Journal Cover Bioorganic & Medicinal Chemistry
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   Published by Elsevier Homepage  [3177 journals]
  • Chemical synthesis of febrifugine and analogues
    • Authors: Shaun Smullen; Noel P. McLaughlin; Paul Evans
      Pages: 2199 - 2220
      Abstract: Publication date: 15 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 9
      Author(s): Shaun Smullen, Noel P. McLaughlin, Paul Evans
      The quinazolinone-containing 2,3-disubstituted piperidines febrifugine and isofebrifugine have been the subject of significant research efforts since their occurrence in Dichroa febrifuga and their anti-malarial actions were first described in the late 1940s. Subsequently they have also been shown to be present in other plants belonging to the hydrangea family and various analogues of febrifugine have been prepared in attempts to tune biological properties. The most notable analogue is termed halofuginone and a substantial body of work now demonstrates that this compound possesses potent human disease relevant activities. This review focuses on the literature associated with efforts dedicated towards uncovering the structures of febrifugine and isofebrifugine, the development of practical methods for their synthesis and the syntheses of structural analogues.
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      PubDate: 2018-05-02T10:23:29Z
      DOI: 10.1016/j.bmc.2018.04.027
       
  • Cyclization of PLP139-151 peptide reduces its encephalitogenic potential
           in experimental autoimmune encephalomyelitis
    • Authors: Athanasios Lourbopoulos; Minos-Timotheos Matsoukas; Maria Katsara; George Deraos; Aggeliki Giannakopoulou; Roza Lagoudaki; Nikolaos Grigoriadis; John Matsoukas; Vasso Apostolopoulos
      Pages: 2221 - 2228
      Abstract: Publication date: 15 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 9
      Author(s): Athanasios Lourbopoulos, Minos-Timotheos Matsoukas, Maria Katsara, George Deraos, Aggeliki Giannakopoulou, Roza Lagoudaki, Nikolaos Grigoriadis, John Matsoukas, Vasso Apostolopoulos
      We report the novel synthesis of cyclic PLP139-151 (cPLP) and its application in SJL/J mice to study its encephalitogenic effects. Our results indicate that the cPLP analog is minimally encephalitogenic when administered to induce experimental autoimmune encephalomyelitis (low disease burden, minimal inflammatory, demyelinating and axonopathic pathology compared to its linear counterpart). Proliferation assays confirmed the low stimulatory potential of the cPLP compared to linPLP (2.5-fold lower proliferation) as well as inducing lower antibody responses. Molecular modeling showed a completely different TCR recognition profile of cPLP in regard to linPLP, where H147 replaces W144 and F151-K150 replace H147 as TCR contacts, which may explain the difference on each peptide’s response.
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      PubDate: 2018-05-02T10:23:29Z
      DOI: 10.1016/j.bmc.2017.12.024
       
  • Discovery of 1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazoles as novel
           class of corticotropin releasing factor 1 receptor antagonists
    • Authors: Takuto Kojima; Michiyo Mochizuki; Takafumi Takai; Yasutaka Hoashi; Sachie Morimoto; Masaki Seto; Minoru Nakamura; Katsumi Kobayashi; Yuu Sako; Maiko Tanaka; Naoyuki Kanzaki; Yohei Kosugi; Takahiko Yano; Kazuyoshi Aso
      Pages: 2229 - 2250
      Abstract: Publication date: 15 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 9
      Author(s): Takuto Kojima, Michiyo Mochizuki, Takafumi Takai, Yasutaka Hoashi, Sachie Morimoto, Masaki Seto, Minoru Nakamura, Katsumi Kobayashi, Yuu Sako, Maiko Tanaka, Naoyuki Kanzaki, Yohei Kosugi, Takahiko Yano, Kazuyoshi Aso
      A new class of corticotropin releasing factor 1 (CRF1) receptor antagonists characterized by a tricyclic core ring was designed and synthesized. Novel tricyclic derivatives 2a–e were designed as CRF1 receptor antagonists based on conformation analysis of our original 2-anilinobenzimidazole CRF1 receptor antagonist. The synthesized tricyclic derivatives 2a–e showed CRF1 receptor binding activity with IC50 values of less than 400 nM, and the 1,2,3,4-tetrahydropyrimido-[1,2-a]benzimidazole derivative 2e was selected as a lead compound with potent in vitro CRF1 receptor binding activity (IC50 = 7.1 nM). To optimize the pharmacokinetic profiles of lead compound 2e, we explored suitable substituents on the 1-position and 6-position, leading to the identification of compound 42c-R , which exhibited potent CRF1 receptor binding activity (IC50 = 58 nM) with good oral bioavailability (F = 68% in rats). Compound 42c-R exhibited dose-dependent inhibition of [125I]-CRF binding in the frontal cortex (5 and 10 mg/kg, p.o.) as well as suppression of locomotor activation induced by intracerebroventricular administration of CRF in rats (10 mg/kg, p.o.). These results suggest that compound 42c-R successfully binds CRF1 receptors in the brain and exhibits the potential to be further examined for clinical studies.
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      PubDate: 2018-05-02T10:23:29Z
      DOI: 10.1016/j.bmc.2018.01.020
       
  • Synthesis of S-linked NeuAc-α(2-6)-di-LacNAc bearing liposomes for H1N1
           influenza virus inhibition assays
    • Authors: Hou-Wen Cheng; Hsiao-Wen Wang; Tsung-Yun Wong; Hsien-Wei Yeh; Yi-Chun Chen; Der-Zen Liu; Pi-Hui Liang
      Pages: 2262 - 2270
      Abstract: Publication date: 15 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 9
      Author(s): Hou-Wen Cheng, Hsiao-Wen Wang, Tsung-Yun Wong, Hsien-Wei Yeh, Yi-Chun Chen, Der-Zen Liu, Pi-Hui Liang
      S-NeuAc-α(2-6)-di-LacNAc (5) was efficiently synthesized by a [2+2] followed by a [1+4] glycosylation, and later conjugated with 1,2-dilauroyl-sn-glycero-3-phosphoethanolamine (DLPE) to form both single-layer and multi-layer homogeneous liposomes in the presence of dipalmitoyl phosphatidylcholine (DPPC) and cholesterol. These liposomes were found to be weak inhibitors in both the influenza virus entry assay and the hemagglutination inhibition assay. The single layer liposome was found to more efficiently interfere with the entry of the H1N1 influenza virus into MDCK cells than the multilayer liposome containing 5.
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      PubDate: 2018-05-02T10:23:29Z
      DOI: 10.1016/j.bmc.2018.02.012
       
