Publications by authors named "Jinhong Ren"

21 Publications

  • Page 1 of 1

Na/K-ATPase-Targeted Cytotoxicity of (+)-Digoxin and Several Semisynthetic Derivatives.

J Nat Prod 2020 03 25;83(3):638-648. Epub 2020 Feb 25.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States.

(+)-Digoxin () is a well-known cardiac glycoside long used to treat congestive heart failure and found more recently to show anticancer activity. Several known cardenolides (-) and two new analogues, (+)-8(9)-β-anhydrodigoxigenin () and (+)-17--20,22-dihydro-21α-hydroxydigoxin (), were synthesized from and evaluated for their cytotoxicity toward a small panel of human cancer cell lines. A preliminary structure-activity relationship investigation conducted indicated that the C-12 and C-14 hydroxy groups and the C-17 unsaturated lactone unit are important for to mediate its cytotoxicity toward human cancer cells, but the C-3 glycosyl residue seems to be less critical for such an effect. Molecular docking profiles showed that the cytotoxic and the noncytotoxic derivative bind differentially to Na/K-ATPase. The HO-12β, HO-14β, and HO-3'aα hydroxy groups of (+)-digoxin () may form hydrogen bonds with the side-chains of Asp121 and Asn122, Thr797, and Arg880 of Na/K-ATPase, respectively, but the altered lactone unit of results in a rotation of its steroid core, which depotentiates the binding between this compound and Na/K-ATPase. Thus, was found to inhibit Na/K-ATPase, but did not. In addition, the cytotoxic did not affect glucose uptake in human cancer cells, indicating that this cardiac glycoside mediates its cytotoxicity by targeting Na/K-ATPase but not by interacting with glucose transporters.
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http://dx.doi.org/10.1021/acs.jnatprod.9b01060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243443PMC
March 2020

Cytotoxic and non-cytotoxic cardiac glycosides isolated from the combined flowers, leaves, and twigs of Streblus asper.

Bioorg Med Chem 2020 02 7;28(4):115301. Epub 2020 Jan 7.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States. Electronic address:

A new non-cytotoxic [(+)-17β-hydroxystrebloside (1)] and two known cytotoxic [(+)-3'-de-O-methylkamaloside (2) and (+)-strebloside (3)] cardiac glycosides were isolated and identified from the combined flowers, leaves, and twigs of Streblus asper collected in Vietnam, with the absolute configuration of 1 established from analysis of its ECD and NMR spectroscopic data and confirmed by computational ECD calculations. A new 14,21-epoxycardanolide (3a) was synthesized from 3 that was treated with base. A preliminary structure-activity relationship study indicated that the C-14 hydroxy group and the C-17 lactone unit and the established conformation are important for the mediation of the cytotoxicity of 3. Molecular docking profiles showed that the cytotoxic 3 and its non-cytotoxic analogue 1 bind differentially to Na/K-ATPase. Compound 3 docks deeply in the Na/K-ATPase pocket with a sole pose, and its C-10 formyl and C-5, C-14, and C-4' hydroxy groups may form hydrogen bonds with the side-chains of Glu111, Glu117, Thr797, and Arg880 of Na/K-ATPase, respectively. However, 1 fits the cation binding sites with at least three different poses, which all depotentiate the binding between 1 and Na/K-ATPase. Thus, 3 was found to inhibit Na/K-ATPase, but 1 did not. In addition, the cytotoxic and Na/K-ATPase inhibitory 3 did not affect glucose uptake in human lung cancer cells, against which it showed potent activity, indicating that this cardiac glycoside mediates its cytotoxicity by targeting Na/K-ATPase but not by interacting with glucose transporters.
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http://dx.doi.org/10.1016/j.bmc.2019.115301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029422PMC
February 2020

MD simulations reveal alternate conformations of the oxyanion hole in the Zika virus NS2B/NS3 protease.

Proteins 2020 02 9;88(2):345-354. Epub 2019 Sep 9.

Center for Biomolecular Sciences, University of Illinois at Chicago, Chicago, Illinois.

