Publications by authors named "Peter A Crooks"

322 Publications

Characterizing the Access of Cholinergic Antagonists to Efferent Synapses in the Inner Ear.

Front Neurosci 2021 14;15:754585. Epub 2021 Dec 14.

Department of Otolaryngology, University of Rochester, Rochester, NY, United States.

Stimulation of cholinergic efferent neurons innervating the inner ear has profound, well-characterized effects on vestibular and auditory physiology, after activating distinct ACh receptors (AChRs) on afferents and hair cells in peripheral endorgans. Efferent-mediated fast and slow excitation of vestibular afferents are mediated by α4β2*-containing nicotinic AChRs (nAChRs) and muscarinic AChRs (mAChRs), respectively. On the auditory side, efferent-mediated suppression of distortion product otoacoustic emissions (DPOAEs) is mediated by α9α10nAChRs. Previous characterization of these synaptic mechanisms utilized cholinergic drugs, that when systemically administered, also reach the CNS, which may limit their utility in probing efferent function without also considering central effects. Use of peripherally-acting cholinergic drugs with local application strategies may be useful, but this approach has remained relatively unexplored. Using multiple administration routes, we performed a combination of vestibular afferent and DPOAE recordings during efferent stimulation in mouse and turtle to determine whether charged mAChR or α9α10nAChR antagonists, with little CNS entry, can still engage efferent synaptic targets in the inner ear. The charged mAChR antagonists glycopyrrolate and methscopolamine blocked efferent-mediated slow excitation of mouse vestibular afferents following intraperitoneal, middle ear, or direct perilymphatic administration. Both mAChR antagonists were effective when delivered to the middle ear, contralateral to the side of afferent recordings, suggesting they gain vascular access after first entering the perilymphatic compartment. In contrast, charged α9α10nAChR antagonists blocked efferent-mediated suppression of DPOAEs only upon direct perilymphatic application, but failed to reach efferent synapses when systemically administered. These data show that efferent mechanisms are viable targets for further characterizing drug access in the inner ear.
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http://dx.doi.org/10.3389/fnins.2021.754585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8712681PMC
December 2021

Biobanked Glioblastoma Patient-Derived Organoids as a Precision Medicine Model to Study Inhibition of Invasion.

Int J Mol Sci 2021 Oct 3;22(19). Epub 2021 Oct 3.

Department of Neurosurgery, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.

Glioblastoma (GBM) is highly resistant to treatment and invasion into the surrounding brain is a cancer hallmark that leads to recurrence despite surgical resection. With the emergence of precision medicine, patient-derived 3D systems are considered potentially robust GBM preclinical models. In this study, we screened a library of 22 anti-invasive compounds (i.e., NF-kB, GSK-3-B, COX-2, and tubulin inhibitors) using glioblastoma U-251 MG cell spheroids. We evaluated toxicity and invasion inhibition using a 3D Matrigel invasion assay. We next selected three compounds that inhibited invasion and screened them in patient-derived glioblastoma organoids (GBOs). We developed a platform using available macros for FIJI/ImageJ to quantify invasion from the outer margin of organoids. Our data demonstrated that a high-throughput invasion screening can be done using both an established cell line and patient-derived 3D model systems. Tubulin inhibitor compounds had the best efficacy with U-251 MG cells, however, in ex vivo patient organoids the results were highly variable. Our results indicate that the efficacy of compounds is highly related to patient intra and inter-tumor heterogeneity. These results indicate that such models can be used to evaluate personal oncology therapeutic strategies.
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http://dx.doi.org/10.3390/ijms221910720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509225PMC
October 2021

Novel hydroxybenzylamine-deoxyvasicinone hybrids as anticholinesterase therapeutics for Alzheimer's disease.

Bioorg Med Chem 2021 09 14;45:116311. Epub 2021 Jul 14.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States. Electronic address:

A series of novel 2-hydroxybenzylamine-deoxyvasicinone hybrid analogs (8a-8n) have been synthesized and evaluated as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and as inhibitors of amyloid peptide (Aβ) aggregation, for treatment of Alzheimer's disease (AD). These dual acting compounds exhibited good AChE inhibitory activities ranging from 0.34 to 6.35 µM. Analogs8g and 8n were found to be the most potent AChE inhibitors in the series with ICvalues of 0.38 µM and 0.34 µM, respectively. All the analogs (8a-8n) exhibited weak BuChE inhibitory activities ranging from 14.60 to 21.65 µM. Analogs8g and 8n exhibited BuChE with ICvalues of 15.38 µM and 14.60 µM, respectively, demonstrating that these analogs were greater than 40-fold more selective for inhibition of AChE over BuChE. Additionally, compounds8g and 8n were also found to be the best inhibitors of self-induced Aβ peptide aggregation with ICvalues of 3.91 µM and 3.22 µM, respectively; 8g and 8n also inhibited AChE-induced Aβ peptide aggregation by 68.7% and 72.6%, respectively. Kinetic analysis and molecular docking studies indicate that analogs 8g and 8n bind to a new allosteric pocket (site B) on AChE. In addition, the observed inhibition of AChE-induced Aβ peptide aggregation by 8n is likely due to allosteric inhibition of the binding of this peptide at the CAS site on AChE. Overall, these results indicate that 8g and 8n are examples of dual-acting lead compounds for the development of highly effective anti-AD drugs.
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http://dx.doi.org/10.1016/j.bmc.2021.116311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405574PMC
September 2021

Antitumor properties of novel sesquiterpene lactone analogs as NFκB inhibitors that bind to the IKKβ ubiquitin-like domain (ULD).

Eur J Med Chem 2021 Nov 30;224:113675. Epub 2021 Jun 30.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, United States. Electronic address:

Melampomagnolide B (MMB, 3) is a parthenolide (PTL, 1) based sesquiterpene lactone that has been used as a template for the synthesis of a plethora of lead anticancer agents owing to its reactive C-10 primary hydroxyl group. Such compounds have been shown to inhibit the IKKβ subunit, preventing phosphorylation of the cytoplasmic IκB inhibitory complex. The present study focuses on the synthesis and in vitro antitumor properties of novel benzyl and phenethyl carbamates of MMB (7a-7k). Screening of these MMB carbamates identified analogs with potent growth inhibition properties against a panel of 60 human cancer cell lines (71% of the molecules screened had GI values < 2 μM). Two analogs, the benzyl carbamate 7b and the phenethyl carbamate7k, were the most active compounds. Lead compound 7b inhibited cell proliferation in M9 ENL AML cells, and in TMD-231, OV-MD-231 and SUM149 breast cancer cell lines. Interestingly, mechanistic studies showed that 7b did not inhibit p65 phosphorylation in M9 ENL AML and OV-MD-231 cells, but did inhibit phophorylation of both p65 and IκBα in SUM149 cells. 7b also reduced NFκB binding to DNA in both OV-MD-231 and SUM149 cells. Molecular docking studies indicated that 7b and 7k are both predicted to interact with the ubiquitin-like domain (ULD) of the IKKβ subunit. These data suggest that in SUM149 cells, 7b is likely acting as an allosteric inhibitor of IKKβ, whereas in M9 ENL AML and OV-MD-231 cells 7b is able to inhibit an event after IκB/p65/p50 phosphorylation by IKKβ that leads to inhibition of NFκB activation and reduction in NFκB-DNA binding. Analog 7b was by far the most potent compound in either carbamate series, and was considered an important lead compound for further optimization and development as an anticancer agent.
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http://dx.doi.org/10.1016/j.ejmech.2021.113675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511328PMC
November 2021

Aging-associated skeletal muscle defects in HER2/Neu transgenic mammary tumor model.

