Medicinal Chemistry
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Structure-guided design of an Hsp90â N-terminal isoform-selective inhibitor
(Nature Publishing Group, 2018-01-30)The 90 kDa heat shock protein (Hsp90) is a molecular chaperone responsible for folding proteins that are directly associated with cancer progression. Consequently, inhibition of the Hsp90 protein folding machinery results ... -
A novel C-terminal HSP90 inhibitor KU135 induces apoptosis and cell cycle arrest in melanoma cells
(Elsevier, 2011-12-22)Heat shock protein 90 (Hsp90) is differentially expressed in tumor cells including melanoma and involved in proper folding, stabilization and regulation of cellular proteins. We investigated a novobiocin-derived Hsp90 ... -
Grp94 Protein Delivers γ-Aminobutyric Acid Type A (GABAA) Receptors to Hrd1 Protein-mediated Endoplasmic Reticulum-associated Degradation
(American Society for Biochemistry and Molecular Biology, 2016-03-04)Proteostasis maintenance of γ-aminobutyric acid type A (GABAA) receptors dictates their function in controlling neuronal inhibition in mammalian central nervous systems. However, as a multisubunit, multispan, integral ... -
Endoplasmic reticulum chaperone Gp96 controls actomyosin dynamics and protects against pore-forming toxins
(American Society for Biochemistry and Molecular Biology, 2016-02-12)Heat shock protein 90 (HSP90) is a molecular chaperone that is up-regulated in cancer and is required for the folding of numerous signaling proteins. Consequently, HSP90 represents an ideal target for the development of ... -
The amyloid-beta forming tripeptide cleavage mechanism of γ-secretase
(eLife Sciences Publications, 2016-08-30)γ-secretase is responsible for the proteolysis of amyloid precursor protein (APP) into short, aggregation-prone amyloid-beta (Aβ) peptides, which are centrally implicated in the pathogenesis of Alzheimer’s disease (AD). ... -
The Dlk1-Gtl2 Locus Preserves LT-HSC Function by Inhibiting the PI3K-mTOR Pathway to Restrict Mitochondrial Metabolism
(Elsevier, 2016-02)The mammalian imprinted Dlk1-Gtl2 locus produces multiple non-coding RNAs (ncRNAs) from the maternally inherited allele, including the largest miRNA cluster in the mammalian genome. This locus has characterized functions ... -
Structure-Based Exploration and Exploitation of the S4 Subsite of Norovirus 3CL Protease in the Design of Potent and Permeable Inhibitors
(Elsevier, 2017-01-27)Human noroviruses are the primary cause of epidemic and sporadic acute gastroenteritis. The worldwide high morbidity and mortality associated with norovirus infections, particularly among the elderly, immunocompromised ... -
Novel synthetic inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity that inhibit tumor cell proliferation and are structurally unrelated to existing statins
(Spandidos Publications, 2009-11)Pilot-scale libraries of eight-membered medium ring lactams (MRLs) and related tricyclic compounds (either seven-membered lactams, thiolactams or amines) were screened for their ability to inhibit the catalytic activity ... -
The discriminative effects of the κ-opioid hallucinogen salvinorin A in nonhuman primates: dissociation from classic hallucinogen effects
(Elsevier, 2010-06)RATIONALE: The widely available hallucinogen salvinorin A is a unique example of a plant-derived compound selective for κ-opioid receptors and may produce effects distinct from those of other compounds with classic ... -
Dose-related Effects of Salvinorin A in Humans: Dissociative, Hallucinogenic, and Memory Effects
(Elsevier, 2013-03)RATIONALE: Salvinorin A is a kappa opioid agonist and the principal psychoactive constituent of the plant Salvia divinorum, which has increased in popularity as a recreational drug over the past decade. Few human studies ... -
Benzylmorpholine Analogs as Selective Inhibitors of Lung Cytochrome P450 2A13 for the Chemoprevention of Lung Cancer in Tobacco Users
(Springer Verlag, 2013-09)PURPOSE 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), one of the most prevalent and procarcinogenic compounds in tobacco, is bioactivated by respiratory cytochrome P450 (CYP) 2A13, forming DNA adducts and initiating ... -
Antiproliferative withanolides from several Solanaceous species
(Taylor & Francis, 2014-11)To date, our work on Solanaceous species (Datura wrightii, Jaborosa caulescens, Physalis hispida, P. longifolia, Vassobia breviflora, and Withania somnifera) has resulted in the isolation of 65 withanolides, 31 of which ... -
Swe1Wee1-dependent tyrosine phosphorylation of Hsp90 regulates distinct facets of chaperone function
(Elsevier, 2010-02-12)Swe1 (Saccharomyces WEE1), the only “true” tyrosine kinase in budding yeast, is an Hsp90 client protein. Here we show that Swe1Wee1 phosphorylates a conserved tyrosine residue (Y24 in yeast Hsp90 and Y38 in human Hsp90α) ... -
Triazole Containing Novobiocin and Biphenyl Amides as Hsp90 C-Terminal Inhibitors
(Royal Society of Chemistry, 2017-09-01)Hsp90 C-terminal inhibitors are advantageous for the development of new cancer chemotherapeutics due to their ability to segregate client protein degradation from induction of the prosurvival heat shock response, which is ... -
Potential Drug Abuse Therapeutics Derived from the Hallucinogenic Natural Product Salvinorin A
(Royal Society of Chemistry, 2011-12)Previous structure-activity relationship studies of salvinorin A have shown that modification of the acetate functionality off the C-2 position to a methoxy methyl or methoxy ethyl ether moiety leads to increased potency ... -
Interaction of 3â-amino-5-cholestene with phospholipids in binary and ternary bilayer membranes
(American Chemical Society, 2012-01-10)3β-Amino-5-cholestene (aminocholesterol) is a synthetic sterol whose properties in bilayer membranes have been examined. In fluid palmitoyl sphingomyelin (PSM) bilayers, aminocholesterol and cholesterol were equally effective ... -
Protection of Trabecular Bone in Ovariectomized Rats by Turmeric (Curcuma longa L.) is Dependent on Extract Composition
(American Chemical Society, 2010-09-08)Extracts prepared from turmeric (Curcuma longa L., [Zingiberaceae]) containing bioactive phenolic curcuminoids were evaluated for bone-protective effects in a hypogonadal rat model of postmenopausal osteoporosis. Three-month ... -
Anti-Arthritic Effects and Toxicity of the Essential Oils of Turmeric (Curcuma longa L.)
(American Chemical Society, 2010-01-27)Abstract Turmeric (Curcuma longa L., Zingiberaceae) rhizomes contain two classes of secondary metabolites, curcuminoids and the less well-studied essential oils. Having previously identified potent anti-arthritic effects ... -
Oxidative cytotoxic agent withaferin A resensitizes temozolomide-resistant glioblastomas via MGMT depletion and induces apoptosis through Akt/mTOR pathway inhibitory modulation
(Springer Verlag, 2014-08)Temozolomide (TMZ) has remained the chemotherapy of choice in patients with glioblastoma multiforme (GBM) primarily due to the lack of more effective drugs. Tumors, however, quickly develop resistance to this line of ... -
Cytotoxicity of withaferin A in glioblastomas involves induction of an oxidative stress-mediated heat shock response while altering Akt/mTOR and MAPK signaling pathways
(Springer Verlag, 2013-06)Withaferin A (WA), a steroidal lactone derived from the plant Vassobia breviflora, has been reported to have anti-proliferative, pro-apoptotic, and anti-angiogenic properties against cancer growth. In this study, we ...
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