  • Antibody drug conjugates of cleavable amino-alkyl and aryl maytansinoids
    • Authors: Thomas Nittoli; Marcus P. Kelly; Frank Delfino; John Rudge; Arthur Kunz; Thomas Markotan; Jan Spink; Zhaoyuan Chen; Jing Shan; Elizabeth Navarro; Michele Tait; Kathleen Provoncha; Jason Giurleo; Feng Zhao; Xiaobo Jiang; Donna Hylton; Sosina Makonnen; Carlos Hickey; Jessica R. Kirshner; Gavin Thurston; Nicholas Papadopoulos
      Pages: 2271 - 2279
      Abstract: Publication date: 15 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 9
      Author(s): Thomas Nittoli, Marcus P. Kelly, Frank Delfino, John Rudge, Arthur Kunz, Thomas Markotan, Jan Spink, Zhaoyuan Chen, Jing Shan, Elizabeth Navarro, Michele Tait, Kathleen Provoncha, Jason Giurleo, Feng Zhao, Xiaobo Jiang, Donna Hylton, Sosina Makonnen, Carlos Hickey, Jessica R. Kirshner, Gavin Thurston, Nicholas Papadopoulos
      Natural products have been used for many medicinal purposes for centuries. Antibody drug conjugates (ADCs) have utilized this rich source of small molecule therapeutics to produce several clinically useful treatments. ADCs based on the natural product maytansine have been successful clinically. The authors further the utility of the anti-cancer natural product maytansine by developing efficacious payloads and linker-payloads for conjugating to antibodies. The success of our approach was realized in the EGFRvIII targeting ADC EGFRvIII-16. The ADC was able to regress tumors in 2 tumor models (U251/EGFRvIII and MMT/EGFRvIII). When compared to a positive control ADC, the efficacy observed was similar or improved while the isotype control ADCs had no effect.
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      PubDate: 2018-05-02T10:23:29Z
      DOI: 10.1016/j.bmc.2018.02.025
       
  • Investigation of novel pyrazole carboxamides as new apoptosis inducers on
           neuronal cells in Helicoverpa zea
    • Authors: Yuanhang Ren; Na Yang; Ying Yue; Hong Jin; Ke Tao; Taiping Hou
      Pages: 2280 - 2286
      Abstract: Publication date: 15 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 9
      Author(s): Yuanhang Ren, Na Yang, Ying Yue, Hong Jin, Ke Tao, Taiping Hou
      Novel pyrazole carboxamides with a diarylamine-modified scaffold were modified based on the bixafen (Bayer) fungicide, which has excellent activity against Rhizoctonia solani, Rhizoctonia cerealis and Sclerotinia sclerotiorum. To discover the potential insecticidal activity of these novel pyrazole carboxamides, the present study explored their possible cytoactivity on the insect neuronal cells (RP-HzVNC-AW1) in Helicoverpa zea. The preliminary bioassays showed that some of the target compounds exhibited good cytoactivity against AW1 cells. Among them, compounds a5 and b4–b7 showed good activity in vitro with IC50 values of 11.28, 10.46, 9.04, 11.72 and 12.19 μM, respectively. Notably, the IC50 value of compound b5 was better than 11.81 μM for fipronil. We subsequently attempted to illustrate the mechanism of b5. Intracellular biochemical assays showed that b5 induced AW1 cell apoptosis with a decrease in themitochondrial membrane potential, as well as a significantly increased intracellular calcium ion concentration and caspase-3 activity. A significant decrease in Bcl-2 levels and a marked augmentation of cytochrome-c and Bax were also detected. These results indicate that a mitochondrially dependent intrinsic pathway contributes to compound b5-induced apoptosis in AW1 cells. This study suggests that b5 may act as a potential insecticide that can be used for further optimization.
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      PubDate: 2018-05-02T10:23:29Z
      DOI: 10.1016/j.bmc.2018.03.010
       
  • Selective binding and controlled release of anticancer drugs by
           polyanionic cyclodextrins
    • Authors: Jian-Guang Cheng; Hua-Jiang Yu; Yong Chen; Yu Liu
      Pages: 2287 - 2290
      Abstract: Publication date: 15 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 9
      Author(s): Jian-Guang Cheng, Hua-Jiang Yu, Yong Chen, Yu Liu
      The binding stoichiometry, binding constants, and inclusion mode of some water-soluble negatively charged cyclodextrin derivatives, i.e. heptakis-[6-deoxy-6-(3-sulfanylpropanoic acid)]-β-cyclodextrin(H1), heptakis-[6-deoxy-6-(2-sulfanylacetic acid)]-β-cyclodextrin(H2), mono-[6-deoxy-6-(3-sulfanylpropanoic acid)]-β-cyclodextrin (H3) and mono-[6-deoxy-6-(2-sulfanylacetic acid)]-β-cyclodextrin (H4), with three anticancer drugs, i.e. irinotecan hydrochloride; topotecan hydrochloride; doxorubicin hydrochloride, were investigated by means of 1H NMR, UV–Vis spectroscopy, mass spectra and 2D NMR. Polyanionic cyclodextrins H1-H2 showed the significantly high binding abilities of up to 2.6 × 104–2.0 × 105 M−1 towards the selected anticancer drugs, which were nearly 50–1000 times higher than the corresponding Ks values of native β-cyclodextrin. In addition, these polyanionic cyclodextrins also showed the pH-controlled release behaviors. That is, the anticancer drugs could be efficiently encapsulated in the cyclodextrin cavity at a pH value similar to that of serum but sufficiently released at an endosomal pH value of a cancer cell, which would make these cyclodextrin derivatives the potential carriers for anticancer drugs.
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      PubDate: 2018-05-02T10:23:29Z
      DOI: 10.1016/j.bmc.2018.03.013
       