JCSM Rapid Commun 2021 Jan-Jun;4(1):24-39. Epub 2020 Jul 15.

Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

Background: Loss of skeletal muscle volume and resulting in functional limitations are poor prognostic markers in breast cancer patients. Several molecular defects in skeletal muscle including reduced MyoD levels and increased protein turn over due to enhanced proteosomal activity have been suggested as causes of skeletal muscle loss in cancer patients. However, it is unknown whether molecular defects in skeletal muscle are dependent on tumor etiology.

Methods: We characterized functional and molecular defects of skeletal muscle in MMTV-Neu (Neu+) mice (n= 6-12), an animal model that represents HER2+ human breast cancer, and compared the results with well-characterized luminal B breast cancer model MMTV-PyMT (PyMT+). Functional studies such as grip strength, rotarod performance, and ex vivo muscle contraction were performed to measure the effects of cancer on skeletal muscle. Expression of muscle-enriched genes and microRNAs as well as circulating cytokines/chemokines were measured. Since NF-κB pathway plays a significant role in skeletal muscle defects, the ability of NF-κB inhibitor dimethylaminoparthenolide (DMAPT) to reverse skeletal muscle defects was examined.

Results: Neu+ mice showed skeletal muscle defects similar to accelerated aging. Compared to age and sex-matched wild type mice, Neu+ tumor-bearing mice had lower grip strength (202±6.9 vs. 179±6.8 g grip force, p=0.0069) and impaired rotarod performance (108±12.1 vs. 30±3.9 seconds, P<0.0001), which was consistent with reduced muscle contractibility (p<0.0001). Skeletal muscle of Neu+ mice (n=6) contained lower levels of CD82+ (16.2±2.9 vs 9.0±1.6) and CD54+ (3.8±0.5 vs 2.4±0.4) muscle stem and progenitor cells (p<0.05), suggesting impaired capacity of muscle regeneration, which was accompanied by decreased MyoD, p53 and miR-486 expression in muscles (p<0.05). Unlike PyMT+ mice, which showed skeletal muscle mitochondrial defects including reduced mitochondria levels and Pgc1β, Neu+ mice displayed accelerated aging-associated changes including muscle fiber shrinkage and increased extracellular matrix deposition. Circulating "aging factor" and cachexia and fibromyalgia-associated chemokine Ccl11 was elevated in Neu+ mice (1439.56±514 vs. 1950±345 pg/ml, p<0.05). Treatment of Neu+ mice with DMAPT significantly restored grip strength (205±6 g force), rotarod performance (74±8.5 seconds), reversed molecular alterations associated with skeletal muscle aging, reduced circulating Ccl11 (1083.26 ±478 pg/ml), and improved animal survival.

Conclusions: These results suggest that breast cancer subtype has a specific impact on the type of molecular and structure changes in skeletal muscle, which needs to be taken into consideration while designing therapies to reduce breast cancer-induced skeletal muscle loss and functional limitations.
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http://dx.doi.org/10.1002/rco2.23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028024PMC
July 2020

Evaluation of bone and kidney toxicity of BT2-peg2, a potential carrier for the targeted delivery of antibiotics to bone.

Toxicol Rep 2021 9;8:359-364. Epub 2021 Feb 9.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, United States.

Previous studies have demonstrated that the bone targeting agent BT2-peg2 (BT2-minipeg2, ), when conjugated to vancomycin and delivered systemically by intravenous (IV) or intraperitoneal (IP) injection accumulates in bone to a greater degree than vancomycin alone, but that this accumulation is associated with severe nephrotoxicity. To determine whether this nephrotoxicity could be attributed to BT2-peg2 itself, we used a rat model to assess the distribution and toxicity of BT2-peg2 after IP injection of 11 mg/kg twice daily for 21 days. The results demonstrated that BT2-peg2 accumulates in bone but there was no evidence of nephrotoxicity or any histopathological abnormalities in the bone. This suggests the nephrotoxicity observed in previous studies is likely due to the altered pharmacokinetics of vancomycin when conjugated to BT2-peg2 rather than to BT2-peg2 itself. Thus, BT2-peg2 may be a safe carrier for the enhanced delivery of antibiotics other than vancomycin to the bone as a means of combating bone infection. However, the data also emphasizes the need to carefully examine the pharmacokinetic characteristics of any BT2-peg2-antibiotic conjugate utilized for treatment of bone infections.
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http://dx.doi.org/10.1016/j.toxrep.2021.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898066PMC
February 2021

A pharmacokinetic study of morphine-6-O-sulfate in rat plasma and brain.

Drug Dev Res 2021 Sep 11;82(6):802-814. Epub 2021 Jan 11.

Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.

Morphine-6-O-sulfate (M6S), a polar, zwitterionic sulfate ester of morphine, is a powerful and safe analgesic in several rat models of pain. A sensitive liquid chromatography-tandem mass spectrometry bioanalytical method was developed and validated for the simultaneous determination of M6S and morphine (MOR) in rat plasma and brain after M6S administration. Morphine-d was used as internal standard. Multiple reaction monitoring was used for detection and quantitation of M6S, MOR, and morphine-d in the turbo ion spray positive mode. The chromatographic separation was carried out on an Alltech Altima C18 column. The analytical method was validated for linearity, precision, accuracy, specificity, and stability over a concentration range of 3-8000 ng/ml in rat plasma and 10-10,000 ng/ml in brain samples for both M6S and MOR. The validated method was applied to determine the PK profile of M6S in plasma after i.v., i.p., and oral dosing in male Sprague-Dawley rats. Rats were administered M6S by i.p. administration (5.6 and 10.0 mg/kg) or orally (10 and 30 mg/kg) and bioavailability compared to an i.v. injection (1 mg/kg) of M6S. The in vivo results indicate that M6S is not a prodrug of morphine, since M6S is not biotransformed into MOR in plasma after either i.p. or oral administration, and MOR was not detected in brain. The bioavailability of M6S was >93% and about 5% after i.p. and oral dosing, respectively. The low oral bioavailability of M6S may be due to poor permeation of the intestinal epithelial membrane. After i.p.-administration, M6S appears to reach brain tissues in low, but significant, concentrations.
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http://dx.doi.org/10.1002/ddr.21785DOI Listing
September 2021

Targeting NPM1 in irradiated cells inhibits NPM1 binding to RAD51, RAD51 foci formation and radiosensitizes NSCLC.

