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CHEMISTRY (593 journals)                  1 2 3 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
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        1 2 3 | Last

Journal Cover Bioorganic & Medicinal Chemistry
  [SJR: 1.064]   [H-I: 119]   [124 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0968-0896
   Published by Elsevier Homepage  [3044 journals]
  • Peptide & protein ligation
    • Authors: Christian F.W. Becker
      First page: 4925
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 18
      Author(s): Christian F.W. Becker

      PubDate: 2017-09-19T02:40:22Z
      DOI: 10.1016/j.bmc.2017.08.041
  • Chemical protein synthesis: Inventing synthetic methods to decipher how
           proteins work
    • Authors: Stephen Kent
      Pages: 4926 - 4937
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 18
      Author(s): Stephen Kent
      Total chemical synthesis of proteins has been rendered practical by the chemical ligation principle: chemoselective condensation of unprotected peptide segments equipped with unique, mutually reactive functional groups, enabled by formation of a non-native replacement for the peptide bond. Ligation chemistries are briefly described, including native chemical ligation – thioester-mediated, amide-forming reaction at Xaa-Cys sites – and its extensions. Case studies from the author’s own works are used to illustrate the utility and applications of chemical protein synthesis. Selected recent developments in the field are briefly discussed.
      Graphical abstract image

      PubDate: 2017-09-19T02:40:22Z
      DOI: 10.1016/j.bmc.2017.06.020
  • A statistical view of protein chemical synthesis using NCL and extended
    • Authors: Vangelis Agouridas; Ouafâa El Mahdi; Marine Cargoët; Oleg Melnyk
      Pages: 4938 - 4945
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 18
      Author(s): Vangelis Agouridas, Ouafâa El Mahdi, Marine Cargoët, Oleg Melnyk
      Native chemical ligation and extended methodologies are the most popular chemoselective reactions for protein chemical synthesis. Their combination with desulfurization techniques can give access to small or challenging proteins that are exploited in a large variety of research areas. In this report, we have conducted a statistical review of their use for protein chemical synthesis in order to provide a flavor of the recent trends and identify the most popular chemical tools used by protein chemists. To this end, a protein chemical synthesis (PCS) database ( was created by collecting a set of relevant data from more than 450 publications covering the period 1994–2017. A preliminary account of what this database tells us is presented in this report.
      Graphical abstract image

      PubDate: 2017-09-19T02:40:22Z
      DOI: 10.1016/j.bmc.2017.05.050
  • Aligator: A computational tool for optimizing total chemical synthesis of
           large proteins
    • Authors: Michael T. Jacobsen; Patrick W. Erickson; Michael S. Kay
      Pages: 4946 - 4952
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 18
      Author(s): Michael T. Jacobsen, Patrick W. Erickson, Michael S. Kay
      The scope of chemical protein synthesis (CPS) continues to expand, driven primarily by advances in chemical ligation tools (e.g., reversible solubilizing groups and novel ligation chemistries). However, the design of an optimal synthesis route can be an arduous and fickle task due to the large number of theoretically possible, and in many cases problematic, synthetic strategies. In this perspective, we highlight recent CPS tool advances and then introduce a new and easy-to-use program, Aligator (Automated Ligator), for analyzing and designing the most efficient strategies for constructing large targets using CPS. As a model set, we selected the E. coli ribosomal proteins and associated factors for computational analysis. Aligator systematically scores and ranks all feasible synthetic strategies for a particular CPS target. The Aligator script methodically evaluates potential peptide segments for a target using a scoring function that includes solubility, ligation site quality, segment lengths, and number of ligations to provide a ranked list of potential synthetic strategies. We demonstrate the utility of Aligator by analyzing three recent CPS projects from our lab: TNFα (157 aa), GroES (97 aa), and DapA (312 aa). As the limits of CPS are extended, we expect that computational tools will play an increasingly important role in the efficient execution of ambitious CPS projects such as production of a mirror-image ribosome.
      Graphical abstract image

      PubDate: 2017-09-19T02:40:22Z
      DOI: 10.1016/j.bmc.2017.05.061
  • Total chemical synthesis of methylated analogues of histone 3 revealed
           KDM4D as a potential regulator of H3K79me3
    • Authors: Muhammad Jbara; Noga Guttmann-Raviv; Suman Kumar Maity; Nabieh Ayoub; Ashraf Brik
      Pages: 4966 - 4970
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 18
      Author(s): Muhammad Jbara, Noga Guttmann-Raviv, Suman Kumar Maity, Nabieh Ayoub, Ashraf Brik
      Histone H3 methylation plays an important role in regulating gene expression. In histones in general, this mark is dynamically regulated via various demethylases, which found to control cell fate decisions as well as linked to several diseases, including neurological and cancer. Despite major progress in studying methylation mark at various positions in H3 histone proteins, less is known about the regulation of methylated H3 at Lys79. Methylation at this site is known to have direct cross-talk with monoubiquitination of histone H2B at positions Lys120 and 34, as well as with acetylated H3 at Lys9. Herein we applied convergent total chemical protein synthesis to prepare trimethylated H3 at Lys79 to perform initial studies related to the regulation of this mark. Our study enabled us to identify KDM4D lysine demethylase as a potential regulator for trimethylated H3 at Lys79.
      Graphical abstract image

      PubDate: 2017-09-19T02:40:22Z
      DOI: 10.1016/j.bmc.2017.04.015
  • Semisynthesis of autophagy protein LC3 conjugates
    • Authors: Aimin Yang; Inken Hacheney; Yao-Wen Wu
      Pages: 4971 - 4976
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 18
      Author(s): Aimin Yang, Inken Hacheney, Yao-Wen Wu
      Autophagy is a conserved catabolic process involved in the elimination of proteins, organelles and pathogens. Autophagosome formation is the key process in autophagy. Lipidated Atg8/LC3 proteins that are conjugated to phosphatidylethanolamine (PE) play a key role in autophagosome biogenesis. To understand the function of Atg8/LC3-PE in autophagosome formation and host-pathogen interaction requires preparation and structural manipulation of lipidated Atg8/LC3 proteins. Herein, we report the semisynthesis of LC3 proteins and mutants with modifications of different PE fragments or lipids using native chemical ligation and aminolysis approaches.
      Graphical abstract image

      PubDate: 2017-09-19T02:40:22Z
      DOI: 10.1016/j.bmc.2017.05.051
  • O-GlcNAc modification inhibits the calpain-mediated cleavage of
    • Authors: Paul M. Levine; Cesar A. De Leon; Ana Galesic; Aaron Balana; Nicholas P. Marotta; Yuka E. Lewis; Matthew R. Pratt
      Pages: 4977 - 4982
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 18
      Author(s): Paul M. Levine, Cesar A. De Leon, Ana Galesic, Aaron Balana, Nicholas P. Marotta, Yuka E. Lewis, Matthew R. Pratt
      The major protein associated with Parkinson’s disease (PD) is α-synuclein, as it can form toxic amyloid-aggregates that are a hallmark of many neurodegenerative diseases. α-Synuclein is a substrate for several different posttranslational modifications (PTMs) that have the potential to affect its biological functions and/or aggregation. However, the biophysical effects of many of these modifications remain to be established. One such modification is the addition of the monosaccharide N-acetyl-glucosamine, O-GlcNAc, which has been found on several α-synuclein serine and threonine residues in vivo. We have previously used synthetic protein chemistry to generate α-synuclein bearing two of these physiologically relevant O-GlcNAcylation events at threonine 72 and serine 87 and demonstrated that both of these modifications inhibit α-synuclein aggregation. Here, we use the same synthetic protein methodology to demonstrate that these same O-GlcNAc modifications also inhibit the cleavage of α-synuclein by the protease calpain. This further supports a role for O-GlcNAcylation in the modulation of α-synuclein biology, as proteolysis has been shown to potentially affect both protein aggregation and degradation.
      Graphical abstract image

      PubDate: 2017-09-19T02:40:22Z
      DOI: 10.1016/j.bmc.2017.04.038
  • Revisiting ligation at selenomethionine: Insights into native chemical
           ligation at selenocysteine and homoselenocysteine
    • Authors: Rebecca Notis Dardashti; Norman Metanis
      Pages: 4983 - 4989
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 18
      Author(s): Rebecca Notis Dardashti, Norman Metanis
      Selenomethionine (Sem) has been incorporated recombinantly into proteins many times to elucidate their structure and function. In this paper, we revisit incorporation via chemical protein synthesis to shed light on the mechanism of native chemical ligation. The effect of chalcogen position on ligation is investigated, and selenium-containing peptide ligation is optimized. Additionally, selective methylation is performed on selenolates in a peptide in the presence of unprotected thiols.
      Graphical abstract image

      PubDate: 2017-09-19T02:40:22Z
      DOI: 10.1016/j.bmc.2017.05.006
  • Synthesis and structure-activity relationship of teixobactin analogues via
           convergent Ser ligation
    • Authors: Kang Jin; Kathy Hiu Laam Po; Shengxi Wang; Jonathan Avraham Reuven; Chi Nga Wai; Ho Ting Lau; Ting Ho Chan; Sheng Chen; Xuechen Li
      Pages: 4990 - 4995
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 18
      Author(s): Kang Jin, Kathy Hiu Laam Po, Shengxi Wang, Jonathan Avraham Reuven, Chi Nga Wai, Ho Ting Lau, Ting Ho Chan, Sheng Chen, Xuechen Li
      Convergent Ser/Thr ligation has been used to prepare a series of teixobactin analogues (28 in total) to establish a structure-activity relationship of teixobactin. anti-bacterial evaluations of these synthetic analogues have revealed the critical amino acid residues and the sites tolerable of modifications. These studies will shed lights on the further development of teixobactin analogues with improved antibacterial activities.
      Graphical abstract image