  • Structure–activity relationships of succinimidyl-Cys-C(O)-Glu
           derivatives with different near-infrared fluorophores as optical imaging
           probes for prostate-specific membrane antigen
    • Authors: Daiko Matsuoka; Hiroyuki Watanabe; Yoichi Shimizu; Hiroyuki Kimura; Yusuke Yagi; Ryoko Kawai; Masahiro Ono; Hideo Saji
      Pages: 2291 - 2301
      Abstract: Publication date: 15 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 9
      Author(s): Daiko Matsuoka, Hiroyuki Watanabe, Yoichi Shimizu, Hiroyuki Kimura, Yusuke Yagi, Ryoko Kawai, Masahiro Ono, Hideo Saji
      Prostate-specific membrane antigen (PSMA), which is overexpressed in malignant prostate cancer (PCa), is an ideal target for imaging and therapy of PCa. We previously reported a PSMA imaging probe, 800CW-SCE, based on succinimidyl-Cys-C(O)-Glu (SCE) for optical imaging of PCa. In this study, we investigated the structure–activity relationships of novel SCE derivatives with five different near-infrared (NIR) fluorophores (IRDye 680LT, IRDye 750, Indocyanine Green, Cyanine 5.5, and Cyanine 7) as optical imaging probes targeting PSMA. An in vitro binding assay revealed that 800CW-SCE, 680LT-SCE, and 750-SCE exhibited higher binding affinity than 2-PMPA, which is known as a PSMA inhibitor. These three SCE derivatives were internalized into PSMA-positive cells (LNCaP cells) but not into PSMA-negative cells (PC-3 cells). In the in vivo imaging study, 800CW-SCE and 750-SCE were highly accumulated in LNCaP tumors but not in PC-3 tumors, and the ratio of LNCaP/PC-3 accumulation of 800CW-SCE was higher than that of 750-SCE. The present study may provide valuable molecular design information for the future development of new PSMA imaging probes based on the SCE scaffold.
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      PubDate: 2018-05-02T10:23:29Z
      DOI: 10.1016/j.bmc.2018.03.015
       
  • DNA sequence-specific ligands. XVII. Synthesis, spectral properties,
           virological and biochemical studies of fluorescent dimeric
           bisbenzimidazoles DBA(n)
    • Authors: Vasiliy S. Koval; Albert F. Arutyunyan; Victor L. Salyanov; Regina R. Klimova; Alla A. Kushch; Ekaterina Yu. Rybalkina; Olga Yu. Susova; Alexei L. Zhuze
      Pages: 2302 - 2309
      Abstract: Publication date: 15 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 9
      Author(s): Vasiliy S. Koval, Albert F. Arutyunyan, Victor L. Salyanov, Regina R. Klimova, Alla A. Kushch, Ekaterina Yu. Rybalkina, Olga Yu. Susova, Alexei L. Zhuze
      A series of DNA minor groove binding fluorescent dimeric bisbenzimidazoles DBA(n) bearing linkers of various length were synthesized and their biochemical and antiviral activities were evaluated. Their antiviral activity was assessed in model cell systems infected with human herpes simplex virus (HSV-1) and cytomegalovirus (CMV). Compounds DBA(1) and DBA(7) demonstrated in vitro inhibitory properties towards HSV-1, and DBA(7) completely blocked the viral infection. Compound DBA(11) displayed the in vitro therapeutic activity towards both HSV-1 and CMV. All of the DBA(n) could fluoresce, were well soluble in water, not cytotoxic to a concentration of 240 µM, penetrated well into cell nuclei by binding to DNA and could inhibit topo-I at low micromolecular concentrations.
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      PubDate: 2018-05-02T10:23:29Z
      DOI: 10.1016/j.bmc.2018.03.018
       
  • Discovery of new A- and B-type laxaphycins with synergistic anticancer
           activity
    • Authors: Weijing Cai; Susan Matthew; Qi-Yin Chen; Valerie J. Paul; Hendrik Luesch
      Pages: 2310 - 2319
      Abstract: Publication date: 15 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 9
      Author(s): Weijing Cai, Susan Matthew, Qi-Yin Chen, Valerie J. Paul, Hendrik Luesch
      Two new cyclic lipopeptides termed laxaphycins B4 (1) and A2 (2) were discovered from a collection of the marine cyanobacterium Hormothamnion enteromorphoides, along with the known compound laxaphycin A. The planar structures were solved based on a combined interpretation of 1D and 2D NMR data and mass spectral data. The absolute configurations of the subunits were determined by chiral LC-MS analysis of the hydrolysates, advanced Marfey’s analysis and 1D and 2D ROESY experiments. Consistent with similar findings on other laxaphycin A- and B-type peptides, laxaphycin B4 (1) showed antiproliferative effects against human colon cancer HCT116 cells with IC50 of 1.7 µM, while laxaphycins A and A2 (2) exhibited weak activities. The two major compounds isolated from the sample, laxaphycins A and B4, were shown to act synergistically to inhibit the growth of HCT116 colorectal cancer cells.
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      PubDate: 2018-05-02T10:23:29Z
      DOI: 10.1016/j.bmc.2018.03.022
       
  • Design, synthesis, and functional assessment of Cmpd-15 derivatives as
           negative allosteric modulators for the β2-adrenergic receptor
    • Authors: Kaicheng Meng; Paul Shim; Qingtin Wang; Shuai Zhao; Ting Gu; Alem W. Kahsai; Seungkirl Ahn; Xin Chen
      Pages: 2320 - 2330
      Abstract: Publication date: 15 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 9
      Author(s): Kaicheng Meng, Paul Shim, Qingtin Wang, Shuai Zhao, Ting Gu, Alem W. Kahsai, Seungkirl Ahn, Xin Chen
      The β2-adrenergic receptor (β2AR), a G protein-coupled receptor, is an important therapeutic target. We recently described Cmpd-15, the first small molecule negative allosteric modulator (NAM) for the β2AR. Herein we report in details the design, synthesis and structure-activity relationships (SAR) of seven Cmpd-15 derivatives. Furthermore, we provide in a dose-response paradigm, the details of the effects of these derivatives in modulating agonist-induced β2AR activities (G-protein-mediated cAMP production and β-arrestin recruitment to the receptor) as well as the binding affinity of an orthosteric agonist in radio-ligand competition binding assay. Our results show that some modifications, including removal of the formamide group in the para-formamido phenylalanine region and bromine in the meta-bromobenzyl methylbenzamide region caused dramatic reduction in the functional activity of Cmpd-15. These SAR results provide valuable insights into the mechanism of action of the NAM Cmpd-15 as well as the basis for future development of more potent and selective modulators for the β2AR based on the chemical scaffold of Cmpd-15.
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      PubDate: 2018-05-02T10:23:29Z
      DOI: 10.1016/j.bmc.2018.03.023
       
