A5074065870- Tuberculosis Research and Epidemiology
- Cancer therapeutics and mechanisms
- Computational Drug Discovery Methods
- Biochemical and Molecular Research
- Inflammatory mediators and NSAID effects
- Estrogen and related hormone effects
- Receptor Mechanisms and Signaling
- Synthesis and biological activity
- Immune Cell Function and Interaction
- Chemical Synthesis and Analysis
- RNA and protein synthesis mechanisms
- Adenosine and Purinergic Signaling
- T-cell and B-cell Immunology
- Neurotransmitter Receptor Influence on Behavior
- Cancer Mechanisms and Therapy
- Microbial Natural Products and Biosynthesis
- NF-κB Signaling Pathways
- Endoplasmic Reticulum Stress and Disease
- Neuropeptides and Animal Physiology
- Trypanosoma species research and implications
- Vitamin C and Antioxidants Research
- Adrenal Hormones and Disorders
- bioluminescence and chemiluminescence research
- PI3K/AKT/mTOR signaling in cancer
- Fibroblast Growth Factor Research
University of Dundee
2016-2020
Wellcome Centre for Anti-Infectives Research
2019-2020
University of Alabama at Birmingham
2018
Division of Chemistry
2015
Southern Research Institute
2008-2014
University of Michigan–Ann Arbor
2006
Visceral leishmaniasis (VL), caused by the protozoan parasites Leishmania donovani and infantum, is one of major parasitic diseases worldwide. There an urgent need for new drugs to treat VL, because current therapies are unfit purpose in a resource-poor setting. Here, we describe development preclinical drug candidate, GSK3494245/DDD01305143/compound 8, with potential this neglected tropical disease. The compound series was discovered repurposing hits from screen against related parasite...
Melatonin is widely present in Nature. It has pleiotropic activities, part mediated by interactions with high-affinity G-protein-coupled melatonin type 1 and 2 (MT1 MT2) receptors or under extreme conditions, e.g., ischemia/reperfusion. In pharmacological concentrations, it given to counteract the massive damage caused MT1- MT2-independent mechanisms. The aryl hydrocarbon receptor (AhR) a perfect candidate for mediating latter effects because structural similarity its natural ligands,...
Abstract Nonsteroidal anti-inflammatory drugs such as sulindac have shown promising antineoplastic activity, although toxicity from cyclooxygenase (COX) inhibition and the suppression of prostaglandin synthesis limits their use for chemoprevention. Previous studies concluded that mechanism responsible activity may be COX independent. To selectively design out inhibitory sulfide (SS), in silico modeling were done revealed crucial role carboxylate moiety COX-1 COX-2 binding. These prompted a...
Abstract Using LC/qTOF-MS we detected lumisterol, 20-hydroxylumisterol, 22-hydroxylumisterol, 24-hydroxylumisterol, 20,22-dihydroxylumisterol, pregnalumisterol, 17-hydroxypregnalumisterol and 17,20-dihydroxypregnalumisterol in human serum epidermis, the porcine adrenal gland. The hydroxylumisterols inhibited proliferation of skin cells a cell type-dependent fashion with predominant effects on epidermal keratinocytes. They also melanoma both monolayer soft agar. 20-Hydroxylumisterol...
The antigen-presenting molecule MR1 presents riboflavin-based metabolites to Mucosal-Associated Invariant T (MAIT) cells. While egress the cell surface is ligand-dependent, ability of small-molecule ligands impact on cellular trafficking remains unknown. Arising from an in silico screen ligand-binding pocket, we identify one ligand, 3-([2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl]formamido)propanoic acid, DB28, as well analog, methyl...
Antagonist and partial agonist modulators of the dopamine D3 receptor (D3R) have emerged as promising therapeutics for treatment substance abuse neuropsychiatric disorders. However, development druglike lead compounds with selectivity has been challenging because high sequence homology between D3R D2 (D2R). In this effort, we synthesized a series acylaminobutylpiperazines incorporating aza-aromatic units evaluated their binding functional activities at receptors. Docking studies results from...
The human pathogen Mycobacterium tuberculosis is the causative agent of pulmonary (TB), a disease with high worldwide mortality rates. Current treatment programs are under significant threat from multi-drug and extensively-drug resistant strains M. tuberculosis, it essential to identify new inhibitors their targets. We generated spontaneous mutants in bovis BCG presence 10× minimum inhibitory concentration (MIC) compound 1, previously identified potent inhibitor mycobacterial growth culture....