Cancer Lett 2021 03 21;500:220-227. Epub 2020 Dec 21.

Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. Electronic address:

The ability of chemo-radiation therapy to control locally advanced stage III non-small cell lung cancer (NSCLC) is poor. While addition of consolidation immunotherapy has improved outcomes in subsets of patients there is still an urgent need for new therapeutic targets. Emerging research indicates that nucleophosmin1 (NPM1) is over-expressed in NSCLC, promotes tumor growth and that over-expression correlates with a lower survival probability. NPM1 is critical for APE1 base excision activity and for RAD51-mediated repair of DNA double strand breaks (DSBs). YTR107 is a small molecule radiation sensitizer that has been shown to bind to NPM1, suppressing pentamer formation. Here we show that in irradiated cells YTR107 inhibits SUMOylated NPM1 from associating with RAD51, RAD51 foci formation and repair of DSBs. YTR107 acts synergistically with the PARP1/2 inhibitor ABT 888 to increase replication stress and radiation-induced cell lethality. YTR107 was found to radiosensitize tumor initiating cells. Congruent with this knowledge, adding YTR107 to a fractionated irradiation regimen diminished NSCLC xenograft growth and increased overall survival. These data support the hypothesis that YTR107 represents a therapeutic target for control of NSCLC.
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http://dx.doi.org/10.1016/j.canlet.2020.12.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822076PMC
March 2021

Structural modeling of GSK3β implicates the inactive (DFG-out) conformation as the target bound by TDZD analogs.

Sci Rep 2020 10 27;10(1):18326. Epub 2020 Oct 27.

McClellan Veterans Medical Ctr., Central Arkansas Veterans Healthcare Service, Little Rock, AR, 72205, USA.

Glycogen synthase kinase-3β (GSK3β) controls many physiological pathways, and is implicated in many diseases including Alzheimer's and several cancers. GSK3β-mediated phosphorylation of target residues in microtubule-associated protein tau (MAPTAU) contributes to MAPTAU hyperphosphorylation and subsequent formation of neurofibrillary tangles. Inhibitors of GSK3β protect against Alzheimer's disease and are therapeutic for several cancers. A thiadiazolidinone drug, TDZD-8, is a non-ATP-competitive inhibitor targeting GSK3β with demonstrated efficacy against multiple diseases. However, no experimental data or models define the binding mode of TDZD-8 with GSK3β, which chiefly reflects our lack of an established inactive conformation for this protein. Here, we used metadynamic simulation to predict the three-dimensional structure of the inactive conformation of GSK3β. Our model predicts that phosphorylation of GSK3β Serine9 would hasten the DFG-flip to an inactive state. Molecular docking and simulation predict the TDZD-8 binding conformation of GSK3β to be inactive, and are consistent with biochemical evidence for the TDZD-8-interacting residues of GSK3β. We also identified the pharmacophore and assessed binding efficacy of second-generation TDZD analogs (TDZD-10 and Tideglusib) that bind GSK3β as non-ATP-competitive inhibitors. Based on these results, the predicted inactive conformation of GSK3β can facilitate the identification of novel GSK3β inhibitors of high potency and specificity.
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http://dx.doi.org/10.1038/s41598-020-75020-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591898PMC
October 2020

Binding Modes and Selectivity of Cannabinoid 1 (CB1) and Cannabinoid 2 (CB2) Receptor Ligands.

ACS Chem Neurosci 2020 10 30;11(20):3455-3463. Epub 2020 Sep 30.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, United States.

The cannabinoid (CB) receptors (CBR and CBR) represent a promising therapeutic target for several indications such as nociception and obesity. The ligands with nonselectivity can be traced to the high similarity in the binding sites of both cannabinoid receptors. Therefore, the need for selectivity, potency, and G-protein coupling bias has further complicated the design of desired compounds. The bias of currently studied cannabinoid agonists is seldom investigated, and agonists that do exhibit bias are typically nonselective. However, certain long-chain endocannabinoids represent a class of selective and potent CBR agonists. The binding mode for this class of compounds has remained elusive, limiting the implementation of its binding features to currently studied agonists. Hence, in the present study, the binding poses for these long-chain cannabinoids, along with other interesting ligands, with the receptors have been determined, by using a combination of molecular docking and molecular dynamics (MD) simulations along with molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations. The binding poses for the long-chain cannabinoids implicate that a site surrounded by the transmembrane (TM)2, TM7, and extracellular loop (ECL)2 is vital for providing the long-chain ligands with the selectivity for CBR, especially I267 of CBR (corresponding to L182 of CBR). Based on the obtained binding modes, the calculated relative binding free energies and selectivity are all in good agreement with the corresponding experimental data, suggesting that the determined binding poses are reasonable. The computational strategy used in this study may also prove fruitful in applications with other GPCRs or membrane-bound proteins.
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http://dx.doi.org/10.1021/acschemneuro.0c00551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756905PMC
October 2020

7-Azaindolequinuclidinones (7-AIQD): A novel class of cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor ligands.

Bioorg Med Chem Lett 2020 11 31;30(22):127501. Epub 2020 Aug 31.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. Electronic address:

A series of N-benzyl-7-azaindolequinuclidinone (7-AIQD) analogs have been synthesized and evaluated for affinity toward CB1 and CB2 cannabinoid receptors and identified as a novel class of cannabinoid receptor ligands. Structure-activity relationship (SAR) studies indicate that 7-AIQD analogs are dual CB1/CB2 receptor ligands exhibiting high potency with somewhat greater selectivity towards CB2 receptors compared to the previously reported indolequinuclidinone (IQD) analogs. Initial binding assays showed that 7-AIQD analogs 8b, 8d, 8f, 8g and 9b (1 μM) produced more that 50% displacement of the CB1/CB2 non-selective agonist CP-55,940 (0.1 nM). Furthermore, Ki values determined from full competition binding curves showed that analogs 8a, 8b and 8g exhibit high affinity (110, 115 and 23.7 nM, respectively) and moderate selectivity (26.3, 6.1 and 9.2-fold, respectively) for CB2 relative to CB1 receptors. Functional studies examining modulation of G-protein activity demonstrated that 8a acts as a neutral antagonist at CB1 and CB2 receptors, while 8b exhibits inverse agonist activity at these receptors. Analogs 8f and 8g exhibit different intrinsic activities, depending on the receptor examined. Molecular docking and binding free energy calculations for the most active compounds (8a, 8b, 8f, and 8g) were performed to better understand the CB2 receptor-selective mechanism at the atomic level. Compound 8g exhibited the highest predicted binding affinity at both CB1 and CB2 receptors, and all four compounds were shown to have higher predicted binding affinities with the CB2 receptor compared to their corresponding binding affinities with the CB1 receptor. Further structural optimization of 7-AIQD analogs may lead to the identification of potential clinical agents.
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http://dx.doi.org/10.1016/j.bmcl.2020.127501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686103PMC
November 2020

Design and Synthesis of Novel Hybrid 8-Hydroxy Quinoline-Indole Derivatives as Inhibitors of Aβ Self-Aggregation and Metal Chelation-Induced Aβ Aggregation.