      PubDate: 2017-09-19T02:40:22Z
      DOI: 10.1016/j.bmc.2017.04.039
  • Improved synthesis of (S)-N-Boc-5-oxaproline for protein synthesis with
           the α-ketoacid-hydroxylamine (KAHA) ligation
    • Authors: Claudia E. Murar; Thibault J. Harmand; Jeffrey W. Bode
      Pages: 4996 - 5001
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 18
      Author(s): Claudia E. Murar, Thibault J. Harmand, Jeffrey W. Bode
      We describe a new route for the synthesis of (S)-N-Boc-5-oxaproline. This building block is a key element for the chemical synthesis of proteins with the α-ketoacid-hydroxylamine (KAHA) ligation. The new synthetic pathway to the enantiopure oxaproline is based on a chiral amine mediated enantioselective conjugate addition of a hydroxylamine to trans-4-oxo-2-butenoate. This route is practical, scalable and economical and provides decagram amounts of material for protein synthesis and conversion to other protected forms of (S)-oxaproline.
      Graphical abstract image

      PubDate: 2017-09-19T02:40:22Z
      DOI: 10.1016/j.bmc.2017.06.019
  • Identification of sortase substrates by specificity profiling
    • Authors: Lena Schmohl; Jan Bierlmeier; Nicolai von Kügelgen; Leonie Kurz; Pascal Reis; Fabian Barthels; Pia Mach; Mike Schutkowski; Christian Freund; Dirk Schwarzer
      Pages: 5002 - 5007
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 18
      Author(s): Lena Schmohl, Jan Bierlmeier, Nicolai von Kügelgen, Leonie Kurz, Pascal Reis, Fabian Barthels, Pia Mach, Mike Schutkowski, Christian Freund, Dirk Schwarzer
      Sortases catalyze the attachment of surface proteins to the peptidoglycan layer of gram-positive bacteria and further represent powerful tools of protein chemistry. During catalysis sortases cleave a donor substrate containing the LPxTG (x=any amino acid) sorting motif under formation of an enzyme-bound thioester and ligate this intermediate to an acceptor protein containing an N-terminal glycine residue. In addition to the well-established sortase A of Staphylococcus aureus several homologs of this enzyme have been identified in the genomes of gram-positive bacteria. We have profiled the specificity of seven sortases of Staphylococci and Streptococci origin and observed that sortases of the latter class displayed a more relaxed specificity for donor and acceptor substrates than their Staphylococci counterparts. Streptococci sortases prefer an LPKLG donor substrate sequence compared to the canonical sorting motif LPKTG. These findings might facilitate the use of Streptococci sortases as tools of protein chemistry.
      Graphical abstract image

      PubDate: 2017-09-19T02:40:22Z
      DOI: 10.1016/j.bmc.2017.06.033
  • An orthogonally protected CycloTriVeratrylene (CTV) as a highly
           pre-organized molecular scaffold for subsequent ligation of different
           cyclic peptides towards protein mimics
    • Authors: Ondřej Longin; Helmus van de Langemheen; Rob M.J. Liskamp
      Pages: 5008 - 5015
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 18
      Author(s): Ondřej Longin, Helmus van de Langemheen, Rob M.J. Liskamp
      The synthesis of a semi-orthogonally protected CycloTriVeratrilene (CTV) scaffold derivative as well as the sequential introduction of three different peptide loops onto this molecular scaffold via Cu(I)-catalyzed azide alkyne cycloaddition towards a medium-sized protein mimic is described. This approach for the construction of medium-sized protein mimics is illustrated by the synthesis of a paratope mimic of the monoclonal antibody Infliximab (Remicade®) and provides access to a range of highly pre-organized molecular constructs bearing three different peptide segments. This approach may find wide applications for development of protein-protein interaction disruptors as well as synthetic vaccines.
      Graphical abstract image