Recent crystallography studies have shown that the binding site oxyanion hole plays an important role in inhibitor binding, but can exist in two conformations (active/inactive). We have undertaken molecular dynamics (MD) calculations to better understand oxyanion hole dynamics and thermodynamics. We find that the Zika virus (ZIKV) NS2B/NS3 protease maintains a stable closed conformation over multiple 100-ns conventional MD simulations in both the presence and absence of inhibitors. The S1, S2, and S3 pockets are stable as well. However, in two of eight simulations, the A132-G133 peptide bond in the binding pocket of S1' spontaneously flips to form a 3 -helix that corresponds to the inactive conformation of the oxyanion hole, and then maintains this conformation until the end of the 100-ns conventional MD simulations without inversion of the flip. This conformational change affects the S1' pocket in ZIKV NS2B/NS3 protease active site, which is important for small molecule binding. The simulation results provide evidence at the atomic level that the inactive conformation of the oxyanion hole is more favored energetically when no specific interactions are formed between substrate/inhibitor and oxyanion hole residues. Interestingly, however, transition between the active and inactive conformation of the oxyanion hole can be observed by boosting the valley potential in accelerated MD simulations. This supports a proposed induced-fit mechanism of ZIKV NS2B/NS3 protease from computational methods and provides useful direction to enhance inhibitor binding predictions in structure-based drug design.
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http://dx.doi.org/10.1002/prot.25809DOI Listing
February 2020

Colony-stimulating factor 1 and its receptor are new potential therapeutic targets for allergic asthma.

Allergy 2020 02 11;75(2):357-369. Epub 2019 Oct 11.

Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.

Background: A new approach targeting aeroallergen sensing in the early events of mucosal immunity could have greater benefit. The CSF1-CSF1R pathway has a critical role in trafficking allergens to regional lymph nodes through activating dendritic cells. Intervention in this pathway could prevent allergen sensitization and subsequent Th2 allergic inflammation.

Objective: To examine the therapeutic effectiveness of CSF1 and CSF1R inhibition for blocking the dendritic cell function of sensing aeroallergens.

Methods: We adopted a model of chronic asthma induced by a panel of three naturally occurring allergens and novel delivery system of CSF1R inhibitor encapsulated nanoprobe.

Results: Selective depletion of CSF1 in airway epithelial cells abolished the production of allergen-reactive IgE, resulting in prevention of new asthma development as well as reversal of established allergic lung inflammation. CDPL-GW nanoprobe containing GW2580, a selective CSF1R inhibitor, showed favorable pharmacokinetics for inhalational treatment and intranasal insufflation delivery of CDPL-GW nanoprobe ameliorated asthma pathologies including allergen-specific serum IgE production, allergic lung and airway inflammation and airway hyper-responsiveness (AHR) with minimal pulmonary adverse reaction.

Conclusion: The inhibition of the CSF1-CSF1R signaling pathway effectively suppresses sensitization to aeroallergens and consequent allergic lung inflammation in a murine model of chronic asthma. CSF1R inhibition is a promising new target for the treatment of allergic asthma.
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http://dx.doi.org/10.1111/all.14011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002247PMC
February 2020

Identification of Small Molecules Exhibiting Oxacillin Synergy through a Novel Assay for Inhibition of Expression in Methicillin-Resistant Staphylococcus aureus.

Antimicrob Agents Chemother 2019 09 23;63(9). Epub 2019 Aug 23.

Center for Biomolecular Sciences and Department of Medicinal Chemistry & Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois, USA

Methicillin-resistant (MRSA) strains that are resistant to all forms of penicillin have become an increasingly common and urgent problem threatening human health. They are responsible for a wide variety of infectious diseases ranging from minor skin abscesses to life-threatening severe infections. The operon that is conserved among strains encodes a three-component signal transduction system () that is responsible for sensing and responding to cell wall stress. We developed a novel and multifaceted assay to identify compounds that potentiate the activity of oxacillin, essentially restoring efficacy of oxacillin against MRSA, and performed high-throughput screening (HTS) to identify oxacillin potentiators. HTS of 13,840 small-molecule compounds from an antimicrobial-focused Life Chemicals library, using the MRSA cell-based assay, identified three different inhibitor scaffolds. Checkerboard assays for synergy with oxacillin, reverse transcriptase PCR (RT-PCR) assays against expression, and direct confirmation of interaction with VraS by surface plasmon resonance (SPR) further verified them to be viable hit compounds. A subsequent structure-activity relationship (SAR) study of the best scaffold with diverse analogs was utilized to improve potency and provides a strong foundation for further development.
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http://dx.doi.org/10.1128/AAC.02593-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709460PMC
September 2019

Exploring small molecules with pan-genotypic inhibitory activities against hepatitis C virus NS3/4A serine protease.