Molecules 2020 Aug 8;25(16). Epub 2020 Aug 8.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.

A series of novel hybrid 8-hydroxyquinoline-indole derivatives (, and ) were synthesized and screened for inhibitory activity against self-induced and metal-ion induced Aβ aggregation as potential treatments for Alzheimer's disease (AD). In vitro studies identified the most inhibitory compounds against self-induced Aβ aggregation as , and (EC = 1.72, 1.48 and 1.08 µM, respectively) compared to the known anti-amyloid drug, clioquinol (, EC = 9.95 µM). The fluorescence of thioflavin T-stained amyloid formed by Aβ aggregation in the presence of Cu or Zn ions was also dramatically decreased by treatment with , and . The most potent hybrid compound afforded 82.3% and 88.3% inhibition, respectively, against Cu- induced and Zn- induced Aβ aggregation. Compounds , and were shown to be effective in reducing protein aggregation in HEK-tau and SY5Y-APP cells. Molecular docking studies with the most active compounds performed against Aβ peptide indicated that the potent inhibitory activity of and were predicted to be due to hydrogen bonding interactions, π-π stacking interactions and π-cation interactions with Aβ which may inhibit both self-aggregation as well as metal ion binding to Aβ to favor the inhibition of Aβ aggregation.
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http://dx.doi.org/10.3390/molecules25163610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463714PMC
August 2020

Oxone-Mediated TEMPO-Oxidized Cellulose Nanomaterial Ultrafiltration and Dialysis Mixed-Matrix Hollow Fiber Membranes.

Polymers (Basel) 2020 Jun 15;12(6). Epub 2020 Jun 15.

Ralph E. Martin Department of Chemical Engineering, University of Arkansas, Fayetteville, AR 72701, USA.

Recent exploration of cellulose nanomaterials has resulted in the creation of Oxone-Mediated TEMPO-Oxidized Cellulose Nanomaterials (OTO-CNMs). These materials, when incorporated into a polymer matrix, have properties showing increased flux, decreased membrane resistance, and improved clearance, making them an ideal material for dialysis. This study is the first to focus on the implementation of OTO-CNMs into hollow fiber membranes and a comparison of these membranes for ultrafiltration and dialysis. Ultrafiltration and dialysis were performed using bovine serum albumin (BSA), lysozyme, and urea to analyze various properties of each hollow fiber membrane type. The results presented in this study provide the first quantitative evaluation of the clearance and sieving characteristics of Oxone-Mediated TEMPO-Oxidized Cellulose-Nanomaterial-doped cellulose triacetate mixed-matrix hemodialyzers. While the cellulose nanomaterials increased flux (10-30%) in ultrafiltration mode, this was offset by increased removal of albumin. However, in dialysis mode, these materials drastically increased the mass transfer of components (50-100%), which could lead to significantly lower dialysis times for patients. This change in the performance between the two different modes is most likely due to the increased porosity of the cellulose nanomaterials.
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http://dx.doi.org/10.3390/polym12061348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361684PMC
June 2020

Oxone-Mediated TEMPO-Oxidized Cellulose Nanomaterials form I and form II.

Molecules 2020 Apr 17;25(8). Epub 2020 Apr 17.

Ralph E. Martin Department of Chemical Engineering, University of Arkansas, Fayetteville, AR 72701, USA.

The 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) oxidation of cellulose, when mediated with Oxone (KHSO), can be performed simply and under mild conditions. Furthermore, the products of the reaction can be isolated into two major components: Oxone-mediated TEMPO-oxidized cellulose nanomaterials Form I and Form II (OTO-CNM Form I and Form II). This study focuses on the characterization of the properties of OTO-CNMs. Nanoparticle-sized cellulose fibers of 5 and 16 nm, respectively, were confirmed through electron microscopy. Infrared spectroscopy showed that the most carboxylation presented in Form II. Conductometric titration showed a two-fold increase in carboxylation from Form I (800 mmol/kg) to Form II (1600 mmol/kg). OTO-CNMs showed cellulose crystallinity in the range of 64-68% and crystallite sizes of 1.4-3.3 nm, as shown through XRD. OTO-CNMs show controlled variability in hydrophilicity with contact angles ranging from 16 to 32°, within or below the 26-47° reported in the literature for TEMPO-oxidized CNMs. Newly discovered OTO-CNM Form II shows enhanced hydrophilic properties as well as unique crystallinity and chemical functionalization in the field of bio-sourced material and nanocomposites.
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http://dx.doi.org/10.3390/molecules25081847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221945PMC
April 2020

Deuteration of the farnesyl terminal methyl groups of δ-tocotrienol and its effects on the metabolic stability and ability of inducing G-CSF production.

Bioorg Med Chem 2020 06 8;28(11):115498. Epub 2020 Apr 8.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, United States. Electronic address:

δ-tocotrienol (DT3), a member of vitamin E family, has been shown to have a potent radio-protective effect. However, its application as a radioprotectant is limited, at least in part, by its short plasma elimination half-life and low bioavailability. In an effort to increase the metabolic stability of DT3, a deuterium substituted DT3 derivative, d-DT3, was designed and synthesized. d-DT3 showed improved in vitro and in vivo metabolic stability compared to DT3. The unexpected lower potency of d-DT3 in inducing granulocyte-colony stimulating factor (G-CSF) production in mouse revealed that the metabolite(s) of DT3 might play a major role in inducing G-CSF induction.
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http://dx.doi.org/10.1016/j.bmc.2020.115498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433030PMC
June 2020

A Novel Microtubule-Binding Drug Attenuates and Reverses Protein Aggregation in Animal Models of Alzheimer's Disease.

Front Mol Neurosci 2019 12;12:310. Epub 2019 Dec 12.

BioInformatics Program, University of Arkansas for Medical Sciences and University of Arkansas at Little Rock, Little Rock, AR, United States.