Tuberculosis represents a significant public health crisis. There is an urgent need for novel molecular scaffolds against this pathogen. We screened small library of marine-derived compounds shikimate kinase from Mycobacterium tuberculosis (MtSK), promising target antitubercular drug development. Six manzamines previously shown to be active M. were characterized as MtSK inhibitors: manzamine A (1), 8-hydroxymanzamine (2), E (3), F (4), 6-deoxymanzamine X (5), and 6-cyclohexamidomanzamine...
A variety of commercial analogs and a newer series Sulindac derivatives were screened for inhibition M. tuberculosis (Mtb) in vitro specifically as inhibitors the essential mycobacterial tubulin homolog, FtsZ. Due to ease preparing diverse favorable vivo pharmacokinetic toxicity profile representative analog, scaffold may be useful further development against Mtb with respect bacterial growth selective activity FtsZ versus mammalian tubulin. Further discovery efforts will require separating...
A highly reproducible and robust cell-based high-throughput screening (HTS) assay was adapted for of small molecules antiviral activity against influenza virus strain A/Vietnam/1203/2004 (H5N1). The NIH Molecular Libraries Small Molecule Repository (MLSMR) Screening Centers Network (MLSCN) 100,000-compound library screened at 50 µM. "hit" rate (>25% inhibition the viral cytopathic effect) from single-dose screen 0.32%. hits were evaluated their activity, cell toxicity, selectivity in...
Abstract Malignant gliomas have low survival expectations regardless of current treatments. Nonsteroidal anti‐inflammatory drugs (NSAIDs) prevent cell transformation and slow cancer growth by mechanisms independent cyclooxygenase (COX) inhibition. Certain NSAIDs trigger the endoplasmic reticulum stress response (ERSR), as revealed upregulation molecular chaperones such GRP78 C/EBP homologous protein (CHOP). Although celecoxib (CELE) inhibits sarcoendoplasmic Ca 2+ ATPase (SERCA), an effect...
Tuberculosis (TB) remains a leading cause of mortality worldwide. With the emergence multidrug resistant TB, extensively drug TB and HIV-associated it is imperative that new targets be identified. The potential Mycobacterium tuberculosis inosine monophosphate dehydrogenase (IMPDH) as novel target was explored in present study. IMPDH exclusively catalyzes conversion (IMP) to xanthosine (XMP) presence cofactor nicotinamide adenine dinucleotide (NAD(+)). Although enzyme dehydrogenase, does not...
In this letter we report first nonpeptide inhibitors of hepatocyte growth factor (HGF) activation. These compounds inhibit the three proteases (matriptase, hepsin, and HGF activator) required for maturation. We show that 6, 8a, 8b, 8d block activation fibroblast-derived pro-HGF, thus preventing fibroblast-induced scattering DU145 prostate cancer cells. Compound 6 (SRI 31215) is very soluble (91 μM) has excellent microsome stability (human t1/2 = 162 min; mouse 296 min). an in vivo 5.8 h...
Sulindac is a non-steroidal anti-inflammatory drug (NSAID) that has shown significant anticancer activity. sulfide amide (1) possessing greatly reduced COX-related inhibition relative to sulindac displayed in vivo antitumor activity was comparable human colon tumor xenograft model. Inspired by these observations, panel of diverse derivatives have been synthesized and their probed against three cancer cell lines (prostate, breast). A neutral analog, compound 79 identified with potency lead 1...
As part of an ongoing program to study the anticancer activity non-steroidal anti-inflammatory drugs (NSAIDs) through generating diversity libraries multiple NSAID scaffolds, we synthesized a series amide derivatives and screened these sets against three cancer cell lines (prostate, colon breast) Wnt/β-catenin signaling. The evaluated analog show significant activity/cell proliferation inhibition, specific members inhibition
Activation of invariant natural killer T lymphocytes (iNKT cells) by α-galactosylceramide (α-GC) elicits a range pro-inflammatory or anti-inflammatory immune responses. We report the synthesis and characterization series α-GC analogues with acyl chains varying length terminal benzophenone. These bound efficiently to glycolipid antigen presenting protein CD1d, upon photoactivation formed stable CD1d-glycolipid covalent conjugates. Conjugates benzophenone α-GCs soluble cell-bound CD1d proteins...
Neuronal noncytokine-dependent p50/p65 nuclear factor-κB (the primary NF-κB complex in the brain) activation has been shown to exert neuroprotective actions. Thus neuronal of could represent a viable target. We have developed cell-based assay able detect expression enhancement, and through its use we identified small molecules up-regulate hence trigger neurons. successfully screened approximately 300,000 compounds 1,647 active compounds. Cluster analysis structures within hit population...