Bioorg Med Chem Lett 2019 08 8;29(16):2349-2353. Epub 2019 Jun 8.

Center for Biomolecular Sciences, University of Illinois at Chicago, 900 S. Ashland Ave, Chicago, IL 60607, USA; Biophysics Core at Research Resource Center, University of Illinois at Chicago, Chicago, IL 60612, USA; Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 S. Wood Street, IL 60612, USA. Electronic address:

Among the many Hepatitis C virus (HCV) genotypes and subtypes, genotypes 1b and 3a are most prevalent in United States and Asia, respectively. A total of 132 commercially available analogs of a previous lead compound were initially investigated against wild-type HCV genotype 1b NS3/4A protease. Ten compounds showed inhibitory activities (IC values) below 10 µM with comparable direct binding affinities (K values) determined by surface plasmon resonance (SPR). To identify pan-genotypic inhibitors, these ten selected compounds were tested against four additional genotypes (1a, 2a, 3a, and 4) and three drug-resistant mutants (A156S, R155K, and V36M). Four new analogs have been identified with better activities against all five tested genotypes than the prior lead compound. Further, the original lead compound did not show activity against genotype 3a NS3/4A, whereas four newly identified compounds exhibited IC values below 33 µM against genotype 3a NS3/4A. Encouragingly, the best new compound F1813-0710 possessed promising activity toward genotype 3a, which is a huge improvement over the previous lead compound that had no effect on genotype 3a. This intriguing observation was further analyzed by molecular docking and molecular dynamics (MD) simulations to understand their different binding interactions, which should benefit future pan-genotypic inhibitor design and drug discovery.
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http://dx.doi.org/10.1016/j.bmcl.2019.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690791PMC
August 2019

High-Resolution Structure of ClpC1-Rufomycin and Ligand Binding Studies Provide a Framework to Design and Optimize Anti-Tuberculosis Leads.

ACS Infect Dis 2019 06 3;5(6):829-840. Epub 2019 May 3.

Institute for Tuberculosis Research, College of Pharmacy , University of Illinois at Chicago , 833 S. Wood Street , Chicago , Illinois 60612 , United States.

Addressing the urgent need to develop novel drugs against drug-resistant Mycobacterium tuberculosis ( M. tb) strains, ecumicin (ECU) and rufomycin I (RUFI) are being explored as promising new leads targeting cellular proteostasis via the caseinolytic protein ClpC1. Details of the binding topology and chemical mode of (inter)action of these cyclopeptides help drive further development of novel potency-optimized entities as tuberculosis drugs. ClpC1 M. tb protein constructs with mutations driving resistance to ECU and RUFI show reduced binding affinity by surface plasmon resonance (SPR). Despite certain structural similarities, ECU and RUFI resistant mutation sites did not overlap in their SPR binding patterns. SPR competition experiments show ECU prevents RUFI binding, whereas RUFI partially inhibits ECU binding. The X-ray structure of the ClpC1-NTD-RUFI complex reveals distinct differences compared to the previously reported ClpC1-NTD-cyclomarin A structure. Surprisingly, the complex structure revealed that the epoxide moiety of RUFI opened and covalently bound to ClpC1-NTD via the sulfur atom of Met1. Furthermore, RUFI analogues indicate that the epoxy group of RUFI is critical for binding and bactericidal activity. The outcomes demonstrate the significance of ClpC1 as a novel target and the importance of SAR analysis of identified macrocyclic peptides for drug discovery.
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http://dx.doi.org/10.1021/acsinfecdis.8b00276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657506PMC
June 2019

Identification and design of novel small molecule inhibitors against MERS-CoV papain-like protease via high-throughput screening and molecular modeling.

Bioorg Med Chem 2019 05 26;27(10):1981-1989. Epub 2019 Mar 26.