Age-progressive neurodegenerative pathologies, including Alzheimer's disease (AD), are distinguished and diagnosed by disease-specific components of intra- or extra-cellular aggregates. Increasing evidence suggests that neuroinflammation promotes protein aggregation, and is involved in the etiology of neurological diseases. We synthesized and tested analogs of the naturally occurring tubulin-binding compound, combretastatin A-4. One such analog, PNR502, markedly reduced the quantity of Alzheimer-associated amyloid aggregates in the BRI-Aβ mouse model of AD, while blunting the ability of the pro-inflammatory cytokine IL-1β to raise levels of amyloid plaque and its protein precursors in a neuronal cell-culture model. In transgenic () strains that express human Aβ in muscle or neurons, PNR502 rescued Aβ-induced disruption of motility (3.8-fold, < 0.0001) or chemotaxis (1.8-fold, < 0.05), respectively. Moreover, in with neuronal expression of Aβ, a single day of PNR502 exposure reverses the chemotaxis deficit by 54% ( < 0.01), actually exceeding the protection from longer exposure. Moreover, continuous PNR502 treatment extends nematode lifespan 23% ( ≤ 0.001). Given that PNR502 can slow, prevent, or reverse Alzheimer-like protein aggregation in human-cell-culture and animal models, and that its principal predicted and observed binding targets are proteins previously implicated in Alzheimer's, we propose that PNR502 has therapeutic potential to inhibit cerebral Aβ aggregation and prevent or reverse neurodegeneration.
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http://dx.doi.org/10.3389/fnmol.2019.00310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920216PMC
December 2019

Aggregate Interactome Based on Protein Cross-linking Interfaces Predicts Drug Targets to Limit Aggregation in Neurodegenerative Diseases.

iScience 2019 Oct 21;20:248-264. Epub 2019 Sep 21.

McClellan Veterans Medical Ctr., Central Arkansas Veterans Healthcare Service, Little Rock, AR 72205, USA; Department of Geriatrics, Reynolds Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. Electronic address:

Diagnosis of neurodegenerative diseases hinges on "seed" proteins detected in disease-specific aggregates. These inclusions contain diverse constituents, adhering through aberrant interactions that our prior data indicate are nonrandom. To define preferential protein-protein contacts mediating aggregate coalescence, we created click-chemistry reagents that cross-link neighboring proteins within human, APP-driven, neuroblastoma-cell aggregates. These reagents incorporate a biotinyl group to efficiently recover linked tryptic-peptide pairs. Mass-spectroscopy outputs were screened for all possible peptide pairs in the aggregate proteome. These empirical linkages, ranked by abundance, implicate a protein-adherence network termed the "aggregate contactome." Critical hubs and hub-hub interactions were assessed by RNAi-mediated rescue of chemotaxis in aging nematodes, and aggregation-driving properties were inferred by multivariate regression and neural-network approaches. Aspirin, while disrupting aggregation, greatly simplified the aggregate contactome. This approach, and the dynamic model of aggregate accrual it implies, reveals the architecture of insoluble-aggregate networks and may reveal targets susceptible to interventions to ameliorate protein-aggregation diseases.
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http://dx.doi.org/10.1016/j.isci.2019.09.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817627PMC
October 2019

GZ-11608, a Vesicular Monoamine Transporter-2 Inhibitor, Decreases the Neurochemical and Behavioral Effects of Methamphetamine.

J Pharmacol Exp Ther 2019 11 14;371(2):526-543. Epub 2019 Aug 14.

Department of Pharmaceutical Sciences, College of Pharmacy (N.-R.L., M.L., J.R.N., L.P.D.), and Department of Psychology, College of Arts & Sciences (M.T.B.), University of Kentucky, Lexington, Kentucky; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida (G.Z.); and Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas (V.J., P.A.C.)

Despite escalating methamphetamine use and high relapse rates, pharmacotherapeutics for methamphetamine use disorders are not available. Our iterative drug discovery program had found that --(1,2-dihydroxypropyl)-2,6--di-(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A), a selective vesicular monoamine transporter-2 (VMAT2) inhibitor, specifically decreased methamphetamine's behavioral effects. However, GZ-793A inhibited human-ether-a-go-go-related gene (hERG) channels, suggesting cardiotoxicity and prohibiting clinical development. The current study determined if replacement of GZ-793A's piperidine ring with a phenylalkyl group to yield -3-(4-methoxyphenyl)--(1-phenylpropan-2-yl)propan-1-amine (GZ-11608) diminished hERG interaction while retaining pharmacological efficacy. VMAT2 inhibition, target selectivity, and mechanism of GZ-11608-induced inhibition of methamphetamine-evoked vesicular dopamine release were determined. We used GZ-11608 doses that decreased methamphetamine-sensitized activity to evaluate the potential exacerbation of methamphetamine-induced dopaminergic neurotoxicity. GZ-11608-induced decreases in methamphetamine reinforcement and abuse liability were determined using self-administration, reinstatement, and substitution assays. Results show that GZ-11608 exhibited high affinity (K = 25 nM) and selectivity (92-1180-fold) for VMAT2 over nicotinic receptors, dopamine transporter, and hERG, suggesting low side-effects. GZ-11608 (EC = 620 nM) released vesicular dopamine 25-fold less potently than it inhibited VMAT2 dopamine uptake. GZ-11608 competitively inhibited methamphetamine-evoked vesicular dopamine release (Schild regression slope = 0.9 ± 0.13). GZ-11608 decreased methamphetamine sensitization without altering striatal dopamine content or exacerbating methamphetamine-induced dopamine depletion, revealing efficacy without neurotoxicity. GZ-11608 exhibited linear pharmacokinetics and rapid brain penetration. GZ-11608 decreased methamphetamine self-administration, and this effect was not surmounted by increasing methamphetamine unit doses. GZ-11608 reduced cue- and methamphetamine-induced reinstatement, suggesting potential to prevent relapse. GZ-11608 neither served as a reinforcer nor substituted for methamphetamine, suggesting low abuse liability. Thus, GZ-11608, a potent and selective VMAT2 inhibitor, shows promise as a therapeutic for methamphetamine use disorder. SIGNIFICANCE STATEMENT: GZ-11608 is a potent and selective vesicular monoamine transporter-2 inhibitor that decreases methamphetamine-induced dopamine release from isolated synaptic vesicles from brain dopaminergic neurons. Results from behavioral studies show that GZ-11608 specifically decreases methamphetamine-sensitized locomotor activity, methamphetamine self-administration, and reinstatement of methamphetamine-seeking behavior, without exhibiting abuse liability. Tolerance does not develop to the efficacy of GZ-11608 to decrease the behavioral effects of methamphetamine. In conclusion, GZ-11608 is an outstanding lead in our search for a therapeutic to treat methamphetamine use disorder.
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http://dx.doi.org/10.1124/jpet.119.258699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863457PMC
November 2019

Inhibition of Human DNA Polymerases Eta and Kappa by Indole-Derived Molecules Occurs through Distinct Mechanisms.

ACS Chem Biol 2019 06 22;14(6):1337-1351. Epub 2019 May 22.

Department of Biochemistry and Molecular Biology , University of Arkansas for Medical Sciences , Little Rock , Arkansas 72205-7199 , United States.