  • Kinase-catalyzed biotinylation of DNA
    • Authors: Thilani M. Anthony; Mary Kay H. Pflum
      Pages: 2331 - 2336
      Abstract: Publication date: 15 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 9
      Author(s): Thilani M. Anthony, Mary Kay H. Pflum
      Prior work documented use of γ-phosphate modified ATP analogs to label DNA using T4 polynucleotide kinases (T4PNK), although applications have been limited. To fully characterize kinase-catalyzed labeling of nucleic acids, we explored use of ATP-biotin as a cosubstrate with T4PNK. T4PNK accepted ATP-biotin to 5′-label single stranded DNA. However, T4PNK-mediated labeling of double stranded substrates was low yielding. In addition, the phosphoramidate bond connecting the biotin group to the DNA was unstable. These results suggest that kinase-catalyzed biotinylation will be useful with single stranded DNA substrates and mild reaction conditions. By revealing the scope and limitations of kinase-catalyzed biotinylation, these studies provide a foundation for future development and application of kinase-catalyzed labeling to DNA-based biological studies.
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      PubDate: 2018-05-02T10:23:29Z
      DOI: 10.1016/j.bmc.2018.03.027
       
  • Hydrophobic structure of hairpin ten-ring pyrrole-imidazole polyamides
           enhances tumor tissue accumulation/retention in vivo
    • Authors: Takahiro Inoue; Osamu Shimozato; Nina Matsuo; Yusuke Mori; Yoshinao Shinozaki; Jason Lin; Takayoshi Watanabe; Atsushi Takatori; Nobuko Koshikawa; Toshinori Ozaki; Hiroki Nagase
      Pages: 2337 - 2344
      Abstract: Publication date: 15 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 9
      Author(s): Takahiro Inoue, Osamu Shimozato, Nina Matsuo, Yusuke Mori, Yoshinao Shinozaki, Jason Lin, Takayoshi Watanabe, Atsushi Takatori, Nobuko Koshikawa, Toshinori Ozaki, Hiroki Nagase
      To examine the hydrophobic structure of PI polyamides on tumor accumulation in vivo, PI polyamide-fluorescein conjugates 1–5 with the distinct number of N-methylimidazole (Im) units were synthesized. There existed an inverse relationship between the Im unit number of the compounds and their hydrophobicity. Compound 1 with one Im unit and 3 with three Im units accumulated and retained preferentially in tumor tissues compared to 5 with five Im units. These results suggest the importance of a PI polyamide’s primary structure, which partly contributes to its hydrophobic property, on its accumulation and/or retention in tumor tissues in vivo.
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      PubDate: 2018-05-02T10:23:29Z
      DOI: 10.1016/j.bmc.2018.03.029
       
  • Small-molecules that bind to the ubiquitin-binding motif of REV1 inhibit
           REV1 interaction with K164-monoubiquitinated PCNA and suppress DNA damage
           tolerance
    • Authors: Murugendra Vanarotti; Benjamin J. Evison; Marcelo L. Actis; Akira Inoue; Ezelle T. McDonald; Youming Shao; Richard J. Heath; Naoaki Fujii
      Pages: 2345 - 2353
      Abstract: Publication date: 15 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 9
      Author(s): Murugendra Vanarotti, Benjamin J. Evison, Marcelo L. Actis, Akira Inoue, Ezelle T. McDonald, Youming Shao, Richard J. Heath, Naoaki Fujii
      REV1 protein is a mutagenic DNA damage tolerance (DDT) mediator and encodes two ubiquitin-binding motifs (i.e., UBM1 and UBM2) that are essential for the DDT function. REV1 interacts with K164-monoubiquitinated PCNA (UbPCNA) in cells upon DNA-damaging stress. By using AlphaScreen assays to detect inhibition of REV1 and UbPCNA protein interactions along with an NMR-based strategy, we identified small-molecule compounds that inhibit the REV1/UbPCNA interaction and that directly bind to REV1 UBM2. In cells, one of the compound prevented recruitment of REV1 to PCNA foci on chromatin upon cisplatin treatment, delayed removal of UV-induced cyclopyrimidine dimers from nuclei, prevented UV-induced mutation of HPRT gene, and diminished clonogenic survival of cells that were challenged by cyclophosphamide or cisplatin. This study demonstrates the potential utility of a small-molecule REV1 UBM2 inhibitor for preventing DDT.
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      PubDate: 2018-05-02T10:23:29Z
      DOI: 10.1016/j.bmc.2018.03.028
       