Center for Biomolecular Sciences and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, IL 60607, USA. Electronic address:

The development of new therapeutic agents against the coronavirus causing Middle East Respiratory Syndrome (MERS) is a continuing imperative. The initial MERS-CoV epidemic was contained entirely through public health measures, but episodic cases continue, as there are currently no therapeutic agents effective in the treatment of MERS-CoV, although multiple strategies have been proposed. In this study, we screened 30,000 compounds from three different compound libraries against one of the essential proteases, the papain-like protease (PL), using a fluorescence-based enzymatic assay followed by surface plasmon resonance (SPR) direct binding analysis for hit confirmation. Mode of inhibition assays and competition SPR studies revealed two compounds to be competitive inhibitors. To improve upon the inhibitory activity of the best hit compounds, a small fragment library consisting of 352 fragments was screened in the presence of each hit compound, resulting in one fragment that enhanced the IC value of the best hit compound by 3-fold. Molecular docking and MM/PBSA binding energy calculations were used to predict potential binding sites, providing insight for design and synthesis of next-generation compounds.
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http://dx.doi.org/10.1016/j.bmc.2019.03.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6638567PMC
May 2019

Hit-to-Lead: Hit Validation and Assessment.

Methods Enzymol 2018 25;610:265-309. Epub 2018 Oct 25.

Center for Biomolecular Sciences, University of Illinois at Chicago, Chicago, IL, United States; Department of Medicinal Chemistry & Pharmacognosy, University of Illinois at Chicago, Chicago, IL, United States. Electronic address:

High-throughput screening assays have become nearly ubiquitous in the search for small compounds or peptides that can modulate biological processes for therapeutic purposes. While many assays have become quite robust, with well-established protocols, the subsequent steps of validating the hits and choosing the best ones to take forward into leads for further chemical development are less established. In this chapter, we describe a variety of approaches, including chemical assessment, the use of various computational approaches, a variety of counter-screens, and "orthogonal" biophysical assays using nuclear magnetic resonance, surface plasmon resonance, isothermal titration calorimetry or thermal shift assays as methods for validating and assessing the quality of hits.
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http://dx.doi.org/10.1016/bs.mie.2018.09.022DOI Listing
June 2019

Discovery of small molecule inhibitors of adenovirus by disrupting E3-19K/HLA-A2 interactions.

Bioorg Med Chem Lett 2018 09 29;28(17):2837-2841. Epub 2018 Jul 29.

Center for Biomolecular Sciences, University of Illinois at Chicago, 900 S. Ashland Ave, Chicago, IL 60607, USA; Department of Bioengineering, University of Illinois at Chicago, 835 S Wolcott Ave, Chicago, IL 60612, USA; Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland Ave, Chicago, IL 60607, USA. Electronic address:

The binding of the adenovirus (Ad) protein E3-19K with the human leukocyte antigen (HLA) plays an important role in Ad infections, which is the causative agent of a series of gastrointestinal, respiratory and ocular diseases. The objective of this research is to evaluate the essential interactions between E3-19K and HLA-A2 using the X-ray crystal structure of the E3-19K/HLA-A2 complex, and to identify small molecules that could potentially disrupt their binding. Computational methods, including molecular dynamic simulations, MM/GBSA calculations, and computational solvent mapping, were implemented to determine potential binding site(s) for small molecules. The previous experimentally determined hot spot residues, Q54 and E177 in HLA-A2, were also predicted to be the dominant residues for binding to E3-19K by our theoretical calculations. Several other residues were also found to play pivotal roles for the binding of E3-19K with HLA-A2. Residues adjacent to E177, including Q54 and several other residues theoretically predicted to be crucial in HLA-A2 were selected as a potential binding pocket to perform virtual screening with 1200 compounds from the Prestwick library. Seven hits were validated by surface plasmon resonance (SPR) as binders to HLA-A2 as a first step in identifying molecules that can perturb its association with the Ad E3-19K protein.
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http://dx.doi.org/10.1016/j.bmcl.2018.07.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109590PMC
September 2018

The Flavonoid Apigenin Is a Progesterone Receptor Modulator with In Vivo Activity in the Uterus.

Horm Cancer 2018 08 7;9(4):265-277. Epub 2018 May 7.

Department of Medicinal Chemistry and Pharmacognosy, Center for Biomolecular Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, 60607, USA.