Overexpression of human DNA polymerase kappa (hpol κ) in glioblastoma is associated with shorter survival time and resistance to the alkylating agent temozolomide (TMZ), making it an attractive target for the development of small-molecule inhibitors. We previously reported on the development and characterization of indole barbituric acid-derived (IBA) inhibitors of translesion DNA synthesis polymerases (TLS pols). We have now identified a potent and selective inhibitor of hpol κ based on the indole-aminoguanidine (IAG) chemical scaffold. The most promising IAG analogue, IAG-10, exhibited greater inhibitory action against hpol κ than any other human Y-family member, as well as pols from the A-, B-, and X-families. Inhibition of hpol κ by IAG analogues appears to proceed through a mechanism that is distinct from inhibition of hpol η based on changes in DNA binding affinity and nucleotide insertion kinetics. By way of comparison, both IAG and IBA analogues inhibited binary complex formation by hpol κ and ternary complex formation by hpol η. Decreasing the concentration of enzyme and DNA in the reaction mixture lowered the IC value of IAG-10 to submicromolar values, consistent with inhibition of binary complex formation for hpol κ. Chemical footprinting experiments revealed that IAG-10 binds to a cleft between the finger, little finger, and N-clasp domains on hpol κ and that this likely disrupts the interaction between the N-clasp and the TLS pol core. In cell culture, IAG-10 potentiated the antiproliferative activity and DNA damaging effects of TMZ in hpol κ-proficient cells but not in hpol κ-deficient cells, indicative of a target-dependent effect. Mutagenic replication across alkylation damage increased in hpol κ-proficient cells treated with IAG-10, while no change in mutation frequency was observed for hpol κ-deficient cells. In summary, we developed a potent and selective small-molecule inhibitor of hpol κ that takes advantage of structural features unique to this TLS enzyme to potentiate TMZ, a standard-of-care drug used in the treatment of malignant brain tumors. Furthermore, the IAG scaffold represents a new chemical space for the exploration of TLS pol inhibitors, which could prove useful as a strategy for improving patient response to genotoxic drugs.
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http://dx.doi.org/10.1021/acschembio.9b00304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357868PMC
June 2019

Reduced Tolerance and Asymmetrical Crosstolerance to Effects of the Indole Quinuclidinone Analog PNR-4-20, a G Protein-Biased Cannabinoid 1 Receptor Agonist in Mice: Comparisons with Δ-Tetrahydrocannabinol and JWH-018.

J Pharmacol Exp Ther 2019 05 4;369(2):259-269. Epub 2019 Mar 4.

Department of Pharmacology and Toxicology, College of Medicine (B.M.F., C.V.C., S.T., L.N.F., P.L.P., W.E.F.), and Department of Pharmaceutical Sciences, College of Pharmacy (N.R.P., P.A.C.), University of Arkansas for Medical Sciences, Little Rock, Arkansas

Most cannabinoid 1 receptor (CBR) agonists will signal through both G protein-dependent and -independent pathways in an unbiased manner. Recruitment of -arrestin 2 desensitizes and internalizes receptors, producing tolerance that limits therapeutic utility of cannabinoids for chronic conditions. We developed the indole quinuclidinone (IQD) analog (Z)-2-((1-(4-fluorobenzyl)-1H-indol-3-yl)methylene)quinuclidin-3-one (PNR-4-20) as a novel G protein-biased agonist at CBRs, and the present studies determine if repeated administration of PNR-4-20 produces lesser tolerance to in vivo effects compared with unbiased CBR agonists Δ-tetrahydrocannabinol (Δ-THC) and 1-pentyl-3-(1-naphthoyl)indole (JWH-018). Adult male National Institutes of Health Swiss mice were administered comparable doses of PNR-4-20 (100 mg/kg), Δ-THC (30 mg/kg), or JWH-018 (3 mg/kg) once per day for five consecutive days to determine tolerance development to hypothermic, antinociceptive, and cataleptic effects. Persistence of tolerance was then determined after a drug abstinence period. We found that unbiased CBR agonists Δ-THC and JWH-018 produced similar tolerance to these effects, but lesser tolerance was observed with PNR-4-20 for hypothermic and cataleptic effects. Tolerance to the effects of PNR-4-20 completely recovered after drug abstinence, while residual tolerance was always observed with unbiased CBR agonists. Repeated treatment with PNR-4-20 and Δ-THC produced asymmetric crosstolerance to hypothermic effects. Importantly, binding studies suggest PNR-4-20 produced significantly less downregulation of CBRs relative to Δ-THC in hypothalamus and thalamus of chronically treated mice. These studies suggest that the G protein-biased CBR agonist PNR-4-20 produces significantly less tolerance than unbiased cannabinoid agonists, and that the IQD analogs should be investigated further as a novel molecular scaffold for development of new therapeutics.
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http://dx.doi.org/10.1124/jpet.118.252965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447997PMC
May 2019

Canvass: A Crowd-Sourced, Natural-Product Screening Library for Exploring Biological Space.

ACS Cent Sci 2018 Dec 5;4(12):1727-1741. Epub 2018 Dec 5.

Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, Indiana 47405, United States.

Natural products and their derivatives continue to be wellsprings of nascent therapeutic potential. However, many laboratories have limited resources for biological evaluation, leaving their previously isolated or synthesized compounds largely or completely untested. To address this issue, the Canvass library of natural products was assembled, in collaboration with academic and industry researchers, for quantitative high-throughput screening (qHTS) across a diverse set of cell-based and biochemical assays. Characterization of the library in terms of physicochemical properties, structural diversity, and similarity to compounds in publicly available libraries indicates that the Canvass library contains many structural elements in common with approved drugs. The assay data generated were analyzed using a variety of quality control metrics, and the resultant assay profiles were explored using statistical methods, such as clustering and compound promiscuity analyses. Individual compounds were then sorted by structural class and activity profiles. Differential behavior based on these classifications, as well as noteworthy activities, are outlined herein. One such highlight is the activity of (-)-2()-cathafoline, which was found to stabilize calcium levels in the endoplasmic reticulum. The workflow described here illustrates a pilot effort to broadly survey the biological potential of natural products by utilizing the power of automation and high-throughput screening.
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http://dx.doi.org/10.1021/acscentsci.8b00747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311695PMC
December 2018

N-Naphthoyl-substituted indole thio-barbituric acid analogs inhibit the helicase activity of the hepatitis C virus NS3.

Bioorg Med Chem Lett 2019 02 13;29(3):430-434. Epub 2018 Dec 13.

Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA. Electronic address:

The hepatitis C virus (HCV) represents a substantial threat to human health worldwide. The virus expresses a dual-function protein, NS3 having both protease and RNA helicase activities that are essential for productive viral replication and sustained infections. While viral protease and polymerase inhibitors have shown great successes in treating chronic HCV infections, drugs that specifically target the helicase activity have not advanced. A robust and quantitative 96-well plate-based fluorescent DNA unwinding assay was used to screen a class of indole thio-barbituric acid (ITBA) analogs using the full-length, recombinant HCV NS3, and identified three naphthoyl-containing analogs that efficiently inhibited NS3 helicase activity in a dose-dependent manner, with observed IC values of 21-24 µM. Standard gel electrophoresis helicase assays using radiolabeled duplex DNA and RNA NS3 substrates confirmed the inhibition of NS3 unwinding activity. Subsequent anisotropy measurements demonstrated that the candidate compounds did not disrupt NS3 binding to nucleic acids. Additionally, the rate of ATP hydrolysis and the protease activity were also not affected by the inhibitors. Thus, these results indicate that the three ITBA analogs containing N-naphthoyl moieties are the foundation of a potential series of small molecules capable of inhibiting NS3 activity via a novel interaction with the helicase domain that prevents the productive unwinding of nucleic acid substrates, and may represent the basis for a new class of therapeutic agents with the potential to aid in the treatment and eradication of hepatitis C virus.
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http://dx.doi.org/10.1016/j.bmcl.2018.12.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377802PMC
February 2019

A novel tetrazole analogue of resveratrol is a potent anticancer agent.