      PubDate: 2017-09-19T02:40:22Z
      DOI: 10.1016/j.bmc.2017.05.038
  • A dual functional peptide-auxiliary conjugate for C-to-N and N-to-C
           sequential native chemical ligation of glycopeptides
    • Authors: Claudia Bello; Christian F.W. Becker
      Pages: 5016 - 5021
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 18
      Author(s): Claudia Bello, Christian F.W. Becker
      Long, homogeneously glycosylated peptides and proteins can be assembled from multiple segments via sequential chemoselective reactions. The efficiency of the synthesis depends on the effectiveness and number of steps and on their compatibility with glycosylation methods. Here, we present how the combination of auxiliary-mediated native chemical ligation and thioester generation via hydrazinolysis from Wang-type resin enables multiple, sequential N-to-C and C-to-N ligations. The method can be applied to glycosylated peptides and peptide α-thioesters and has the potential to be further extended to sequential glycosylation, thus paving the way to the synthesis of complex homogeneous glycoproteins. We applied this methodology to the synthesis of long MUC1 variants comprising 2, 4 and 6 tandem repeats and three O-glycosylations.
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      PubDate: 2017-09-19T02:40:22Z
      DOI: 10.1016/j.bmc.2017.05.046
  • A fluorogenic native chemical ligation for assessing the role of distance
           in peptide-templated peptide ligation
    • Authors: Henrik Petszulat; Oliver Seitz
      Pages: 5022 - 5030
      Abstract: Publication date: 15 September 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 18
      Author(s): Henrik Petszulat, Oliver Seitz
      Protein-templated reactions have been used for fragment-based drug discovery as well as for covalent labeling, detection and manipulation of proteins. In spite of the growing interest in protein-templated reactions, little is known about the design criteria. Herein we present a systematic study on the effects of proximity in peptide-templated reactions. To facilitate reaction monitoring at low concentrations we developed a fluorogenic native chemical ligation that is based on the integration of a fluorescence quencher in the thiol leaving group. The reaction system provided up to 39-fold increases of emission from a fluorescein unit. By using templates based on coiled coils as models we investigated the effect of misalignments. The distance-reactivity pattern for remotely aligned peptides was remarkably different to reaction scenarios that involved seamlessly annealed peptides with overhanging functional groups.
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      PubDate: 2017-09-19T02:40:22Z
      DOI: 10.1016/j.bmc.2017.08.007
  • Recent synthetic and medicinal perspectives of tryptanthrin
    • Authors: Ramandeep Kaur; Sundeep Kaur Manjal; Ravindra K. Rawal; Kapil Kumar
      Pages: 4533 - 4552
      Abstract: Publication date: 1 September 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17
      Author(s): Ramandeep Kaur, Sundeep Kaur Manjal, Ravindra K. Rawal, Kapil Kumar
      Tryptanthrin is a natural alkaloidal compound having basic indoloquinazoline moiety. It is obtained from various natural plant sources as well as different cell cultures including yeast etc. Trptanthrin is considered as biogenetic precursor for phaitanthrin A–C, pyrroloindoloquinazoline, (±)-cruciferane. Different synthetic approaches for the synthesis of tryptanthrin have been very well reported. It has broad spectrum of biological activities including anticancer activity, anti-inflammatory, antiprotozoal, antiallergic, antioxidant, and antimicrobial. In this review, our focus will be, on the various approaches for the synthesis of tryptanthrins and its derivatives along with the biological activities.
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      PubDate: 2017-08-31T04:56:59Z
      DOI: 10.1016/j.bmc.2017.07.003
  • Synthesis and evaluation of osimertinib derivatives as potent EGFR
    • Authors: Hongying Gao; Zimo Yang; Xinglin Yang; Yu Rao
      Pages: 4553 - 4559
      Abstract: Publication date: 1 September 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17
      Author(s): Hongying Gao, Zimo Yang, Xinglin Yang, Yu Rao
      Osimertinib has been identified as a promising therapeutic drug targeting for EGFR T790M mutant non-small cell lung cancer (NSCLC). A new series of N-oxidized and fluorinated osimertinib derivatives were designed and synthesized. The cellular anti-proliferative activity, kinase inhibitory activity and the activation of EGFR signaling pathways of 1–6 in vitro were determined against L858R/T790M and wild-type EGFR, the antitumor efficacy in NCI-H1975 xenografts in vivo were further studied. Compound 2, the newly synthesized N-oxide metabolite in N,N,N′-trimethylethylenediamine side chain of osimertinib, showed a comparable kinase selectivity in vitro and a slightly better antitumor efficacy in vivo to osimertinib, making it valuable and suitable for the potential lung cancer therapy.
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      PubDate: 2017-08-31T04:56:59Z
      DOI: 10.1016/j.bmc.2017.06.004
  • 1,3-Oxazole-based selective picomolar inhibitors of cytosolic human
           carbonic anhydrase II alleviate ocular hypertension in rabbits: Potency is
           supported by X-ray crystallography of two leads
    • Authors: Marta Ferraroni; Laura Lucarini; Emanuela Masini; Mikhail Korsakov; Andrea Scozzafava; Claudiu T. Supuran; Mikhail Krasavin
      Pages: 4560 - 4565
      Abstract: Publication date: 1 September 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17
      Author(s): Marta Ferraroni, Laura Lucarini, Emanuela Masini, Mikhail Korsakov, Andrea Scozzafava, Claudiu T. Supuran, Mikhail Krasavin
      Two lead 1,3-oxazole-based carbonic anhydrase inhibitors (CAIs) earlier identified as selective, picomolar inhibitors of hCA II (a cytosolic target for treatment of glaucoma) have been investigated further. Firstly, they were found to be conveniently synthesized on multigram scale, which enables further development. These compounds were found to be comparable in efficacy to dorzolamide eye drops when applied in the eye drop form as well. Finally, the reasons for unusually high potency of these compounds became understood from their high-resolution X-ray crystallography structures. These data significantly expand our understanding of heterocycle-based primary sulfonamides, many of which have recently emerged from our labs - particularly, from the corneal permeability standpoint.
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      PubDate: 2017-08-31T04:56:59Z
      DOI: 10.1016/j.bmc.2017.06.054
  • Brassinolide-like activity of castasterone analogs with varied side chains
           against rice lamina inclination
    • Authors: Bunta Watanabe; Shuji Yamamoto; Taiyo Yokoi; Airi Sugiura; Shinri Horoiwa; Takanori Aoki; Hisashi Miyagawa; Yoshiaki Nakagawa
      Pages: 4566 - 4578
      Abstract: Publication date: 1 September 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17
      Author(s): Bunta Watanabe, Shuji Yamamoto, Taiyo Yokoi, Airi Sugiura, Shinri Horoiwa, Takanori Aoki, Hisashi Miyagawa, Yoshiaki Nakagawa
      Brassinolide (BL) and castasterone (CS) are the representative members of brassinosteroid class of plant steroid hormone having plant growth promoting activity. In this study, eleven CS analogs bearing a variety of side chains were synthesized to determine the effect of the side chain structures on the BL-like activity. The plant hormonal activity was evaluated in a dwarf rice lamina inclination assay, and the potency was determined as the reciprocal logarithm of the 50% effective dose (ED50) from each dose-response curve. The reciprocal logarithm of ED50 (pED50) was decreased dramatically upon deletion of the C-28 methyl group of CS. The introduction of oxygen-containing groups such as hydroxy, methoxy, and ethoxycarbonyl was also unfavorable to the activity. The pED50 was influenced by the geometry of carbon-carbon double bond between C-24 and C-25 (cis and trans), but the introduction of a fluorine atom at the C-25 position of the double bond did not significantly change the activity. The binding free energy (ΔG) was calculated for all ligand–receptor binding interactions using molecular dynamics, resulting that ΔG is linearly correlated with the pED50.
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      PubDate: 2017-08-31T04:56:59Z
      DOI: 10.1016/j.bmc.2017.06.012
  • Cycloalkane analogues of sinefungin as EHMT1/2 inhibitors
    • Authors: Qing Liu; Xiaoqing Cai; Dehua Yang; Yi Chen; Yafang Wang; Liming Shao; Ming-Wei Wang
      Pages: 4579 - 4594
      Abstract: Publication date: 1 September 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17
      Author(s): Qing Liu, Xiaoqing Cai, Dehua Yang, Yi Chen, Yafang Wang, Liming Shao, Ming-Wei Wang
      A series of cycloalkyl substituted analogues of the natural product sinefungin lacking the amino-acid moiety was designed and synthesized. Two stereoisomers (6-R and 6-S) were separated and their bioactivities examined against EHMT1/2. Of which, compound 14d showed an inhibitory activity against EHMT1/2 (88.9%, IC50 =21.8μM for EHMT1 and 77.6%, IC50 =39.6μM for EHMT2, respectively) similar to that of sinefungin (100.0%, IC50 =28.4μM for EHMT1 and 79.5%, IC50 =30.1μM for EHMT2, respectively). Further studies against other methyltransferases such as PRMT1 showed no activity except that 12d displayed about 20% inhibition.
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      PubDate: 2017-08-31T04:56:59Z
      DOI: 10.1016/j.bmc.2017.06.032
  • pH responsive biodegradable nanogels for sustained release of bleomycin
    • Authors: Prashant Sahu; Sushil K. Kashaw; Varun Kushwah; Samaresh Sau; Sanyog Jain; Arun K. Iyer
      Pages: 4595 - 4613
      Abstract: Publication date: 1 September 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17
      Author(s): Prashant Sahu, Sushil K. Kashaw, Varun Kushwah, Samaresh Sau, Sanyog Jain, Arun K. Iyer
      Site specific drug delivery with desired therapeutic effect still remains challenging task due to suboptimal release, tissue toxicity, low selectivity and meager therapeutic efficacy in skin cancers. The aim of the current study was to fabricate pH responsive, self-assembled, chemically cross-linked biodegradable chitosan nanogel loaded with bleomycin to target the dermal area of the skin. The nanogel synthesized by ion gelation technique and was characterized for drug loading, swelling and thermal stability followed by in vitro analysis. HaCaT (Human Keratinocyte cell) and HDF (Human dermal fibroblast) cell line were used for the biocompatibility and cytocompatibility evaluation prior to the hemolysis assay and coagulation assessment. The nanogel had a size range of 150nm as determined by TEM and DLS. The nanogel possessed optimum thermal stability as analyzed by thermogravimetry (TG) and differential thermal analysis (DTA). Biodegradation was confirmed by lysozyme enzyme degradation assays. The drug entrapment efficacy was about 55% in the swollen state. The In vitro drug release profile revealed sustained release pattern. The hemolysis of 2.39% and prothrombin time (PT) and activated partial thromboplastin time (APTT) of 12.9 and 31s revealed the biocompatibility of nanogels. The cell uptake and localization profile was validated by fluorescence and confocal microscopy using HDF and HaCaT cell lines. Finally, the MTT assay demonstrated the cytocompatibility of nanogels. In conclusion, the present findings suggest that biodegradable chitosan nanogels with stimuli responsive nature can release the anticancer drug cargo in a sustained and controlled manner and offer promising potentials for treating skin cancers. Statement of Significance Drug delivery to the targeted site is a major challenge in clinical medicine. The newly constructed pH responsive biodegradable nanogel consisting of bleomycin revealed pH triggered drug release in a sustained manner to the dermal area offering novel approach against skin cancer. The nanogel system is biodegradable in nature possessing high drug entrapment efficiency and offers patient compliance with biocompatible and cytocompatible characteristics. This nanogel system can thus be highly useful for delivery of anticancer drugs to the skin in a controlled and sustained manner.
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      PubDate: 2017-08-31T04:56:59Z
      DOI: 10.1016/j.bmc.2017.06.038
  • Discovery of a tetrahydroisoquinoline-based HDAC inhibitor with improved
           plasma stability
    • Authors: Nan Zhou; Yugang Yan; Chunxi Liu; Jinning Hou; Wenfang Xu; Yingjie Zhang
      Pages: 4614 - 4619
      Abstract: Publication date: 1 September 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17
      Author(s): Nan Zhou, Yugang Yan, Chunxi Liu, Jinning Hou, Wenfang Xu, Yingjie Zhang
      Histone deacetylase inhibitors with desirable pharmacokinetic profiles which can be delivered to solid tumor tissues in large amount might be promising to treat solid tumor effectively. Herein, structural modification of a previously reported tetrahydroisoquinoline-based HDAC inhibitor 1 was carried out to improve its plasma stability for more feasible drug delivery. Among three newly synthesized analogs, the in vitro rat plasma stability of compound 2 (t1/2 =630min) was over 5-fold improved than its parent 1 (t1/2 =103min). In vitro activity evaluation showed that compound 2 and 1 exhibited similar HDACs inhibitory activity, which was validated by western blot analysis and antiproliferative assay. Moreover, compared with 1, compound 2 exhibited comparable, if not higher, in vivo antitumor activity in a human breast carcinoma (MDA-MB-231) xenograft model.
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      PubDate: 2017-08-31T04:56:59Z
      DOI: 10.1016/j.bmc.2017.06.039
  • Asymmetric synthesis and evaluation of epoxy-α-acyloxycarboxamides as
           selective inhibitors of cathepsin L
    • Authors: Deborah A. dos Santos; Anna Maria Deobald; Vivian E. Cornelio; Roberta M.D. Ávila; Renata C. Cornea; Gilberto C.R. Bernasconi; Marcio W. Paixão; Paulo C. Vieira; Arlene G. Corrêa
      Pages: 4620 - 4627
      Abstract: Publication date: 1 September 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17
      Author(s): Deborah A. dos Santos, Anna Maria Deobald, Vivian E. Cornelio, Roberta M.D. Ávila, Renata C. Cornea, Gilberto C.R. Bernasconi, Marcio W. Paixão, Paulo C. Vieira, Arlene G. Corrêa
      Cathepsin L plays important roles in physiological processes as well as in the development of many pathologies. Recently the attentions were turned to its association with tumor progress what makes essential the development of more potent and selective inhibitors. In this work, epoxipeptidomimetics were investigated as new cathepsin inhibitors. This class of compounds is straightforward obtained by using a green one-pot asymmetric epoxidation/Passerini 3-MCR. A small library of 17 compounds was evaluated against cathepsin L, and among them LSPN423 showed to be the most potent. Investigations of the mechanism suggested a tight binding uncompetitive inhibition.
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      PubDate: 2017-08-31T04:56:59Z
      DOI: 10.1016/j.bmc.2017.06.048
  • KBE009: An antimalarial bestatin-like inhibitor of the Plasmodium
           falciparum M1 aminopeptidase discovered in an Ugi multicomponent
           reaction-derived peptidomimetic library
    • Authors: Jorge González-Bacerio; Sarah El Chamy Maluf; Yanira Méndez; Isel Pascual; Isabelle Florent; Pollyana M.S. Melo; Alexandre Budu; Juliana C. Ferreira; Ernesto Moreno; Adriana K. Carmona; Daniel G. Rivera; Maday Alonso del Rivero; Marcos L. Gazarini
      Pages: 4628 - 4636
      Abstract: Publication date: 1 September 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17
      Author(s): Jorge González-Bacerio, Sarah El Chamy Maluf, Yanira Méndez, Isel Pascual, Isabelle Florent, Pollyana M.S. Melo, Alexandre Budu, Juliana C. Ferreira, Ernesto Moreno, Adriana K. Carmona, Daniel G. Rivera, Maday Alonso del Rivero, Marcos L. Gazarini
      Malaria is a global human parasitic disease mainly caused by the protozoon Plasmodium falciparum. Increased parasite resistance to current drugs determines the relevance of finding new treatments against new targets. A novel target is the M1 alanyl-aminopeptidase from P. falciparum (PfA-M1), which is essential for parasite development in human erythrocytes and is inhibited by the pseudo-peptide bestatin. In this work, we used a combinatorial multicomponent approach to produce a library of peptidomimetics and screened it for the inhibition of recombinant PfA-M1 (rPfA-M1) and the in vitro growth of P. falciparum erythrocytic stages (3D7 and FcB1 strains). Dose-response studies with selected compounds allowed identifying the bestatin-based peptidomimetic KBE009 as a submicromolar rPfA-M1 inhibitor (Ki =0.4μM) and an in vitro antimalarial compound as potent as bestatin (IC50 =18μM; without promoting erythrocyte lysis). At therapeutic-relevant concentrations, KBE009 is selective for rPfA-M1 over porcine APN (a model of these enzymes from mammals), and is not cytotoxic against HUVEC cells. Docking simulations indicate that this compound binds PfA-M1 without Zn2+ coordination, establishing mainly hydrophobic interactions and showing a remarkable shape complementarity with the active site of the enzyme. Moreover, KBE009 inhibits the M1-type aminopeptidase activity (Ala-7-amido-4-methylcoumarin substrate) in isolated live parasites with a potency similar to that of the antimalarial activity (IC50 =82μM), strongly suggesting that the antimalarial effect is directly related to the inhibition of the endogenous PfA-M1. These results support the value of this multicomponent strategy to identify PfA-M1 inhibitors, and make KBE009 a promising hit for drug development against malaria.
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      PubDate: 2017-08-31T04:56:59Z
      DOI: 10.1016/j.bmc.2017.06.047
  • New prodrugs of two pyrimidine acyclic nucleoside phosphonates: Synthesis
           and antiviral activity
    • Authors: Marcela Krečmerová; Martin Dračínský; Robert Snoeck; Jan Balzarini; Karel Pomeisl; Graciela Andrei
      Pages: 4637 - 4648
      Abstract: Publication date: 1 September 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17
      Author(s): Marcela Krečmerová, Martin Dračínský, Robert Snoeck, Jan Balzarini, Karel Pomeisl, Graciela Andrei
      New 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidine (PMEO-DAPy) and 1-[2-(phosphonomethoxy)ethyl]-5-azacytosine (PME-5-azaC) prodrugs were prepared with a pro-moiety consisting of carbonyloxymethyl esters (POM, POC), alkoxyalkyl esters, amino acid phosphoramidates and/or tyrosine. The activity of the prodrugs was evaluated in vitro against different virus families. None of the synthesized prodrugs demonstrated activity against RNA viruses but some of them proved active against herpesviruses [including herpes simplex virus (HSV), varicella-zoster virus (VZV), and human cytomegalovirus (HCMV)]. The bis(POC) and the bis(amino acid) phosphoramidate prodrugs of PMEO-DAPy inhibited herpesvirus replication at lower doses than the parent compound although the selectivity against HSV and VZV was only slightly improved compared to PMEO-DAPy. The mono-octadecyl ester of PME-5-azaC emerged as the most potent and selective PME-5-azaC prodrug against HSV, VZV and HCMV with EC50’s of 0.15–1.12µM while PME-5-azaC only had marginal anti-herpesvirus activity. Although the bis(hexadecylamido-l-tyrosyl) and the bis(POM) esters of PME-5-azaC were also very potent anti-herpesvirus drugs, these were less selective than the mono-octadecyl ester prodrug.
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      PubDate: 2017-08-31T04:56:59Z
      DOI: 10.1016/j.bmc.2017.06.046
  • A novel antihypertension agent, sargachromenol D from marine brown algae,
           Sargassum siliquastrum, exerts dual action as an L-type Ca2+ channel
           blocker and endothelin A/B2 receptor antagonist
    • Authors: Byong-Gon Park; Woon-Seob Shin; Sangtae Oh; Gab-Man Park; Nam Ik Kim; Seokjoon Lee
      Pages: 4649 - 4655
      Abstract: Publication date: 1 September 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17
      Author(s): Byong-Gon Park, Woon-Seob Shin, Sangtae Oh, Gab-Man Park, Nam Ik Kim, Seokjoon Lee
      We isolated the novel vasoactive marine natural products, (5E,10E)-14-hydroxy-2,6,10-trimethylpentadeca-5,10-dien-4-one (4) and sargachromenol D (5), from Sargassum siliquastrum collected from the coast of the East Sea in South Korea by using activity-guided HPLC purification. The compounds effectively dilated depolarization (50mMK+)-induced basilar artery contraction with EC50 values of 3.52±0.42 and 1.62±0.63μM, respectively, but only sargachromenol D (5) showed a vasodilatory effect on endothelin-1 (ET-1)-induced basilar artery contraction (EC50 =9.8±0.6μM). These results indicated that sargachromenol D (5) could act as a dual antagonist of l-type Ca2+ channel and endothelin A/B2 receptors. Moreover, sargachromenol D (5) lowered blood pressure in spontaneous hypertensive rats (SHRs) 2h after oral treatment at a dose of 80mg/kg dose and the effect was maintained for 24h. Based on our ex vivo and in vivo experiments, we propose that sargachromenol D (5) is a strong candidate for the treatment of hypertension that is not controlled by conventional drugs, in particular, severe-, type II diabetes-, salt-sensitive, and metabolic disease-induced hypertension.
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      PubDate: 2017-08-31T04:56:59Z
      DOI: 10.1016/j.bmc.2017.07.002
  • Synthesis and biological evaluation of fluoro-substituted
           3,4-dihydroquinazoline derivatives for cytotoxic and analgesic effects
    • Authors: Jin Han Kim; Hui Rak Jeong; Da Woon Jung; Hong Bin Yoon; Sun Young Kim; Hyoung Ja Kim; Kyung-Tae Lee; Vinicius M. Gadotti; Junting Huang; Fang-Xiong Zhang; Gerald W. Zamponi; Jae Yeol Lee
      Pages: 4656 - 4664
      Abstract: Publication date: 1 September 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17
      Author(s): Jin Han Kim, Hui Rak Jeong, Da Woon Jung, Hong Bin Yoon, Sun Young Kim, Hyoung Ja Kim, Kyung-Tae Lee, Vinicius M. Gadotti, Junting Huang, Fang-Xiong Zhang, Gerald W. Zamponi, Jae Yeol Lee
      As a bioisosteric strategy to overcome the poor metabolic stability of lead compound KYS05090S, a series of new fluoro-substituted 3,4-dihydroquinazoline derivatives was prepared and evaluated for T-type calcium channel (Cav3.2) block, cytotoxic effects and liver microsomal stability. Among them, compound 8h (KCP10068F) containing 4-fluorobenzyl amide and 4-cyclohexylphenyl ring potently blocked Cav3.2 currents (>90% inhibition) at 10μM concentration and exhibited cytotoxic effect (IC50 =5.9μM) in A549 non-small cell lung cancer cells that was comparable to KYS05090S. Furthermore, 8h showed approximately a 2-fold increase in liver metabolic stability in rat and human species compared to KYS05090S. Based on these overall results, 8h (KCP10068F) may therefore represent a good backup compound for KYS05090S for further biological investigations as novel cytotoxic agent. In addition, compound 8g (KCP10067F) was found to partially protect from inflammatory pain via a blockade of Cav3.2 channels.
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      PubDate: 2017-08-31T04:56:59Z
      DOI: 10.1016/j.bmc.2017.07.010
  • 5-Bromoindirubin 3′-(O-oxiran-2-ylmethyl)oxime: A long-acting anticancer
           agent and a suicide inhibitor for epoxide hydrolase
    • Authors: Yoshimi Ichimaru; Takeshi Fujii; Hiroaki Saito; Makoto Sano; Taketo Uchiyama; Shinichi Miyairi
      Pages: 4665 - 4676
      Abstract: Publication date: 1 September 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17
      Author(s): Yoshimi Ichimaru, Takeshi Fujii, Hiroaki Saito, Makoto Sano, Taketo Uchiyama, Shinichi Miyairi
      Indirubin 3′-oxime (Indox (1b)) suppresses cancer cell growth (IC50: 15μM towards HepG2 cells) and inhibits cell cycle-related kinases such as cyclin-dependent kinases and glycogen synthase kinase-3β. We have previously reported that the conjugation of 1b with oxirane, a protein-reactive component, enhanced the cytotoxic activity of Indox as determined from the IC50 value (1.7μM) of indirubin 3′-(O-oxiran-2-ylmethyl)oxime (Epox/Ind (1c)). Here we prepared Epox/Ind derivatives with one or two halogen atoms or a methoxy group on the aromatic ring(s) of an Indox moiety and studied the structure-activity relationships of the substituent(s). We found that bromine-substitution at the 5-position on 1c or any Epox/Ind derivative(s) having bromine on the aromatic ring except Epox/6′-Br-Ind was efficient to improving anticancer activity. Of the 22 Epox/Ind derivatives, 5-bromoindirubin 3′-(O-oxiran-2-ylmethyl)oxime (Epox/5-Br-Ind (2c)) was the best anticancer agent in both short- (24h) (IC50: 0.67μM) and extended-duration (72h) cultures. The high anticancer activity of 2c was partly due to it being a poor substrate and a suicide inhibitor for epoxide hydrolase as epoxide hydrolase was identified as the enzyme primarily responsible for the metabolism of 2c.
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      PubDate: 2017-08-31T04:56:59Z
      DOI: 10.1016/j.bmc.2017.07.009
  • Synthesis, pharmacological activities and molecular docking studies of
           pyrazolyltriazoles as anti-bacterial and anti-inflammatory agents
    • Authors: Cherupally Dayakar; Buddana Sudheer Kumar; Galande Sneha; Gudem Sagarika; Koneru Meghana; Sistla Ramakrishna; Reddy Shetty Prakasham; Bhimapaka China Raju
      Abstract: Publication date: Available online 15 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Cherupally Dayakar, Buddana Sudheer Kumar, Galande Sneha, Gudem Sagarika, Koneru Meghana, Sistla Ramakrishna, Reddy Shetty Prakasham, Bhimapaka China Raju
      A series of novel pyrazolyl alcohols (5a-h), pyrazolyl azides (6a-h), and pyrazolyltriazoles (8a-h, 10a-p and 12a-l) were prepared and evaluated for their bioactivity (anti-bacterial and anti-inflammatory) profile. The compound 5c displayed the potent anti-bacterial activity against Micrococcus luteus (MIC 3.9 and MBC 7.81µg/mL). In vitro anti-inflammatory activity data denoted that compound 8b is effective among the tested compounds against IL-6 (IC50 6.23μM). Docking analysis of compounds 5f, 8a-b, 8e-f and 8h displayed high binding energies for the compounds 8a-b and 8h towards TNF-α dimer (2AZ5 protein) and IL-6 (1ALU protein). In vivo anti-inflammatory activity of compounds 8b and 8h with respect to LPS induced mice model indicated that compound 8h showed significant reduction in TNF-α.
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      PubDate: 2017-09-19T02:40:22Z
      DOI: 10.1016/j.bmc.2017.08.042
  • Interrogation of Side Chain Biases for Oligomannose Recognition by
           Antibody 2G12 via Structure-Guided Phage Display Libraries
    • Authors: Tsung-Yi Lin; Jonathan R. Lai
      Abstract: Publication date: Available online 15 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Tsung-Yi Lin, Jonathan R. Lai
      Monoclonal antibodies (mAbs) are essential reagents for deciphering gene or protein function and have been a fruitful source of therapeutic and diagnostic agents. However, developing anticarbohydrate antibodies to target glycans for those purposes has been less successful because the molecular basis for glycan-mAb interactions is poorly understood relative to protein- or peptide-binding mAbs. Here, we report our investigation on glycan-mAb interactions by using the unique architectural scaffold of 2G12, an antibody that targets oligomannoses on the HIV-1 glycoprotein gp120, as the template for engineering highly specifc mAbs to target glycans. We first analyzed 24 different X-ray structures of antiglycan mAbs from the Protein Data Bank to determine side chain amino acid distributions in of glycan-mAb interactions. We identified Tyr, Arg, Asn, Ser, Asp, and His as the six most prevalent residues in the glycan-mAb contacts. We then utilized this information to construct two phage display libraries in which positions on the heavy chain variable domains of 2G12 were allowed to vary in restricted manner among Tyr, Asp, Ser, His, Asn, Thr, Ala and Pro to interrogate the minimal physicochemical requirements for oligomannose recognition. We characterized 39 variants from Lib1 and 14 variants from Lib2 following selection against gp120, the results showed that there is a high degree of malleability within the 2G12 for glycan recognitions. We further characterized five unique phage clones from both libraries that exhibited a gp120-specific binding profile. Expression of two of these variants as soluble mAbs indicated that, while specificity of gp120-binding was retained, the affinity of these mutants was significantly reduced relative to WT 2G12. Nonetheiess, the results indicate these is some malleability in the identity of contact residues and provide a novel insight into the nature of glycan-antibody interactions and how they may differ from protein-protein binding interactions.
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      PubDate: 2017-09-19T02:40:22Z
      DOI: 10.1016/j.bmc.2017.09.013
  • Prospects of PASylation® for the design of protein and peptide
           therapeutics with extended half-life and enhanced action
    • Authors: Michaela Gebauer; Arne Skerra
      Abstract: Publication date: Available online 15 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Michaela Gebauer, Arne Skerra
      Pharmacokinetic (PK) extension is no longer just a means to create improved second generation biologics (so-called biobetters), but constitutes an accepted strategy for biopharmaceutical drug development today. Although PEGylation has become a widely accepted methodology to furnish therapeutic proteins and peptides with prolonged plasma half-life, the immunogenicity and missing biodegradablity of this synthetic polymer has prompted an evident need for alternatives. PASylation is based on biological polypeptides made of the small L-amino acids Pro, Ala and/or Ser (PAS), which adopt a random coil structure in aqueous buffers with surprisingly similar biophysical properties as PEG. In contrast, PAS sequences can be conjugated to pharmaceutically active proteins and peptides both via chemical coupling and at the genetic level, as so-called fusion proteins. PASylation has been successfully applied to numerous biologics, including cytokines, growth factors, antibody fragments, enzymes as well as various peptides, and validated in diverse animal models, from mice to monkeys. Here we compare PASylation with other current strategies for half-life extension and we discuss the utility of these approaches for the design of innovative peptide-based therapeutics.
      Graphical abstract image