Apigenin is a flavonoid with well-documented anti-cancer properties; however, its mechanisms of action are still unclear. We previously identified apigenin as a potential phytoprogestin, a natural product with a chemical scaffold that interacts with the progesterone receptor (PR). Our objective was to characterize the ability of apigenin to interact with PR through molecular docking studies, in vitro activity assays, and the ability of apigenin to elicit progestin-like effects in vivo. Molecular docking confirmed that apigenin could interact with PR, though with lower affinity than progesterone due to fewer van der Waals interactions. In Ishikawa cells stably expressing PR-B, apigenin significantly increased progesterone response element/luciferase (PRE/Luc) activity at 5 and 10 μM, but not in the parental Ishikawa cells that lack PR expression. In the presence of 100 nM of progesterone, 10 μM apigenin reduced PRE/Luc activity, indicative of mixed agonist activity. Apigenin also triggered degradation of PR in Ishikawa PR-B cells as measured by western blot. Apigenin reduced proliferation of Ishikawa cells, but through a PR-independent mechanism. In contrast, apigenin and progesterone both stimulated proliferation of T47D cells, an effect blocked by RU486. Apigenin activated other nuclear receptors evidenced by increased luciferase activity in MDA-MB-231 cells, which are PR negative. In vivo, apigenin blocked the genistein-stimulated increase in uterine epithelial cell height; stimulated endometrial expression of Hand2, a transcription factor stimulated by PR, and significantly reduced genistein-induced proliferation. In summary, apigenin is a phytoprogestin, with mixed agonist activity that demonstrates activity in vivo by hindering estrogen receptor-mediated uterine proliferation.
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http://dx.doi.org/10.1007/s12672-018-0333-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222006PMC
August 2018

Determination of absolute configuration and binding efficacy of benzimidazole-based FabI inhibitors through the support of electronic circular dichroism and MM-GBSA techniques.

Bioorg Med Chem Lett 2018 06 22;28(11):2074-2079. Epub 2018 Apr 22.

Center for Biomolecular Sciences, University of Illinois at Chicago, 900 S. Ashland Ave, Chicago, IL 60607, USA; Novalex Therapeutics, Inc., 2242 W Harrison, Chicago, IL 60612, USA. Electronic address:

We have previously reported benzimidazole-based compounds to be potent inhibitors of FabI for Francisella tularensis (FtFabI), making them promising antimicrobial hits. Optically active enantiomers exhibit markedly differing affinities toward FtFabI. The IC of benzimidazole (-)-1 is ∼100× lower than the (+)-enantiomer, with similar results for the 2 enantiomers. Determining the absolute configuration for these optical compounds and elucidating their binding modes is important for further design. Electronic circular dichroism (ECD) quantum calculations have become important in determining absolute configurations of optical compounds. We determined the absolute configuration of (-)/(+)-1 and (-)/(+)-2 by comparing experimental spectra and theoretical density functional theory (DFT) simulations of ECD spectra at the B3LYP/6-311+G(2d, p) level using Gaussian09. Comparison of experimental and calculated ECD spectra indicates that the S configuration corresponds to the (-)-rotation for both compounds 1 and 2, while the R configuration corresponds to the (+)-rotation. Further, molecular dynamics simulations and MM-GBSA binding energy calculations for these two pairs of enantiomers with FtFabI show much tighter binding MM-GBSA free energies for S-1 and S-2 than for their enantiomers, R-1 and R-2, consistent with the S configuration being the more active one, and with the ECD determination of the S configuration corresponding to (-) and the R configuration corresponding to (+). Thus, our computational studies allow us to assign (-) to (S)- and (+) to (R)- for compounds 1 and 2, and to further evaluate structural changes to improve efficacy.
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http://dx.doi.org/10.1016/j.bmcl.2018.04.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5970947PMC
June 2018

A novel series of enoyl reductase inhibitors targeting the ESKAPE pathogens, Staphylococcus aureus and Acinetobacter baumannii.

Bioorg Med Chem 2018 01 11;26(1):65-76. Epub 2017 Nov 11.