  • Synthesis and antiproliferative activity of derivatives of the
           phyllanthusmin class of arylnaphthalene lignan lactones
    • Authors: John L. Woodard; Andrew C. Huntsman; Pratiq A. Patel; Hee-Byung Chai; Ragu Kanagasabai; Soumendrakrishna Karmahapatra; Alexandria N. Young; Yulin Ren; Malcolm S. Cole; Denisse Herrera; Jack C. Yalowich; A. Douglas Kinghorn; Joanna E. Burdette; James R. Fuchs
      Pages: 2354 - 2364
      Abstract: Publication date: 15 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 9
      Author(s): John L. Woodard, Andrew C. Huntsman, Pratiq A. Patel, Hee-Byung Chai, Ragu Kanagasabai, Soumendrakrishna Karmahapatra, Alexandria N. Young, Yulin Ren, Malcolm S. Cole, Denisse Herrera, Jack C. Yalowich, A. Douglas Kinghorn, Joanna E. Burdette, James R. Fuchs
      A series of arylnaphthalene lignan lactones based on the structure of the phyllanthusmins, a class of potent natural products possessing diphyllin as the aglycone, has been synthesized and screened for activity against multiple cancer cell lines. SAR exploration was performed on both the carbohydrate and lactone moieties of this structural class. These studies have revealed the importance of functionalization of the carbohydrate hydroxy groups with both acetylated and methylated analogues showing increased potency relative to those with unsubstituted sugar moieties. In addition, the requirement for the presence and position of the C-ring lactone has been demonstrated through reduction and selective re-oxidation of the lactone ring. The most potent compound in this study displayed an IC50 value of 18 nM in an HT-29 assay with several others ranging from 50 to 200 nM. In an effort to elucidate their potential mechanism(s) of action, the DNA topoisomerase IIa inhibitory activity of the most potent compounds was examined based on previous reports of structurally similar compounds, but does not appear to contribute significantly to their antiproliferative effects.
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      PubDate: 2018-05-02T10:23:29Z
      DOI: 10.1016/j.bmc.2018.03.033
       
  • Chemo-enzymatic synthesis of the exocyclic olefin isomer of thymidine
           monophosphate
    • Authors: Dibyendu Mondal; Eric M. Koehn; Jiajun Yao; David F. Wiemer; Amnon Kohen
      Pages: 2365 - 2371
      Abstract: Publication date: 15 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 9
      Author(s): Dibyendu Mondal, Eric M. Koehn, Jiajun Yao, David F. Wiemer, Amnon Kohen
      Exocyclic olefin variants of thymidylate (dTMP) recently have been proposed as reaction intermediates for the thymidyl biosynthesis enzymes found in many pathogenic organisms, yet synthetic reports on these materials are lacking. Here we report two strategies to prepare the exocyclic olefin isomer of dTMP, which is a putative reaction intermediate in pathogenic thymidylate biosynthesis and a novel nucleotide analog. Our most effective strategy involves preserving the existing glyosidic bond of thymidine and manipulating the base to generate the exocyclic methylene moiety. We also report a successful enzymatic deoxyribosylation of a non-aromatic nucleobase isomer of thymine, which provides an additional strategy to access nucleotide analogs with disrupted ring conjugation or with reduced heterocyclic bases. The strategies reported here are straightforward and extendable towards the synthesis of various pyrimidine nucleotide analogs, which could lead to compounds of value in studies of enzyme reaction mechanisms or serve as templates for rational drug design.
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      PubDate: 2018-05-02T10:23:29Z
      DOI: 10.1016/j.bmc.2018.03.032
       
  • Design, synthesis, and biological evaluation of new B-RafV600E kinase
           inhibitors
    • Authors: Peng-Fei Wang; Yong-Jiao Zhang; Dong Wang; Hui-Min Hu; Zhong-Chang Wang; Chen Xu; Han-Yue Qiu; Hai-Liang Zhu
      Pages: 2372 - 2380
      Abstract: Publication date: 15 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 9
      Author(s): Peng-Fei Wang, Yong-Jiao Zhang, Dong Wang, Hui-Min Hu, Zhong-Chang Wang, Chen Xu, Han-Yue Qiu, Hai-Liang Zhu
      The association of deregulated signal pathways with various diseases has long been a research hotspot. One of the most important signal pathways, the MAPK (mitogen-activated protein kinase) signal pathway, plays a vital role in transducing extracellular signals into vital intracellular mechanisms. While mutations on its key component Raf kinase lead to sever diseases, targeted inhibition has thereby become an attractive therapeutic strategy. Several drugs have been approved for the treatment of Raf relevant diseases, yet more candidates are ever needed as the known drugs have confronted resistance and side effects. In the present study, we primarily investigated the binding modes of type I/II and type II inhibitors with B-Raf kinase. Based on the current knowledge, these ligands were fragmented and recombined to provide new interesting insights. Afterwards, a series of derivatives has been synthesized after the validation of hit compound. In addition, in vitro assays were carried out to profile the pharmacological properties of all the entities. Of all the compounds, compound 5h showed the best profile and may be used in the future study.
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      PubDate: 2018-05-02T10:23:29Z
      DOI: 10.1016/j.bmc.2018.03.038
       
  • Design and discovery of thioether and nicotinamide containing sorafenib
           analogues as multikinase inhibitors targeting B-Raf, B-RafV600E and
           VEGFR-2
    • Authors: Shaofeng Sun; Zuopeng He; Mindong Huang; Ningning Wang; Zongzhong He; Xiangkai Kong; Jianwen Yao
      Pages: 2381 - 2391
      Abstract: Publication date: 15 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 9
      Author(s): Shaofeng Sun, Zuopeng He, Mindong Huang, Ningning Wang, Zongzhong He, Xiangkai Kong, Jianwen Yao
      New sorafenib derivatives containing thioether and nicotinamide moiety were designed and synthesized as B-Raf, B-RafV600E and VEGFR-2 multikinase inhibitors. Their in vitro enzymatic inhibitory activities against B-Raf, B-RafV600E and VEGFR-2 and their antiproliferative activities against HCT-116 and B16BL6 cell lines were evaluated and described. Most of the compounds showed potent activities against both cell lines and specific kinases. Compounds a1, b1 and c4, which exhibited the most potent inhibitory activities against B-Raf with IC50 of 21 nM, 27 nM and 17 nM, B-RafV600E with IC50 of 29 nM, 28 nM and 16 nM, VEGFR-2 with IC50 of 84 nM, 46 nM and 63 nM, respectively, and good antiproliferative activities, also demonstrated competitive antiangiogenic activities to sorafenib in in vitro HUVEC tube formation assay.
      Graphical abstract image

      PubDate: 2018-05-02T10:23:29Z
      DOI: 10.1016/j.bmc.2018.03.039
       
  • Peptide Therapeutics
    • Authors: Thomas Vorherr
      First page: 2699
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10
      Author(s): Thomas Vorherr