      PubDate: 2017-09-19T02:40:22Z
      DOI: 10.1016/j.bmc.2017.09.016
  • Improved molecular recognition of Carbonic Anhydrase IX by polypeptide
           conjugation to acetazolamide
    • Authors: Jie Yang; Katarina Koruza; Zoë Fisher; Wolfgang Knecht; Lars Baltzer
      Abstract: Publication date: Available online 14 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Jie Yang, Katarina Koruza, Zoë Fisher, Wolfgang Knecht, Lars Baltzer
      The small molecule inhibitor acetazolamide (AZM) was conjugated to a set of designed polypeptides and the resulting conjugates were evaluated for their affinity to human Carbonic Anhydrase II (HCA II) using surface plasmon resonance. The dissociation constant of the AZM-HCA II complex was 38 nM and that of the AZM conjugated polypeptide (4-C10L17-AZM) to HCA II was found to be 4 nM, an affinity enhancement of a factor of 10 due to polypeptide conjugation. For Human Carbonic Anhydrase IX (HCA IX) the dissociation constant of AZM was 3 nM, whereas that of the 4-C10L17-AZM conjugate was 90 pM, a 33-fold affinity enhancement. This dramatic affinity increase due to polypeptide conjugation was achieved for a small molecule ligand with an already high affinity to the target protein. This supports the concept that enhancements due to polypeptide conjugation are not limited to small molecule ligands that bind proteins in the mM to μM range but may be used also for nM ligands to provide recognition elements with dissociation constants in the pM range. Evaluations of two HCA IX constructs that do not carry the proteoglycan (PG) domain did not show significant affinity differences between AZM and the polypeptide conjugate, providing evidence that the improved binding of 4-C10L17-AZM to HCA IX emanated from interactions between the polypeptide segment and the PG domain found only in one carbonic anhydrase, HCA IX.
      Graphical abstract image