Novalex Therapeutics, 2242 W. Harrison, Chicago, IL 60612, United States. Electronic address:

S. aureus and A. baumannii are among the ESKAPE pathogens that are increasingly difficult to treat due to the rise in the number of drug resistant strains. Novel therapeutics targeting these pathogens are much needed. The bacterial enoyl reductase (FabI) is as potentially significant drug target for developing pathogen-specific antibiotics due to the presence of alternate FabI isoforms in many other bacterial species. We report the identification and development of a novel N-carboxy pyrrolidine scaffold targeting FabI in S. aureus and A. baumannii, two pathogens for which FabI essentiality has been established. This scaffold is unrelated to other known antibiotic families, and FabI is not targeted by any currently approved antibiotic. Our data shows that this scaffold displays promising enzyme inhibitory activity against FabI from both S. aureus and A. baumannii, as well as encouraging antibacterial activity in S. aureus. Compounds also display excellent synergy when combined with colistin and tested against A. baumannii. In this combination the MIC of colistin is reduced by 10-fold. Our first generation compound displays promising enzyme inhibition, targets FabI in S. aureus with a favorable selectivity index (ratio of cytotoxicity to MIC), and has excellent synergy with colistin against A. baumannii, including a multidrug resistant strain.
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http://dx.doi.org/10.1016/j.bmc.2017.11.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733704PMC
January 2018

Involvement of poly(ADP-ribose) polymerase-1 in Chinese patients with glioma: a potential target for effective patient care.

Int J Biol Markers 2018 Jan;33(1):68-72

2 Department of Medical Imaging, Liaocheng People's Hospital, Shandong - China.

Objective: We aimed to evaluate the genetic variation of poly(ADP-ribose) polymerase-1 (PARP-1) in the development of gliomas among Chinese individuals.

Materials And Methods: Patients with a confirmed diagnosis of glioma and healthy individuals with no clinical symptoms of glioma were enrolled at Liaocheng People's Hospital, China. Genetic polymorphisms were studied in plasma samples by polymerase chain reaction-restriction fragment length polymorphism assay. Cytokine levels were measured routinely in serum samples by sandwich ELISA technique.

Results: A total of 120 Chinese patients with gliomas and 120 healthy Chinese individuals were included. We found that patients with the GG genotype (odds ratio [OR] 2.53, 95% confidence interval [CI] 1.46-4.38, p<0.001) and carriers of the G allele (OR 11.5, 95% CI 6.31-21.3, p<0.0001) were at high risk of developing glioma. A del/ins polymorphism of the NF-κB1 gene (OR 4.27, 95% CI 2.43-7.50, p<0.001) was also found to be associated with glioma. In addition, significantly increased cytokine levels were observed in patients with glioma (p<0.05).

Conclusions: Our findings showed that PARP-1 polymorphisms are involved in the development of glioma in Chinese individuals. Also serum cytokine levels can be considered among the potential risk factors for developing glioma.
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http://dx.doi.org/10.5301/ijbm.5000267DOI Listing
January 2018

(+)-Strebloside-Induced Cytotoxicity in Ovarian Cancer Cells Is Mediated through Cardiac Glycoside Signaling Networks.

J Nat Prod 2017 03 24;80(3):659-669. Epub 2017 Feb 24.

Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , Chicago, Illinois 60612, United States.

(+)-Strebloside, a cardiac glycoside isolated from the stem bark of Streblus asper collected in Vietnam, has shown some potential for further investigation as an antineoplastic agent. A mechanistic study using an in vitro assay and molecular docking analysis indicated that (+)-strebloside binds and inhibits Na/K-ATPase in a similar manner to digitoxin. Inhibition of growth of different high-grade serous ovarian cancer cells including OVCAR3, OVSAHO, Kuramochi, OVCAR4, OVCAR5, and OVCAR8 resulted from treatment with (+)-strebloside. Furthermore, this compound blocked cell cycle progression at the G2 phase and induced PARP cleavage, indicating apoptosis activation in OVCAR3 cells. (+)-Strebloside potently inhibited mutant p53 expression through the induction of ERK pathways and inhibited NF-κB activity in human ovarian cancer cells. However, in spite of its antitumor potential, the overall biological activity of (+)-strebloside must be regarded as being typical of better-known cardiac glycosides such as digoxin and ouabain. Further chemical alteration of cardiac glycosides might help to reduce negative side effects while increasing cancer cell cytotoxicity.
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http://dx.doi.org/10.1021/acs.jnatprod.6b01150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768141PMC
March 2017

Identification of novel small molecule inhibitors against NS2B/NS3 serine protease from Zika virus.