      PubDate: 2018-05-17T15:58:02Z
      DOI: 10.1016/j.bmc.2018.05.007
       
  • Therapeutic peptides: Historical perspectives, current development trends,
           and future directions
    • Authors: Jolene L. Lau; Michael K. Dunn
      Pages: 2700 - 2707
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10
      Author(s): Jolene L. Lau, Michael K. Dunn
      Peptide therapeutics have played a notable role in medical practice since the advent of insulin therapy in the 1920s. Over 60 peptide drugs are approved in the United States and other major markets, and peptides continue to enter clinical development at a steady pace. Peptide drug discovery has diversified beyond its traditional focus on endogenous human peptides to include a broader range of structures identified from other natural sources or through medicinal chemistry efforts. We maintain a comprehensive dataset on peptides that have entered human clinical studies that includes over 150 peptides in active development today. Here we provide an overview of the peptide therapeutic landscape, including historical perspectives, molecular characteristics, regulatory benchmarks, and a therapeutic area breakdown.
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      PubDate: 2018-05-17T15:58:02Z
      DOI: 10.1016/j.bmc.2017.06.052
       
  • Exploiting the human peptidome for novel antimicrobial and anticancer
           agents
    • Authors: Matteo Bosso; Ludger Ständker; Frank Kirchhoff; Jan Münch
      Pages: 2719 - 2726
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10
      Author(s): Matteo Bosso, Ludger Ständker, Frank Kirchhoff, Jan Münch
      Infectious diseases and cancers are leading causes of death and pose major challenges to public health. The human peptidome encompasses millions of compounds that display an enormous structural and functional diversity and represents an excellent source for the discovery of endogenous agents with antimicrobial and/or anticancer activity. Here, we discuss how to exploit the human peptidome for novel antimicrobial and anticancer agents through the generation of peptide libraries from human body fluids and tissues and stepwise purification of bioactive compounds.
      Graphical abstract image

      PubDate: 2018-05-17T15:58:02Z
      DOI: 10.1016/j.bmc.2017.10.038
       
  • Ribosomally-synthesised cyclic peptides from plants as drug leads and
           pharmaceutical scaffolds
    • Authors: David J. Craik; Meng-Han Lee; Fabian B.H. Rehm; Benjamin Tombling; Benjamin Doffek; Hayden Peacock
      Pages: 2727 - 2737
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10
      Author(s): David J. Craik, Meng-Han Lee, Fabian B.H. Rehm, Benjamin Tombling, Benjamin Doffek, Hayden Peacock
      Owing to their exceptional stability and favourable pharmacokinetic properties, plant-derived cyclic peptides have recently attracted significant attention in the field of peptide-based drug design. This article describes the three major classes of ribosomally-synthesised plant peptides – the cyclotides, the PawS-derived peptides and the orbitides – and reviews their applications as leads or scaffolds in drug design. These ribosomally-produced peptides have a range of biological activities, including anti-HIV, cytotoxic and immunomodulatory activity. In addition, recent interest has focused on their use as scaffolds to stabilise bioactive peptide sequences, thereby enhancing their biopharmaceutical properties. There are now more than 30 published papers on such ‘grafting’ applications, most of which have been reported only in the last few years, and several such studies have reported in vivo activity of orally delivered cyclic peptides. In this article, we describe approaches to the synthesis of cyclic peptides and their pharmaceutically-grafted derivatives as well as outlining their biosynthetic routes. Finally, we describe possible bioproduction routes for pharmaceutically active cyclic peptides, involving plants and plant suspension cultures.
      Graphical abstract image

      PubDate: 2018-05-17T15:58:02Z
      DOI: 10.1016/j.bmc.2017.08.005
       
  • Peptide therapeutics from venom: Current status and potential
    • Authors: Michael W. Pennington; Andrzej Czerwinski; Raymond S. Norton
      Pages: 2738 - 2758
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10
      Author(s): Michael W. Pennington, Andrzej Czerwinski, Raymond S. Norton
      Peptides are recognized as being highly selective, potent and relatively safe as potential therapeutics. Peptides isolated from the venom of different animals satisfy most of these criteria with the possible exception of safety, but when isolated as single compounds and used at appropriate concentrations, venom-derived peptides can become useful drugs. Although the number of venom-derived peptides that have successfully progressed to the clinic is currently limited, the prospects for venom-derived peptides look very optimistic. As proteomic and transcriptomic approaches continue to identify new sequences, the potential of venom-derived peptides to find applications as therapeutics, cosmetics and insecticides grows accordingly.
      Graphical abstract image

      PubDate: 2018-05-17T15:58:02Z
      DOI: 10.1016/j.bmc.2017.09.029
       
  • Peptide chemistry toolbox – Transforming natural peptides into
           peptide therapeutics
    • Authors: Miloš Erak; Kathrin Bellmann-Sickert; Sylvia Els-Heindl; Annette G. Beck-Sickinger
      Pages: 2759 - 2765
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10
      Author(s): Miloš Erak, Kathrin Bellmann-Sickert, Sylvia Els-Heindl, Annette G. Beck-Sickinger
      The development of solid phase peptide synthesis has released tremendous opportunities for using synthetic peptides in medicinal applications. In the last decades, peptide therapeutics became an emerging market in pharmaceutical industry. The need for synthetic strategies in order to improve peptidic properties, such as longer half-life, higher bioavailability, increased potency and efficiency is accordingly rising. In this mini-review, we present a toolbox of modifications in peptide chemistry for overcoming the main drawbacks during the transition from natural peptides to peptide therapeutics. Modifications at the level of the peptide backbone, amino acid side chains and higher orders of structures are described. Furthermore, we are discussing the future of peptide therapeutics development and their impact on the pharmaceutical market.
      Graphical abstract image