Bioorg Med Chem Lett 2019 01 4;29(2):172-178. Epub 2018 Dec 4.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. Electronic address:

A series of novel tetrazole analogues of resveratrol were synthesized and evaluated for their anti-leukemic activity against an extensive panel of human cancer cell lines and against the MV4-11 AML cell line. These molecules were designed as drug-like derivatives of the resveratrol analogue DMU-212 and its cyano derivatives. Four compounds 8g, 8h, 10a and 10b exhibited LD values of 4.60 µM, 0.02 µM, 1.46 µM, and 1.08 µM, respectively, against MV4-11 leukemia cells. The most potent compounds, 8h and 10b, were also found to be active against an extensive panel of human hematological and solid tumor cell lines; compound 8h was the most potent compound with GI values <10 nM against more than 90% of the human cancer cell lines in the 60-cell panel. Analogues 8g, 8h, 10a and 10b were also tested for their ability to inhibit the polymerization of tubulin, and compound 8h was found to be the most potent analogue. Molecular modeling studies demonstrated that 8h binds to the colchicine binding site on tubulin. Thus, compound 8h is considered to be a lead druglike molecule from this tetrazole series of compounds.
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http://dx.doi.org/10.1016/j.bmcl.2018.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497071PMC
January 2019

Crystal structure of 13-()-(2-amino-benzyl-idene)parthenolide.

Acta Crystallogr E Crystallogr Commun 2018 Nov 9;74(Pt 11):1543-1546. Epub 2018 Oct 9.

Dept. of Pharm. Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.

The title compound, CHNO [systematic name: (1a,4,7a,8,10a,10b)-8-(2-amino-benzyl-idene)-1a,5-dimethyl-2,3,6,7,7a,8,10a,10b-octa-hydro-oxireno[2',3':9,10]cyclo-deca-[1,2-]furan-9(1a)-one], was synthesized by the reaction of parthenolide [systematic name (1a,7a,10a,10b,)-1a,5-dimethyl-8-methyl-ene-2,3,6,7,7a,8,10,10b-octa-hydro-oxireno[2',3':9,10]cyclo-deca-[1,2-]furan-9(1a)-one] with 2-iodo-aniline Heck reaction conditions. The mol-ecule is composed of fused ten-, five- (lactone), and three-membered (epoxide) rings. The lactone ring shows a flattened envelope-type conformation (r.m.s. deviation from planarity = 0.0477 Å), and bears a 2-amino-benzyl-idene substituent that is disordered over two conformations [occupancy factors 0.901 (4) and 0.099 (4)]. The ten-membered ring has an approximate chair-chair conformation. The dihedral angle between the 2-amino-benzyl-idine moiety (major component) and the lactone ring (mean plane) is 59.93 (7)°. There are no conventional hydrogen bonds, but there are a number of weaker C-H⋯O-type inter-actions.
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http://dx.doi.org/10.1107/S2056989018013622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218918PMC
November 2018

An improved model of ethanol and nicotine co-use in female P rats: Effects of naltrexone, varenicline, and the selective nicotinic α6β2* antagonist r-bPiDI.

Drug Alcohol Depend 2018 12 17;193:154-161. Epub 2018 Oct 17.

Department of Psychology, University of Kentucky, 106 B, Kastle Hall, Lexington, KY 40536, USA. Electronic address:

Background Although pharmacotherapies are available for alcohol (EtOH) or tobacco use disorders individually, it may be possible to develop a single pharmacotherapy to treat heavy drinking tobacco smokers by capitalizing on the commonalities in their mechanisms of action. Methods Female alcohol-preferring (P) rats were trained for EtOH drinking and nicotine self-administration in two phases: (1) EtOH alone (0 vs. 15% EtOH, 2-bottle choice) and (2) concomitant access, during which EtOH access continued with access to nicotine (0.03 mg/kg/infusion, i.v.) using a 2-lever choice procedure (active vs. inactive lever) in which the fixed ratio (FR) requirement was gradually increased to FR30. When stable co-use was obtained, rats were pretreated with varying doses of naltrexone, varenicline, or r-bPiDI, an α6β2* subtype-selective nicotinic acetylcholine receptor antagonist shown previously to reduce nicotine self-administration. Results While EtOH intake was initially suppressed in phase 2 (co-use), pharmacologically relevant intake for both substances was achieved by raising the "price" of nicotine to FR30. In phase 2, naltrexone decreased EtOH and water consumption but not nicotine intake; in contrast, naltrexone in phase 1 (EtOH only) did not significantly alter EtOH intake. Varenicline and r-bPiDI in phase 2 both decreased nicotine self-administration and inactive lever pressing, but neither altered EtOH or water consumption. Conclusions These results indicate that increasing the "price" of nicotine increases EtOH intake during co-use. Additionally, the efficacy of naltrexone, varenicline, and r-bPiDI was specific to either EtOH or nicotine, with no efficacy for co-use. Nevertheless, future studies on combining these treatments may reveal synergistic efficacy.
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http://dx.doi.org/10.1016/j.drugalcdep.2018.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6239925PMC
December 2018

Actinomycin-D and dimethylamino-parthenolide synergism in treating human pancreatic cancer cells.

Drug Dev Res 2018 09 17;79(6):287-294. Epub 2018 Sep 17.

University of Arkansas for Medical Sciences, Little Rock, Arkansas.

Preclinical Research & Development Pancreatic cancer is the third leading cause of death in the US with a poor 5-year survival rate of 8.5%. A novel anti-cancer drug, dimethylamino parthenolide (DMAPT), is the water-soluble analog of the natural sesquiterpene lactone, parthenolide. The putative modes of action of DMAPT are inhibition of the Nuclear chain factor kappa-light-chain enhancer of activated B cells (NFκB) pathway and depletion of glutathione levels; the latter causing cancer cells to be more susceptible to oxidative stress-induced cell death. Actinomycin-D (ActD) is a polypeptide antibiotic that binds to DNA, and inhibits RNA and protein synthesis by inhibiting RNA polymerase II. A phase 2 clinical trial indicated that ActD could be a potent drug against pancreatic cancer; however, it was not a favored drug due to toxicity issues. New drug entities and methods of drug delivery, used alone or in combination, are needed to treat pancreatic cancer more effectively. Thus, it was postulated that combining DMAPT and ActD would result in synergistic inhibition of Panc-1 pancreatic cancer cell growth because DMAPT's inhibition of NFκB would enhance induction of apoptosis by ActD, via phosphorylation of c-Jun, by minimizing NFκB inhibition of c-Jun phosphorylation. Combining these two drugs induced a higher level of cell death than each drug alone. A fixed drug ratio of DMAPT: ActD (1,200:1) was used. Data from metabolic (MTT) and colony formation assays were analyzed for synergism with CompuSyn software, which utilizes the Chou-Talalay equation. The analyses indicated synergism and moderate synergism at combination concentrations of DMAPT/ActD of 12/0.01 and 18/0.015 μM, respectively.
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http://dx.doi.org/10.1002/ddr.21441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193836PMC
September 2018

MMB triazole analogs are potent NF-κB inhibitors and anti-cancer agents against both hematological and solid tumor cells.