      PubDate: 2017-09-19T02:40:22Z
      DOI: 10.1016/j.bmc.2017.09.017
  • Modifications of flexible nonyl chain and nucleobase head group of
           (+)-erythro-9-(2’s-hydroxy-3’s-nonyl)adenine [(+)-EHNA] as adenosine
           deaminase inhibitors
    • Authors: Sachin R. Kandalkar; Parimi Atchuta Ramaiah; Manoj Joshi; Atul Wavhal; Yogesh Waman; Amol Raje; Ashwini Tambe; Shariq Ansari; Siddhartha De; Venkata P. Palle; Kasim A. Mookhtiar; Anil M. Deshpande; Dinesh A. Barawkar
      Abstract: Publication date: Available online 14 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Sachin R. Kandalkar, Parimi Atchuta Ramaiah, Manoj Joshi, Atul Wavhal, Yogesh Waman, Amol Raje, Ashwini Tambe, Shariq Ansari, Siddhartha De, Venkata P. Palle, Kasim A. Mookhtiar, Anil M. Deshpande, Dinesh A. Barawkar
      A series of terminal nonyl chain and nucleobase modified analogues of (+)-EHNA (III) were synthesized and evaluated for their ability to inhibit adenosine deaminase (ADA). The constrained carbon analogues of (+)-EHNA, 7a-7h, 10a-c, 12, 13, 14 and 17a-c appeared very potent with Ki values in the low nanomolar range. Thio-analogues of (+)-EHNA 24a-e wherein 5’C of nonyl chain replaced by sulfur atom found to be less potent compared to (+)-EHNA. Docking of the representative compounds into the active site of ADA was performed to understand structure-activity relationships. Compounds 7a (Ki: 1.1 nM) 7b (Ki: 5.2 nM) and 26a (Ki: 5.9 nM) showed suitable balance of potency, microsomal stability and demonstrated better pharmacokinetic properties as compared to (+)-EHNA and therefore may have therapeutic potential for various inflammatory diseases, hypertension and cancer.
      Graphical abstract image