      PubDate: 2018-05-17T15:58:02Z
      DOI: 10.1016/j.bmc.2018.01.012
       
  • Improving oral bioavailability of cyclic peptides by N-methylation
    • Authors: Andreas F.B. Räder; Florian Reichart; Michael Weinmüller; Horst Kessler
      Pages: 2766 - 2773
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10
      Author(s): Andreas F.B. Räder, Florian Reichart, Michael Weinmüller, Horst Kessler
      The renaissance of peptides in pharmaceutical industry results from their importance in many biological functions. However, low metabolic stability and the lack of oral availability of most peptides is a certain limitation. Whereas metabolic instability may be often overcome by development of small cyclic peptides containing d-amino acids, the very low oral availability of most peptides is a serious limitation for some medicinal applications. The situation is complicated because a twofold optimization – biological activity and oral availability – is required to overcome this problem. Moreover, most simple “rules” for achieving oral availability are not general and are applicable only to limited cases. Many structural modifications for increasing biological activities and metabolic stabilities of cyclic peptides have been described, of which N-alkylation is probably the most common. This mini-review focuses on the effects of N-methylation of cyclic peptides in strategies to optimize bioavailabilities.
      Graphical abstract image

      PubDate: 2018-05-17T15:58:02Z
      DOI: 10.1016/j.bmc.2017.08.031
       
  • Heterocycles: Versatile control elements in bioactive macrocycles
    • Authors: Harjeet S. Soor; Solomon D. Appavoo; Andrei K. Yudin
      Pages: 2774 - 2779
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10
      Author(s): Harjeet S. Soor, Solomon D. Appavoo, Andrei K. Yudin
      The potential of macrocyclic peptides as therapeutics has garnered much attention over the last several years. Unlike their linear counterparts, macrocycles have higher resistance to enzymatic degradation and often display improved bioavailability. However, macrocycles are typically not lipophilic enough for cellular membrane penetration, which prevents them from interacting with intracellular targets. Methods to increase cellular permeability have involved the incorporation of bicyclic scaffolds, d-amino acids and N-methylation of amides. These modifications exert their effect through conformational control of macrocycles and have been well studied in the literature. In contrast, the structural consequences of heterocycle incorporation into macrocyclic rings has not been as exhaustively investigated. In this mini-review we discuss key examples in which heterocycles influence the conformational stability and other properties of macrocycles.
      Graphical abstract image

      PubDate: 2018-05-17T15:58:02Z
      DOI: 10.1016/j.bmc.2017.10.022
       
  • An opportunistic route to success: Towards a change of paradigm to fully
           exploit the potential of cell-penetrating peptides
    • Authors: Estel Collado Camps; Roland Brock
      Pages: 2780 - 2787
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10
      Author(s): Estel Collado Camps, Roland Brock
      About 25years ago it was demonstrated that certain peptides possess the ability to cross the plasma membrane. This led to the development of cell-penetrating peptides (CPPs) as vectors to mediate the cellular entry of (macro-)molecules that do not show cell entry by themselves. Nonetheless, in spite of an early bloom of promising pre-clinical studies, not a single CPP-based drug has been approved, yet. It is a paradigm in CPP research that the peptides are taken up by virtually all cells. In exploratory research and early preclinical development, this assumption guides the choice of the therapeutic target. However, while this indiscriminatory uptake may be the case for tissue culture experiments, in an organism this is clearly not the case. Biodistribution analyses demonstrate that CPPs only target a very limited number of cells and many tissues are hardly reached at all. Here, we review biodistribution analyses of CPPs and CPP-based drug delivery systems. Based on this analysis we propose a paradigm change towards a more opportunistic approach in CPP research. The application of CPPs should focus on those pathophysiologies for which the relevant target cells have been shown to be reached in vivo.
      Graphical abstract image

      PubDate: 2018-05-17T15:58:02Z
      DOI: 10.1016/j.bmc.2017.11.004
       
  • Teixobactin as a scaffold for unlimited new antimicrobial peptides: SAR
           study
    • Authors: Shimaa A.H. Abdel Monaim; Yahya E. Jad; Ayman El-Faham; Beatriz G. de la Torre; Fernando Albericio
      Pages: 2788 - 2796
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10
      Author(s): Shimaa A.H. Abdel Monaim, Yahya E. Jad, Ayman El-Faham, Beatriz G. de la Torre, Fernando Albericio
      It looks that a new era of antimicrobial peptides (AMPs) started with the discovery of teixobactin, which is a “head to side-chain” cyclodepsipeptide. It was isolated from a soil gram-negative b-proteobacteria by means of a revolutionary technique. Since there, several groups have developed synthetic strategies for efficient synthesis of this peptide and its analogues as well. Herein, all chemistries reported as well as the biological activity of the analogues are analyzed. Finally, some inputs regarding new trends for the next generation of analogues are discussed.
      Graphical abstract image

      PubDate: 2018-05-17T15:58:02Z
      DOI: 10.1016/j.bmc.2017.09.040
       
  • Seek & Destroy, use of targeting peptides for cancer detection and
           drug delivery
    • Authors: Vadim Le Joncour; Pirjo Laakkonen
      Pages: 2797 - 2806
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10
      Author(s): Vadim Le Joncour, Pirjo Laakkonen
      Accounting for 16 million new cases and 9 million deaths annually, cancer leaves a great number of patients helpless. It is a complex disease and still a major challenge for the scientific and medical communities. The efficacy of conventional chemotherapies is often poor and patients suffer from off-target effects. Each neoplasm exhibits molecular signatures – sometimes in a patient specific manner – that may completely differ from the organ of origin, may be expressed in markedly higher amounts and/or in different location compared to the normal tissue. Although adding layers of complexity in the understanding of cancer biology, this cancer-specific signature provides an opportunity to develop targeting agents for early detection, diagnosis, and therapeutics. Chimeric antibodies, recombinant proteins or synthetic polypeptides have emerged as excellent candidates for specific homing to peripheral and central nervous system cancers. Specifically, peptide ligands benefit from their small size, easy and affordable production, high specificity, and remarkable flexibility regarding their sequence and conjugation possibilities. Coupled to imaging agents, chemotherapies and/or nanocarriers they have shown to increase the on-site delivery, thus allowing better tumor mass contouring in imaging and increased efficacy of the chemotherapies associated with reduced adverse effects. Therefore, some of the peptides alone or in combination have been tested in clinical trials to treat patients. Peptides have been well-tolerated and shown absence of toxicity. This review aims to offer a view on tumor targeting peptides that are either derived from natural peptide ligands or identified using phage display screening. We also include examples of peptides targeting the high-grade malignant tumors of the central nervous system as an example of the complex therapeutic management due to the tumor’s location. Peptide vaccines are outside of the scope of this review.
      Graphical abstract image