Eur J Med Chem 2018 Sep 10;157:562-581. Epub 2018 Aug 10.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA. Electronic address:

Triazole derivatives of melampomagnolide B (MMB) have been synthesized via click chemistry methodologies and screened against a panel of 60 human cancer cell lines. Several derivatives showed promising anti-cancer activity, affording growth inhibition (GI) values in the nanomolar range (GI = 0.02-0.99 μM). Lead compound 7h exhibited EC values of 400 nM and 700 nM, respectively, against two AML clinical specimens. Compound 7h was significantly more potent than parthenolide as an inhibitor of p65 phosphorylation in both hematological and solid tumor cell lines, indicating its ability to inhibit the NF-κB pathway. In TMD-231 breast cancer cells, treatment with 7h reduced DNA binding activity of NF-κB through inhibition of IKK-β mediated p65 phosphorylation and caused elevation of basal IκBα levels through inhibition of constitutive IκBα turnover and NF-κB activation. Molecular docking and dynamic modeling studies indicated that 7h interacts with the kinase domain of the monomeric IKKβ subunit, leading to inhibition of IKKβ activation, and compromising phosphorylation of downstream targets of the NF-κB pathway; dynamic modeling studies show that this interaction also causes unwinding of the α-helix of the NEMO binding site on IKKβ. Molecular docking studies with 10, a water-soluble analog of 7h, demonstrate that this analog interacts with the dimerization/oligomerization domain of monomeric IKKβ and may inhibit oligomer formation and subsequent autophosphorylation. Sesquiterpene lactones 7h and 10 are considered ideal candidates for potential clinical development.
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http://dx.doi.org/10.1016/j.ejmech.2018.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281399PMC
September 2018

Highly sulphated cellulose: a versatile, reusable and selective desilylating agent for deprotection of alcoholic TBDMS ethers.

Org Biomol Chem 2018 08;16(33):6057-6062

Department of Pharmaceutical Sciences College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.

A mild, efficient and rapid protocol was developed for the deprotection of alcoholic TBDMS ethers using a recyclable, eco-friendly highly sulphated cellulose sulphate acid catalyst in methanol. This acid catalyst selectively cleaves alcoholic TBDMS ethers in bis-TBDMS ethers containing both alcoholic and phenolic TBDMS ether moieties.
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http://dx.doi.org/10.1039/c8ob01438hDOI Listing
August 2018

Parthenolide and DMAPT induce cell death in primitive CML cells through reactive oxygen species.

J Cell Mol Med 2018 10 5;22(10):4899-4912. Epub 2018 Aug 5.

Leukemic Stem Cells Lab, Oncology Research Unit, Mexican Institute of Social Security, Oncology Hospital, "Siglo XXI" National Medical Center, Mexico City, Mexico.

Tyrosine kinase inhibitors (TKI) have become a first-line treatment for chronic myeloid leuakemia (CML). TKIs efficiently target bulk CML cells; however, they are unable to eliminate the leukaemic stem cell (LSC) population that causes resistance and relapse in CML patients. In this study, we assessed the effects of parthenolide (PTL) and dimethyl amino parthenolide (DMAPT), two potent inhibitors of LSCs in acute myeloid leukaemia (AML), on CML bulk and CML primitive (CD34 lin ) cells. We found that both agents induced cell death in CML, while having little effect on the equivalent normal hematopoietic cells. PTL and DMAPT caused an increase in reactive oxygen species (ROS) levels and inhibited NF-κB activation. PTL and DMAPT inhibited cell proliferation and induced cell cycle arrest in G and G phases. Furthermore, we found cell cycle inhibition to correlate with down-regulation of cyclin D1 and cyclin A. In summary, our study shows that PTL and DMAPT have a strong inhibitory effect on CML cells. Given that cell cycle arrest was not dependent on ROS induction, we speculate that this effect could be a direct consequence of NF-κB inhibition and if this mechanism was to be evaded, PTL and DMAPT induced cell death would be potentiated.
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http://dx.doi.org/10.1111/jcmm.13755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156390PMC
October 2018

Evaluation of morphine-like effects of the mixed mu/delta agonist morphine-6--sulfate in rats: Drug discrimination and physical dependence.

Pharmacol Res Perspect 2018 07 19;6(4):e00403. Epub 2018 Jun 19.

Department of Pharmacology and Toxicology University of Arkansas for Medical Sciences Little Rock Arkansas 72205.

Morphine-6-O-sulfate (M6S) is as a mixed-action mu/delta (μ/δ) opioid receptor agonist with high potency and analgesic efficacy. These studies used assays of drug discrimination and schedule-controlled responding to assess abuse-liability, tolerance, and physical dependence as compared to morphine in rats. Attempts to train 0.3 mg/kg (IP) M6S from saline failed, but all rats rapidly acquired the discrimination when the training dose was changed to 3.0 mg/kg morphine, and substitution tests showed that morphine and fentanyl both fully substituted for the training dose, M6S and M3A6S (3-O-acetyl ester of M6S) only partially substituted, and salvinorin A did not elicit morphine-like effects. Tolerance to response rate-decreasing effects was studied in rats administered either 1.0 or 3.0 mg/kg morphine or M6S before food-reinforced operant sessions. At both unit doses, tolerance to M6S-elicited rate suppression developed more slowly than tolerance to morphine-induced reductions in response rates. To assess dependence, rats were maintained on 1.0 mg/kg morphine or 1.0 mg/kg M6S until food-reinforced response rates were stable for at least 5 days. Rats were then administered saline or increasing doses of the opioid antagonist naltrexone (NTX) (0.3, 1.0, 3.0, or 10.0 mg/kg) in order to determine antagonist-precipitated withdrawal. NTX precipitated withdrawal was similar in both morphine-maintained and M6S-maintained rats. In conclusion, the mixed μ/δ agonist activity of M6S failed to completely protect against the development of physical dependence, but delayed tolerance development to behavioral effects and resulted in decreased morphine-like subjective effects, perhaps implying a decreased abuse liability over μ agonists.
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http://dx.doi.org/10.1002/prp2.403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009770PMC
July 2018
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