significant cause of death in women, and few therapeutic options exist for estrogen receptor negative (ER (-)) cancers. Epigenetic reactivation of target genes using histone deacetylase (HDAC) inhibitors has been proposed in ER (-) cancers to resensitize to therapy using selective estrogen receptor modulators (SERMs) that are effective in ER (+) cancer treatment. Based upon preliminary studies in ER (+) and ER (-) breast cancer cells treated with combinations of HDAC inhibitors and SERMs, hybrid drugs, termed SERMostats, were designed with computational guidance. Assay for inhibition of four type I HDAC isoforms and antagonism of estrogenic activity in two cell lines yielded a SERMostat with 1-3 μM potency across all targets. The superior hybrid caused significant cell death in ER (-) human breast cancer cells and elicited cell death at the same concentration as the parent SERM in combination treatment and at an earlier time point.
    No preview · Article · Mar 2014 · ChemMedChem
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    ABSTRACT: The front cover picture shows a novel hybrid SERMostat that acts as both a class I histone deacetylase (HDAC) inhibitor and a selective estrogen receptor modulator (SERM). A combinatorial therapy using an HDAC inhibitor and antiestrogen drug is currently being tested in clinical trials for the treatment of ER() breast cancer, since HDAC inhibitors are proposed to increase transcription of ER (blue arrow). Based on this concept, SERMostats were designed with computational guidance and evaluated for their activity against ER() breast cancer cells. The SERMostats showed increased efficacy compared with the combinatorial treatment using the parent SERM and HDAC inhibitor. For further details, see the Full Paper by Gregory R. J. Thatcher et al. on p. 602 ff.
    Preview · Article · Mar 2014 · ChemMedChem
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    Adrian C. Nicolescu · Gregory R. J. Thatcher
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    ABSTRACT: Classic organic nitrates, such as nitroglycerin (GTN), are important vasodilators classed as NO donors, since biological activity is assumed to result entirely from bioactivation to NO and activation of soluble guanylate cyclase (sGC). Para-substituted aryl disulfanyl nitrate esters (SS-nitrates), designed based on a sulfhydryl-dependent mechanism of NO release, were investigated for their sGC activation. To obtain further insights into their interaction with hemoproteins, SS-nitrates were reacted with oxyhemoglobin (O2-Hb). SS-nitrates activated sGC with higher efficacy than GTN in the presence of cysteine. Some SS-nitrates, unlike GTN, activated sGC in the absence of cysteine. Linear correlations between the σp Hammett parameters and sGC activation efficacies or rates of O2-Hb oxidation by SS-nitrates in the presence of cysteine were found. Our results validate the design of SS-nitrates to circumvent the need for cysteine-mediated bioactivation and hint at NO-dependent and NO-independent mechanisms of sGC activation.
    Full-text · Article · Jan 2014 · Medicinal Chemistry Communication
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    ABSTRACT: Chlormethiazole (CMZ), a clinical sedative/anxiolytic agent, did not reach clinical efficacy in stroke trials despite neuroprotection demonstrated in numerous animal models. Using CMZ as a lead compound, neuroprotective methiazole (MZ) analogues were developed, and neuroprotection and GABAA receptor dependence were studied. Eight MZs were selected from a novel library, of which two were studied in detail. Neuroprotection, glutamate release, intracellular calcium and response to GABA blockade by picrotoxin were measured in rat primary cortical cultures using four cellular models of neurodegeneration. GABA potentiation was assayed in oocytes expressing the α1 β2 γ2 GABAA receptor. Neuroprotection against a range of insults was retained even with substantial chemical modification. Dependence on GABAA receptor activity was variable: at the extremes, neuroprotection by GN-28 was universally sensitive to picrotoxin, while GN-38 was largely insensitive. In parallel, effects on extracellular glutamate and intracellular calcium were associated with GABAA dependence. Consistent with these findings, GN-28 potentiated α1 β2 γ2 GABAA function, whereas GN-38 had weakly inhibitory effect. Neuroprotection against moderate dose oligomeric Aβ1-42 was also tolerant to structural changes. The results support the concept that CMZ does not contain a single pharmacophore, rather that broad-spectrum neuroprotection results from a GABAA -dependent mechanism represented by GN-28, combined with a mechanism represented in GN-38 that shows the least dependence on GABAA receptors. These findings allow further refinement of the neuroprotective pharmacophore and investigation into secondary mechanisms that will assist in identifying methiazole-based compounds of use in treating neurodegeneration.
    Preview · Article · Oct 2013 · British Journal of Pharmacology