Antiviral Res 2017 Mar 26;139:49-58. Epub 2016 Dec 26.

Novalex Therapeutics, Inc., 2242 W Harrison Suite 201, Chicago, IL 60612, USA. Electronic address:

Zika flavivirus infection during pregnancy appears to produce higher risk of microcephaly, and also causes multiple neurological problems such as Guillain-Barré syndrome. The Zika virus is now widespread in Central and South America, and is anticipated to become an increasing risk in the southern United States. With continuing global travel and the spread of the mosquito vector, the exposure is expected to accelerate, but there are no currently approved treatments against the Zika virus. The Zika NS2B/NS3 protease is an attractive drug target due to its essential role in viral replication. Our studies have identified several compounds with inhibitory activity (IC) and binding affinity (K) of ∼5-10 μM against the Zika NS2B-NS3 protease from testing 71 HCV NS3/NS4A inhibitors that were initially discovered by high-throughput screening of 40,967 compounds. Competition surface plasmon resonance studies and mechanism of inhibition analyses by enzyme kinetics subsequently determined the best compound to be a competitive inhibitor with a K value of 9.5 μM. We also determined the X-ray structure of the Zika NS2B-NS3 protease in a "pre-open conformation", a conformation never observed before for any flavivirus proteases. This provides the foundation for new structure-based inhibitor design.
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http://dx.doi.org/10.1016/j.antiviral.2016.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5627664PMC
March 2017

Total Syntheses of (-)-Spirooliganones A and B and Their Diastereoisomers: Absolute Stereochemistry and Inhibitory Activity against Coxsackie Virus B3.

Org Lett 2015 Jun 5;17(12):3118-21. Epub 2015 Jun 5.

†State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

To investigate the effects of configuration on bioactivity, spirooliganones A and B and their six diastereoisomers (1-8) were synthesized in 11 steps. The key benzopyran core was assembled by intermolecular [4 + 2] hetero-Diels-Alder cycloaddition between (-)-sabinene and o-quinone methide, which was generated from the corresponding o-hydroxybenzyl alcohol. After establishing the absolute configuration, the inhibitory activities of spirooliganones 1-8 against Coxsackie virus B3 were evaluated, and the primary structure-activity relationships were analyzed. Compound 3 was the most potent compound, with an IC50 of 0.41 μM.
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http://dx.doi.org/10.1021/acs.orglett.5b01419DOI Listing
June 2015

Synthesis and biological evaluation of 3-phenyl-3-aryl carboxamido propanoic acid derivatives as small molecule inhibitors of retinoic acid 4-hydroxylase (CYP26A1).

Bioorg Med Chem 2015 Mar 21;23(6):1356-65. Epub 2015 Jan 21.

Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China. Electronic address:

All-trans-retinoic acid (ATRA), the biologically active metabolite of vitamin A, is used medicinally for the treatment of hyperproliferative diseases and cancers. However, it is easily metabolized. In this study, the leading compound S8 was found based on virtual screening. To improve the activity of the leading compound S8, a series of novel S8 derivatives were designed, synthesized and evaluated for their in vitro biological activities. All of the prepared compounds showed that substituting the 5-chloro-3-methyl-1-phenyl-1H-pyrazole group for the 2-tertbutyl-5-methylfuran scaffold led to a clear increase in the biological activity. The most promising compound 32, with a CYP26A1 IC50 value of 1.36μM (compared to liarozole (IC50=2.45μM) and S8 (IC50=3.21μM)) displayed strong inhibitory and differentiation activity against HL60 cells. In addition, the study focused on the effect of β-phenylalanine, which forms the coordination bond with the heme of CYP26A1. These studies suggest that the compound 32 can be used as an appropriate candidate for future development.
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http://dx.doi.org/10.1016/j.bmc.2014.11.036DOI Listing
March 2015

2-(2-Methylfuran-3-carboxamido)-3-phenylpropanoic acid, a potential CYP26A1 inhibitor to enhance all-trans retinoic acid-induced leukemia cell differentiation based on virtual screening and biological evaluation.