      PubDate: 2017-09-19T02:40:22Z
      DOI: 10.1016/j.bmc.2017.09.015
  • Exploration of chromen-4-one based scaffold’s potential in Alzheimer’s
           disease: Design, Synthesis and Biological evaluations
    • Authors: Manjinder Singh; Maninder Kaur; Nirmal Singh; Om Silakari
      Abstract: Publication date: Available online 11 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Manjinder Singh, Maninder Kaur, Nirmal Singh, Om Silakari
      A novel series of flavonoid based compounds were designed, synthesized and biologically evaluated for Acetylcholinesterase (AChE) inhibitory activity integrated with advanced glycation end products (AGEs) inhibitory and antioxidant ptential. Most of the derivatives inhibited AChE in nanomolar IC50 range along with good AGEs inhibitory and radical scavenging activity. Among them, 7m, strongly inhibited AChE (IC50=5.87 nM) and found to be potent as compared to the reference drug donepezil (IC50=12.7 nM). Its potent inhibitory activity has been justified by docking analysis that revealed its dual binding characteristic with both CAS (catalytic active site) and PAS (peripheral anionic site) of AChE, simultaneously. Additionally, this compound also displayed ability to prevent advanced glycation end products formation (IC50=23.0 µM) with additional radical scavenging property (IC50=37.12 nM). It (7m) also ameliorated scopolamine induced memory deficit in mice employing Morris water maze test. Thus, flavonoids might be the promising lead compounds as potential polyfunctional anti-Alzheimer’s agents.
      Graphical abstract image

      PubDate: 2017-09-19T02:40:22Z
      DOI: 10.1016/j.bmc.2017.09.012
  • Therapeutic Peptides for CNS indications: progress and challenges
    • Authors: Bruce H. Morimoto
      Abstract: Publication date: Available online 9 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Bruce H. Morimoto
      Attacking neurodegeneration and promoting neuroprotection have been the holy grail in neurology for almost 20 years and represent an area of high unmet medical need. However, indications like Alzheimer’s disease and stroke are areas in drug development fraught with failure. This review will highlight three CNS peptide programs which are tackling targets and indications in which traditional small molecule approaches have been difficult and challenging. The targets for these potential peptide therapeutics include the NMDA receptor, γ-secretase, and cyclin-dependent kinase in which direct inhibition has resulted in on-target (not compound related) problems. For example, direct inhibition of γ-secretase has resulted in gastrointestinal abnormalities and inhibition of the NMDA receptor can result in hallucinations, dizziness, out-of-body sensations, and nightmares. When confronted with show-stopping side effects, the CNS peptide programs profiled in this review strike the problem with intervention and disruption of selective protein-protein interactions. The goal of these peptide programs is to produce selective therapeutics with a better safety profile.
      Graphical abstract image

      PubDate: 2017-09-12T01:59:24Z
      DOI: 10.1016/j.bmc.2017.09.011
  • Eudesmane sesquiterpenes from Chinese liverwort are substrates of Cdrs and
           display antifungal activity by targeting Erg6 and Erg11 of Candida
    • Authors: Siwen Li; Hongzhuo Shi; Wenqiang Chang; Yi Li; Ming Zhang; Yanan Qiao; Hongxiang Lou
      Abstract: Publication date: Available online 9 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Siwen Li, Hongzhuo Shi, Wenqiang Chang, Yi Li, Ming Zhang, Yanan Qiao, Hongxiang Lou
      We isolated twelve sesquiterpenes from Chinese liverwort Tritomaria quinquedentata (Huds.) Buch., including four new compounds. Among them, five eudesmane sesquiterpenes were ineffective against Candida albicans wild strain SC5314 but active towards efflux pumps-deficient strain DSY654 using Alamar blue assay. Further test of the most active agent of ent-isoalantolactone (8, ent-iLL) showed that it also inhibited the yeast-to-hyphal switch of DSY654 cells. The intracellular content measurement using high performance liquid chromatography revealed that ent-iLL was intracellularly accumulated in C. albicans when efflux pumps were deficient or inhibited by Cdrs inhibitor riccardin D, suggesting that the activity of ent-iLL was compromised by efflux pumps Cdrs. Moreover, ent-iLL potentially inhibited the activity of Erg11 and Erg6 of DSY654 and thereby resulted in the alteration of sterol composition by decreasing ergosterol contents and increasing zymosterol and lanosterol accumulation. Our study demonstrated that eudesmane sesquiterpenes, as the substrates of Cdrs, could interfere with sterol synthesis of C. albicans to exert antifungal activity when co-applied with Cdrs inhibitors.
      Graphical abstract image

      PubDate: 2017-09-12T01:59:24Z
      DOI: 10.1016/j.bmc.2017.09.001
  • 1-Hydroxypyrido[2,3-d]pyrimidin-2(1H)-ones as Novel Selective HIV
           Integrase Inhibitors Obtained via Privileged Substructure-Based Compound
    • Authors: Ping Gao; Lingzi Zhang; Lin Sun; Tianguang Huang; Jing Tan; Jian Zhang; Zhongxia Zhou; Tong Zhao; Luis Menéndez-Arias; Christophe Pannecouque; Erik De Clercq; Peng Zhan; Xinyong Liu
      Abstract: Publication date: Available online 8 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Ping Gao, Lingzi Zhang, Lin Sun, Tianguang Huang, Jing Tan, Jian Zhang, Zhongxia Zhou, Tong Zhao, Luis Menéndez-Arias, Christophe Pannecouque, Erik De Clercq, Peng Zhan, Xinyong Liu
      A small library containing 3-hydroxyquinazoline-2,4(1H,3H)-dione and 1-hydroxypyrido[2,3-d]pyrimidin-2(1H)-one scaffolds was obtained via the copper(I)-catalyzed azidealkyne cycloaddition (CuAAC) reaction and evaluated for their anti-HIV activity in MT-4 cells. Among the synthesized compounds, several 1-hydroxypyrido[2,3-d]pyrimidin-2(1H)-one derivatives showed remarkable anti-HIV potency with EC50 values ranging from 0.92 to 26.85 µM. The most active one, IIA-2, also showed remarkable and selective potency against HIV type 1 integrase (IN). To the best of our knowledge, this is the first report showing that 1-hydroxypyrido[2,3-d]pyrimidin-2(1H)-ones are selective HIV IN inhibitors. Preliminary structure-activity relationship (SAR) studies suggested that the divalent metal ion chelators and the nature and position of substituents around the core are important for antiviral potency. Molecular modeling has been used to predict the binding site of the pyrido[2,3-d]pyrimidin-2(1H)-one core in HIV type 1 IN and suggestions are made for improvement of its inhibitory activity.