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    ABSTRACT: SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMS) ARE EFFECTIVE THERAPEUTICS THAT PRESERVE FAVORABLE ACTIONS OF ESTROGENS ON BONE AND ACT AS ANTIESTROGENS IN BREAST TISSUE, DECREASING THE RISK OF VERTEBRAL FRACTURES AND BREAST CANCER, BUT THEIR POTENTIAL IN NEUROPROTECTIVE AND PROCOGNITIVE THERAPY IS LIMITED BY: 1) an increased lifetime risk of thrombotic events; and 2) an attenuated response to estrogens with age, sometimes linked to endothelial nitric oxide synthase (eNOS) dysfunction. Herein, three 3(rd) generation SERMs with similar high affinity for estrogen receptors (ERα, ERβ) were studied: desmethylarzoxifene (DMA), FDMA, and a novel NO-donating SERM (NO-DMA). Neuroprotection was studied in primary rat neurons exposed to oxygen glucose deprivation; reversal of cholinergic cognitive deficit was studied in mice in a behavioral model of memory; long term potentiation (LTP), underlying cognition, was measured in hippocampal slices from older 3×Tg Alzheimer's transgenic mice; vasodilation was measured in rat aortic strips; and anticoagulant activity was compared. Pharmacologic blockade of GPR30 and NOS; denudation of endothelium; measurement of NO; and genetic knockout of eNOS were used to probe mechanism. Comparison of the three chemical probes indicates key roles for GPR30 and eNOS in mediating therapeutic activity. Procognitive, vasodilator and anticoagulant activities of DMA were found to be eNOS dependent, while neuroprotection and restoration of LTP were both shown to be dependent upon GPR30, a G-protein coupled receptor mediating estrogenic function. Finally, the observation that an NO-SERM shows enhanced vasodilation and anticoagulant activity, while retaining the positive attributes of SERMs even in the presence of NOS dysfunction, indicates a potential therapeutic approach without the increased risk of thrombotic events.
    Full-text · Article · Aug 2013 · PLoS ONE
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    ABSTRACT: The promising therapeutic potential of the NO-donating hybrid aspirin prodrugs (NO-ASA) includes induction of chemopreventive mechanisms and has been reported in almost 100 publications. One example, NCX-4040 (pNO-ASA), is bioactivated by esterase to a quinone methide (QM) electrophile. In cell cultures, pNO-ASA and QM-donating X-ASA prodrugs that cannot release NO rapidly depleted intracellular GSH and caused DNA damage; however, induction of Nrf2 signaling elicited cellular defense mechanisms including upregulation of NAD(P)H:quinone oxidoreductase-1 (NQO1) and glutamate-cysteine ligase (GCL). In HepG2 cells, the "NO-specific" 4,5-diaminofluorescein reporter, DAF-DA, responded to NO-ASA and X-ASA, with QM-induced oxidative stress masquerading as NO. LC-MS/MS analysis demonstrated efficient alkylation of Cys residues of proteins including glutathione-S-transferase-P1 (GST-P1) and Kelch-like ECH-associated protein 1 (Keap1). Evidence was obtained for alkylation of Keap1 Cys residues associated with Nrf2 translocation to the nucleus, nuclear translocation of Nrf2, activation of antioxidant response element (ARE), and upregulation of cytoprotective target genes. At least in cell culture, pNO-ASA acts as a QM donor, bioactivated by cellular esterase activity to release salicylates, NO(3)(-), and an electrophilic QM. Finally, two novel aspirin prodrugs were synthesized, both potent activators of ARE, designed to release only the QM and salicylates on bioactivation. Current interest in electrophilic drugs acting via Nrf2 signaling suggests that QM-donating hybrid drugs can be designed as informative chemical probes in drug discovery.
    Full-text · Article · Oct 2012 · Chemical Research in Toxicology
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    ABSTRACT: Learning and memory deficits in Alzheimer's disease (AD) result from synaptic failure and neuronal loss, the latter caused in part by excitotoxicity and oxidative stress. A therapeutic approach is described that uses NO-chimeras directed at restoration of both synaptic function and neuroprotection. 4-Methylthiazole (MZ) derivatives were synthesized, based upon a lead neuroprotective pharmacophore acting in part by GABA(A) receptor potentiation. MZ derivatives were assayed for protection of primary neurons against oxygen-glucose deprivation and excitotoxicity. Selected neuroprotective derivatives were incorporated into NO-chimera prodrugs, coined nomethiazoles. To provide proof of concept for the nomethiazole drug class, selected examples were assayed for restoration of synaptic function in hippocampal slices from AD-transgenic mice, reversal of cognitive deficits, and brain bioavailability of the prodrug and its neuroprotective MZ metabolite. Taken together, the assay data suggest that these chimeric nomethiazoles may be of use in treatment of multiple components of neurodegenerative disorders, such as AD.
    No preview · Article · Jul 2012 · Journal of Medicinal Chemistry

Publication Stats

3k Citations
636.93 Total Impact Points

Institutions

  • 2003-2015
    • University of Illinois at Chicago
      • Department of Medicinal Chemistry and Pharmacognosy
      Chicago, Illinois, United States
  • 1988-2010
    • Queen's University
      • • Department of Chemistry
      • • Department of Pharmacology and Toxicology
      Kingston, Ontario, Canada
  • 2009
    • University of Chicago
      Chicago, Illinois, United States
  • 1997
    • Queens University of Charlotte
      • Chemistry
      New York, United States
  • 1987
    • The University of Sheffield
      • Department of Chemistry
      Sheffield, ENG, United Kingdom
  • 1986
    • University of Toronto
      • Department of Chemistry
      Toronto, Ontario, Canada