Bioorg Med Chem 2013 Jun 3;21(11):3256-61. Epub 2013 Apr 3.

Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.

To develop new CYP26A1 inhibitors, a three-cycle virtual screening was carried out based on the constructed homology model of human CYP26A1 using Dock, Fred, Gold and AutoDock. Twenty-two compounds exhibited high scores and reasonable binding modes in molecular docking were purchased from Specs Company. Eighteen compounds were tested their abilities to enhance ATRA-induced differentiation in human acute promyelocytic leukemia NB4 cells. Eight of them enhanced the ability of ATRA to induce differentiation at concentrations of 0.5 and 1 μM. Among these compounds, 2-(2-methylfuran-3-carboxamido)-3-phenylpropanoic acid (S8) is of most effective in blocking ATRA breaking down in NB4 cells based on the LC-MS/MS assay.
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http://dx.doi.org/10.1016/j.bmc.2013.03.044DOI Listing
June 2013

Synthesis, biological evaluation, and molecular modeling of glycyrrhizin derivatives as potent high-mobility group box-1 inhibitors with anti-heart-failure activity in vivo.

J Med Chem 2013 Jan 24;56(1):97-108. Epub 2012 Dec 24.

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

Novel glycyrrhizin (GL) derivatives were designed and synthesized by introducing various amine or amino acid residues into the carbohydrate chain and at C-30. Their inhibitory effects on high-mobility group box 1 (HMGB1) were evaluated using a cell-based lipopolysaccharide (LPS) induced tumor necrosis factor α (TNF-α) release study. Compounds 10, 12, 18-20, 23, and 24, which had substituents introduced at C-30, demonstrated moderate HMGB1 inhibition with ED₅₀ values ranging from 337 to 141 μM, which are values comparable to that of the leading GL compound (1) (ED₅₀ = 70 μM). Compounds 23 and 24 emerged as novel and interesting HMGB1 inhibitors. These compounds were able to extend the survival of mice with chronic heart failure (CHF) and acute heart failure (AHF), respectively. In addition, molecular modeling studies were performed to support the biological data.
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http://dx.doi.org/10.1021/jm301248yDOI Listing
January 2013

Synthesis, biological evaluation and mechanism studies of deoxytylophorinine and its derivatives as potential anticancer agents.

PLoS One 2012 19;7(1):e30342. Epub 2012 Jan 19.

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Previous studies indicated that (+)-13a-(S)-deoxytylophorinine (1) showed profound anti-cancer activities both in vitro and in vivo and could penetrate the blood brain barrier to distribute well in brain tissues. CNS toxicity, one of the main factors to hinder the development of phenanthroindolizidines, was not obviously found in 1. Based on its fascinating activities, thirty-four derivatives were designed, synthesized; their cytotoxic activities in vitro were tested to discover more excellent anticancer agents. Considering the distinctive mechanism of 1 and interesting SAR of deoxytylophorinine and its derivatives, the specific impacts of these compounds on cellular progress as cell signaling transduction pathways and cell cycle were proceeded with seven representative compounds. 1 as well as three most potent compounds, 9, 32, 33, and three less active compounds, 12, 16, 35, were selected to proform this study to have a relatively deep view of cancer cell growth-inhibitory characteristics. It was found that the expressions of phospho-Akt, Akt, phospho-ERK, and ERK in A549 cells were greater down-regulated by the potent compounds than by the less active compounds in the Western blot analysis. To the best of our knowledge, this is the first report describing phenanthroindolizidines alkaloids display influence on the crucial cell signaling proteins, ERK. Moreover, the expressions of cyclin A, cyclin D1 and CDK2 proteins depressed more dramatically when the cells were treated with 1, 9, 32, and 33. Then, these four excellent compounds were subjected to flow cytometric analysis, and an increase in S-phase was observed in A549 cells. Since the molecular level assay results of Western blot for phospho-Akt, Akt, phospho-ERK, ERK, and cyclins were relevant to the potency of compounds in cellular level, we speculated that this series of compounds exhibit anticancer activities through blocking PI3K and MAPK signaling transduction pathways and interfering with the cell cycle progression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0030342PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3261902PMC
June 2012