      PubDate: 2017-09-12T01:59:24Z
      DOI: 10.1016/j.bmc.2017.09.006
  • Development of a cyclosporin A derivative with excellent anti-hepatitis C
           virus potency
    • Authors: Jiping Fu; Christopher Becker; Li Cao; Michael Capparelli; Regis Denay; Roger Fujimoto; Yu Gai; Zhaobo Gao; Christian Guenat; Subramanian Karur; Hongyong Kim; Weikuan Li; Xiaolin Li; Wei Li; Thomas Lochmann; Amy Lu; Peichao Lu; Alexandre Luneau; Nicole Meier; Wosenu Mergo; Simon Ng; David Parker; Yunshan Peng; Bernard Riss; Alexey Rivkin; Silvio Roggo; Harald Schroeder; Friedrich Schuerch; Robert L. Simmons; Feng Sun; Zachary K. Sweeney; Meiliana Tjandra; Michael Wang; Ruidong Wang; Andrew H. Weiss; Nicolas Wenger; Quanbing Wu; Xin Xiong; Su Xu; Wenjian Xu; Aregahegn Yifru; Jibin Zhao; Jianguang Zhou; Christian Zürcher; Fabrice Gallou
      Abstract: Publication date: Available online 7 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Jiping Fu, Christopher Becker, Li Cao, Michael Capparelli, Regis Denay, Roger Fujimoto, Yu Gai, Zhaobo Gao, Christian Guenat, Subramanian Karur, Hongyong Kim, Weikuan Li, Xiaolin Li, Wei Li, Thomas Lochmann, Amy Lu, Peichao Lu, Alexandre Luneau, Nicole Meier, Wosenu Mergo, Simon Ng, David Parker, Yunshan Peng, Bernard Riss, Alexey Rivkin, Silvio Roggo, Harald Schroeder, Friedrich Schuerch, Robert L. Simmons, Feng Sun, Zachary K. Sweeney, Meiliana Tjandra, Michael Wang, Ruidong Wang, Andrew H. Weiss, Nicolas Wenger, Quanbing Wu, Xin Xiong, Su Xu, Wenjian Xu, Aregahegn Yifru, Jibin Zhao, Jianguang Zhou, Christian Zürcher, Fabrice Gallou
      Synthetic modification of cyclosporin A at P3-P4 positions led to the discovery of NIM258, a next generation cyclophilin inhibitor with excellent anti-hepatitis C virus potency, with decreased transporter inhibition, and pharmacokinetics suitable for coadministration with other drugs. Herein is disclosed the evolution of the synthetic strategy to from the original medicinal chemistry route, designed for late diversification, to a convergent and robust development synthesis. The chiral centers in the P4 fragment were constructed by an asymmetric chelated Claisen rearrangement in the presence of quinidine as the chiral ligand. Identification of advanced crystalline intermediates enabled practical supply of key intermediates. Finally, macrocyclization was carried out at 10% weight concentration by a general and unconventional “slow release” concept.
      Graphical abstract image

      PubDate: 2017-09-12T01:59:24Z
      DOI: 10.1016/j.bmc.2017.09.008
  • Synthesis and Biological Evaluation of an 111In-Labeled Exendin-4
           Derivative as a Single-Photon Emission Computed Tomography Probe for
           Imaging Pancreatic β-cells
    • Authors: Hiroyuki Kimura; Naotaka Fujita; Kaori Kanbe; Hirokazu Matsuda; Hiroyuki Watanabe; Kenji Arimitsu; Hiroyuki Fujimoto; Keita Hamamatsu; Yusuke Yagi; Masahiro Ono; Nobuya Inagaki; Hideo Saji
      Abstract: Publication date: Available online 7 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Hiroyuki Kimura, Naotaka Fujita, Kaori Kanbe, Hirokazu Matsuda, Hiroyuki Watanabe, Kenji Arimitsu, Hiroyuki Fujimoto, Keita Hamamatsu, Yusuke Yagi, Masahiro Ono, Nobuya Inagaki, Hideo Saji
      A non-invasive method of pancreatic β-cell mass measurement is needed to enhance our understanding of the pathogenesis of diabetes, facilitate the early diagnosis of this disease, and promote the development of novel therapeutics. Here, we described the synthesis of a novel indium-111 (111In) exendin-4 derivative, [Lys12(In-BnDTPA-Ahx)]exendin-4, through a process involving isothiocyanate-benzyl-DTPA (BnDTPA) and 6-aminohexanoic acid (Ahx) attached to an ɛ-amino group at the lysine-12 residue. We further evaluated the potential use of this derivative as a SPECT probe for pancreatic β-cell imaging. An in vitro binding assay revealed that [Lys12(natIn-BnDTPA-Ahx)]exendin-4 has a high affinity for GLP-1 receptors (IC50 = 0.43 nM). In biodistribution experiments involving normal mice, high [Lys12(111In-BnDTPA-Ahx)]exendin-4 uptake was observed in the pancreas (21.8 ± 4.0%ID/g) and was maintained for 2 hours after injection. Pre-injection of excess exendin(9-39) markedly reduced the pancreatic uptake of [Lys12(111In-BnDTPA-Ahx)]exendin-4 (95.2%), indicating that the uptake of this tracer is specific and mediated by GLP-1 receptors. Ex vivo autoradiography experiments involving pancreatic sections from MIP-GFP mice confirmed the accumulation of [Lys12(111In-BnDTPA-Ahx)]exendin-4 in pancreatic β-cells. Finally, in mice, [Lys12(111In-BnDTPA-Ahx)]exendin-4 SPECT/CT yielded clear images of the pancreas at 30 min post-injection. In conclusion, SPECT with [Lys12(111In-BnDTPA-Ahx)]exendin-4 enables to visualize β-cells in vivo non-invasively.
      Graphical abstract image

      PubDate: 2017-09-12T01:59:24Z
      DOI: 10.1016/j.bmc.2017.09.005
  • Cell penetrating peptides to dissect host-pathogen protein-protein
           interactions in Theileria-transformed leukocytes
    • Authors: Malak Haidar; Perle Latré de Laté; Eileen J. Kennedy; Gordon Langsley
      Abstract: Publication date: Available online 7 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Malak Haidar, Perle Latré de Laté, Eileen J. Kennedy, Gordon Langsley
      One powerful application of cell penetrating peptides is the delivery into cells of molecules that function as specific competitors or inhibitors of protein-protein interactions. Ablating defined protein-protein interactions is a refined way to explore their contribution to a particular cellular phenotype in a given disease context. Cell-penetrating peptides can be synthetically constrained through various chemical modifications that stabilize a given structural fold with the potential to improve competitive binding to specific targets. Theileria-transformed leukocytes display high PKA activity, but PKAis an enzyme that plays key roles in multiple cellular processes; consequently genetic ablation of kinase activity gives rise to a myriad of confounding phenotypes. By contrast, ablation of a specific kinase-substrate interaction has the potential to give more refined information and we illustrate this here by describing how surgically ablating PKA interactions with BAD gives precise information on the type of glycolysis performed by Theileria-transformed leukocytes. In addition, we provide two other examples of how ablating specific protein-protein interactions in Theileria-infected leukocytes leads to precise phenotypes and argue that constrained penetrating peptides have great therapeutic potential to combat infectious diseases in general.
      Graphical abstract image

      PubDate: 2017-09-12T01:59:24Z
      DOI: 10.1016/j.bmc.2017.08.056
  • Design, Synthesis and Antitumor Activity of Novel Sorafenib Derivatives
           Bearing Pyrazole Scaffold
    • Authors: Min Wang; Shan Xu; Huajun Lei; Caolin Wang; Zhen Xiao; Shuang Jia; Jia Zhi; Pengwu Zheng; Wufu Zhu
      Abstract: Publication date: Available online 6 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Min Wang, Shan Xu, Huajun Lei, Caolin Wang, Zhen Xiao, Shuang Jia, Jia Zhi, Pengwu Zheng, Wufu Zhu
      Four series of Sorafenib derivatives bearing pyrazole scaffold (8a–m, 9a–c, 10a–e and 11a) were synthesized and characterized by NMR and MS. All of the target compounds were evaluated for the cytotoxicity against A549, HepG2, MCF-7, and PC-3 cancer cell lines and some selected compounds were further evaluated for the activity against VEGFR-2/KDR, BRAF, CRAF, c-Met, EGFR and Flt-3 kinases. Compounds 8b and 8i were more active than that of compounds 8h, 9a, especially the IC50 value of compounds 8b on VEGFR-2 kinase was 0.56 μM. And compound 8b exhibited moderate to good activity toward c-Met and showed moderate to no activity against CRAF, c-Met, EGFR, Flt-3 kinases. Eleven of the target compounds exhibited moderate to good antitumor activities. The most promising compound 8b showed strong antitumor activities against A549, HepG2 and MCF-7 cell lines with IC50 values of 2.84±0.78μM, 1.85±0.03μM and 1.96±0.28 μM, which were equivalent to sorafenib (2.92±0.68 μM, 3.44±0.50 μM and 3.18±0.18 μM). Structure–activity relationships (SARs) and docking studies indicated that the pyrazole scaffolds exerted key effect on antitumor activities of target compounds. Substitutions of aryl group at C-3 positions had a significant impact on the antitumor activities, and 3-Br substitution produced the best potency.
      Graphical abstract image

      PubDate: 2017-09-12T01:59:24Z
      DOI: 10.1016/j.bmc.2017.09.003
  • In-cell production of a genetically-encoded library based on the
           θ-defensin RTD-1 using a bacterial expression system
    • Authors: Tao Bi; Yilong Li; Alexander Shekhtman; Julio A. Camarero
      Abstract: Publication date: Available online 6 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Tao Bi, Yilong Li, Alexander Shekhtman, Julio A. Camarero
      We report the high-yield heterologous expression of bioactive θ -defensin RTD-1 inside Escherichia coli cells by making use of intracellular protein trans-splicing in combination with a high efficient split-intein. RTD-1 is a small backbone-cyclized polypeptide with three disulfide bridges and a natural inhibitor of anthrax lethal factor protease. Recombinant RTD-1 was natively folded and able to inhibit anthrax lethal factor protease. In-cell expression of RTD-1 was very efficient and yielded ≈ 0.7 mg of folded RTD-1 per gram of wet E. coli cells. This approach was used to generate of a genetically-encoded RTD-1-based peptide library in live E. coli cells. These results clearly demonstrate the possibility of using genetically-encoded RTD-1-based peptide libraries in live E. coli cells, which is a critical first step for developing in-cell screening and directed evolution technologies using the cyclic peptide RTD-1 as a molecular scaffold.
      Graphical abstract image

      PubDate: 2017-09-12T01:59:24Z
      DOI: 10.1016/j.bmc.2017.09.002
  • Structure-Activity Relationship Study of Small Molecule Inhibitors of the
           DEPTOR-mTOR Interaction
    • Authors: Jihye Lee; Yijiang Shi; Mario Vega; Yonghui Yang; Joseph Gera; Michael E. Jung; Alan Lichtenstein
      Abstract: Publication date: Available online 6 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Jihye Lee, Yijiang Shi, Mario Vega, Yonghui Yang, Joseph Gera, Michael E. Jung, Alan Lichtenstein
      DEPTOR is a 48 kDa protein that binds to mTOR and inhibits this kinase within mTORC1 and mTORC2 complexes. Over-expression of DEPTOR specifically occurs in the multiple myeloma (MM) tumor model and DEPTOR knockdown is cytotoxic to MM cells, suggesting it is a potential therapeutic target. Since mTORC1 paralysis protects MM cells against DEPTOR knockdown, it indicates that the protein-protein interaction between DEPTOR and mTOR is key to MM viability vs death. In a previous study, we used a yeast two-hybrid screen of a small inhibitor library to identify a compound that inhibited DEPTOR/mTOR binding in yeast. This therapeutic (compound B) also prevented DEPTOR/mTOR binding in MM cells and was selectively cytotoxic to MM cells. We now present a structure-activity relationship (SAR) study around this compound as a follow-up report of this previous work. This study has led to the discovery of five new leads – namely compounds 3g, 3k, 4d, 4e and 4g – all of which have anti-myeloma cytotoxic properties superior to compound B. Due to their targeting of DEPTOR, these compounds activate mTORC1 and selectively induce MM cell apoptosis and cell cycle arrest.
      Graphical abstract image

      PubDate: 2017-09-06T08:25:04Z
      DOI: 10.1016/j.bmc.2017.08.050
  • Characterisation of a novel coumarin-based fluorescent probe for
           monitoring nitric oxide production in macrophages
    • Authors: Maiada M. Sadek; Mina Barzegar Amiri Olia; Cameron J. Nowell; Νicholas Barlow; Carl H. Schiesser; Sandra.E. Nicholson; Raymond S. Norton
      Abstract: Publication date: Available online 5 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Maiada M. Sadek, Mina Barzegar Amiri Olia, Cameron J. Nowell, Νicholas Barlow, Carl H. Schiesser, Sandra.E. Nicholson, Raymond S. Norton
      Nitric oxide (NO) is an important effector molecule in host defence against bacterial pathogens. The development of fluorescence imaging to monitor NO production in vitro and in vivo will increase our understanding of its biological role. Recently, a novel “trappable” fluorescent blue ‘turn-on’ Cu(II)-complexed coumarin-based probe (CB) has been developed to detect NO. In this study, CB was investigated to evaluate its ability to detect NO in macrophages. Using confocal microscopy, NO was successfully detected in macrophages in the presence of stimuli that induce nitric oxide synthase (iNOS), the enzyme responsible for production of NO. The time dependence and subcellular compartmentalisation of CB in macrophages were evaluated. The probe can be trapped within cells and reacts directly and specifically with NO, rendering it a promising tool for imaging NO in response to pharmacological agents that modulate its level, for example during bacterial infections.
      Graphical abstract image

      PubDate: 2017-09-06T08:25:04Z
      DOI: 10.1016/j.bmc.2017.08.054
  • A novel class of Plasmodial ClpP protease inhibitors as potential
           antimalarial agents
    • Authors: Sourabh Mundra; Vandana Thakur; Angelica M. Bello; Sumit Rathore; Mohd Asad; Lianhu Wei; Jane Yang; Sai Kumar Chakka; Radhakrishnan Mahesh; Pawan Malhotra; Asif Mohmmed; Lakshmi P. Kotra
      Abstract: Publication date: Available online 5 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Sourabh Mundra, Vandana Thakur, Angelica M. Bello, Sumit Rathore, Mohd Asad, Lianhu Wei, Jane Yang, Sai Kumar Chakka, Radhakrishnan Mahesh, Pawan Malhotra, Asif Mohmmed, Lakshmi P. Kotra
      The prokaryotic ATP-dependent ClpP protease, localized in the relict plastid of malaria parasite, represents a potential drug target. In the present study, we utilized in silico structure-based screening and medicinal chemistry approaches to identify a novel pyrimidine series of compounds inhibiting P. falciparum ClpP protease activity and evaluated their antiparasitic activities. Structure-activity relationship indicated that morpholine moiety at C2, an aromatic substitution at N3 and a 4-oxo moiety on the pyrimidine are important for potent inhibition of ClpP enzyme along with antiparasiticidal activity. Compound 33 exhibited potent antiparasitic activity (EC₅₀ 9.0 ± 0.2 μM), a 9-fold improvement over the antiparasitic activity of the hit molecule 6. Treatment of blood stage P. falciparum cultures with compound 33 caused morphological and developmental abnormalities in the parasites; further, compound 33 treatment hindered apicoplast development indicating the targeting of apicoplast.
      Graphical abstract image

      PubDate: 2017-09-06T08:25:04Z
      DOI: 10.1016/j.bmc.2017.08.049
  • In vitro antitumor activity of novel benzimidazole-based Cu(II) complexes
    • Authors: Jiyong Hu; Yan Guo; Jin'an Zhao; Junshuai Zhang
      Abstract: Publication date: Available online 5 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Jiyong Hu, Yan Guo, Jin'an Zhao, Junshuai Zhang
      Four benzimidazole-based Cu(II) complexes: Cu2(p–2-bmp)2Br4 (1), Cu2(p–2-bmp)2Cl4 (2), Cu2(p-2-bmb)2(DMF)2Br4·(CHCl3) (3), and Cu(p-2-bmb)(NO3)2·(CHCl3) (4) were isolated and characterized, where p–2-bmp is 1-((2-(pyridine-2-yl)-1H-benzoimidazol-1-yl)methyl)-1H- pyridine and p-2-bmb is 1-((2-(pyridin-2-yl)-1-benzoimidazol-1-yl)methyl)-1H-benzotriazole. Complexes 1 and 2 have binuclear configurations, 3 has a mononuclear structure, and 4 has a one-dimensional (1-D) chain skeleton. To evaluate their potential anticancer effects on human carcinoma cells, anti-proliferation, DNA binding and cleavage, and apoptosis elicitation were examined. Compared with complexes 2, 3, and 4, complex 1 exhibited potent in vitro cytotoxicity toward four cell lines (MCF7, EC109, SH-SY5Y and QBC939), with SH-SY5Y cells demonstrating the most sensitivity. Therefore, further in-depth investigations were performed using complex 1. Absorption titration experiments, circular dichroism spectroscopic studies, and ethidium bromide displacement assays suggested that complex 1 binds to DNA through intercalation, significantly cleaves supercoiled pBR322 DNA, and inhibits DNA transcription. Cell cycle analysis revealed that SH-SY5Y cells were arrested in the G2/M phase after treatment with complex 1. Membrane permeability analysis and nuclear staining of SH-SY5Y cells showed that complex 1 could induce apoptosis.
      Graphical abstract image

      PubDate: 2017-09-06T08:25:04Z
      DOI: 10.1016/j.bmc.2017.08.053
  • Conformationally constrained peptides target the allosteric kinase dimer
           interface and inhibit EGFR activation
    • Authors: Melody D. Fulton; Laura E. Hanold; Zheng Ruan; Sneha Patel; Aaron M. Beedle; Natarajan Kannan; Eileen J. Kennedy
      Abstract: Publication date: Available online 5 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Melody D. Fulton, Laura E. Hanold, Zheng Ruan, Sneha Patel, Aaron M. Beedle, Natarajan Kannan, Eileen J. Kennedy
      Although EGFR is a highly sought-after drug target, inhibitor resistance remains a challenge. As an alternative strategy for kinase inhibition, we sought to explore whether allosteric activation mechanisms could effectively be disrupted. The kinase domain of EGFR forms an atypical asymmetric dimer via head-to-tail interactions and serves as a requisite for kinase activation. The kinase dimer interface is primarily formed by the H-helix derived from one kinase monomer and the small lobe of the second monomer. We hypothesized that a peptide designed to resemble the binding surface of the H-helix may serve as an effective disruptor of EGFR dimerization and activation. A library of constrained peptides was designed to mimic the H-helix of the kinase domain and interface side chains were optimized using molecular modeling. Peptides were constrained using peptide “stapling” to structurally reinforce an alpha-helical conformation. Peptide stapling was demonstrated to notably enhance cell permeation of an H-helix derived peptide termed EHBI2. Using cell-based assays, EHBI2 was further shown to significantly reduce EGFR activity as measured by EGFR phosphorylation and phosphorylation of the downstream signaling substrate Akt. To our knowledge, this is the first H-helix-based compound targeting the asymmetric interface of the kinase domain that can successfully inhibit EGFR activation and signaling. This study presents a novel, alternative targeting site for allosteric inhibition of EGFR.
      Graphical abstract image

      PubDate: 2017-09-06T08:25:04Z
      DOI: 10.1016/j.bmc.2017.08.051
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