      PubDate: 2018-05-17T15:58:02Z
      DOI: 10.1016/j.bmc.2017.08.052
       
  • Macrocyclic α helical peptide therapeutic modality: A perspective of
           learnings and challenges
    • Authors: Tomi K. Sawyer; Anthony W. Partridge; Hung Yi Kristal Kaan; Yu-Chi Juang; Shuhui Lim; Charles Johannes; Tsz Ying Yuen; Chandra Verma; Srinivasaraghavan Kannan; Pietro Aronica; Yaw Sing Tan; Brad Sherborne; Sookhee Ha; Jerome Hochman; Shiying Chen; Laura Surdi; Andrea Peier; Berengere Sauvagnat; Peter J. Dandliker; Christopher J. Brown; Simon Ng; Fernando Ferrer; David P. Lane
      Pages: 2807 - 2815
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10
      Author(s): Tomi K. Sawyer, Anthony W. Partridge, Hung Yi Kristal Kaan, Yu-Chi Juang, Shuhui Lim, Charles Johannes, Tsz Ying Yuen, Chandra Verma, Srinivasaraghavan Kannan, Pietro Aronica, Yaw Sing Tan, Brad Sherborne, Sookhee Ha, Jerome Hochman, Shiying Chen, Laura Surdi, Andrea Peier, Berengere Sauvagnat, Peter J. Dandliker, Christopher J. Brown, Simon Ng, Fernando Ferrer, David P. Lane
      Macrocyclic α-helical peptides have emerged as a compelling new therapeutic modality to tackle targets confined to the intracellular compartment. Within the scope of hydrocarbon-stapling there has been significant progress to date, including the first stapled α-helical peptide to enter into clinical trials. The principal design concept of stapled α-helical peptides is to mimic a cognate (protein) ligand relative to binding its target via an α-helical interface. However, it was the proclivity of such stapled α-helical peptides to exhibit cell permeability and proteolytic stability that underscored their promise as unique macrocyclic peptide drugs for intracellular targets. This perspective highlights key learnings as well as challenges in basic research with respect to structure-based design, innovative chemistry, cell permeability and proteolytic stability that are essential to fulfill the promise of stapled α-helical peptide drug development.
      Graphical abstract image

      PubDate: 2018-05-17T15:58:02Z
      DOI: 10.1016/j.bmc.2018.03.008
       
  • Peptides for optical medical imaging and steps towards therapy
    • Authors: Matteo Staderini; Alicia Megia-Fernandez; Kevin Dhaliwal; Mark Bradley
      Pages: 2816 - 2826
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10
      Author(s): Matteo Staderini, Alicia Megia-Fernandez, Kevin Dhaliwal, Mark Bradley
      Optical medical imaging is a rapidly growing area of research and development that offers a multitude of healthcare solutions both diagnostically and therapeutically. In this review, some of the most recently described peptide-based optical probes are reviewed with a special emphasis on their in vivo use and potential application in a clinical setting.
      Graphical abstract image

      PubDate: 2018-05-17T15:58:02Z
      DOI: 10.1016/j.bmc.2017.09.039
       
  • Challenges in the design of insulin and relaxin/insulin-like peptide
           mimetics
    • Authors: Mohammed Akhter Hossain; Ross A.D. Bathgate
      Pages: 2827 - 2841
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10
      Author(s): Mohammed Akhter Hossain, Ross A.D. Bathgate
      Peptidomimetics are designed to overcome the poor pharmacokinetics and pharmacodynamics associated with the native peptide or protein on which they are based. The design of peptidomimetics starts from developing structure-activity relationships of the native ligand-target pair that identify the key residues that are responsible for the biological effect of the native peptide or protein. Then minimization of the structure and introduction of constraints are applied to create the core active site that can interact with the target with high affinity and selectivity. Developing peptidomimetics is not trivial and often challenging, particularly when peptides’ interaction mechanism with their target is complex. This review will discuss the challenges of developing peptidomimetics of therapeutically important insulin superfamily peptides, particularly those which have two chains (A and B) and three disulfide bonds and whose receptors are known, namely insulin, H2 relaxin, H3 relaxin, INSL3 and INSL5.
      Graphical abstract image

      PubDate: 2018-05-17T15:58:02Z
      DOI: 10.1016/j.bmc.2017.09.030
       
  • Personalized neoantigen vaccines: A new approach to cancer immunotherapy
    • Authors: Amanda R. Aldous; Jesse Z. Dong
      Pages: 2842 - 2849
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10
      Author(s): Amanda R. Aldous, Jesse Z. Dong
      Neoantigens arise from somatic mutations that differ from wild-type antigens and are specific to each individual patient, which provide tumor specific targets for developing personalized cancer vaccines. Decades of work has increasingly shown the potential of targeting neoantigens to generate effective clinical responses. Current clinical trials using neoantigen targeting cancer vaccines, including in combination with checkpoint blockade monoclonal antibodies, have demonstrated potent T-cell responses against those neoantigens accompanied by antitumor effects in patients. Personalized neoantigen vaccines represent a potential new class of cancer immunotherapy.
      Graphical abstract image

      PubDate: 2018-05-17T15:58:02Z
      DOI: 10.1016/j.bmc.2017.10.021
       
  • Advances in macrocyclic peptide-based antibiotics
    • Authors: Anatol Luther; Christian Bisang; Daniel Obrecht
      Pages: 2850 - 2858
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10
      Author(s): Anatol Luther, Christian Bisang, Daniel Obrecht
      Macrocyclic peptide-based natural products have provided powerful new antibiotic drugs, drug candidates, and scaffolds for medicinal chemists as a source of inspiration to design novel antibiotics. While most of those natural products are active mainly against Gram-positive pathogens, novel macrocyclic peptide-based compounds have recently been described, which exhibit potent and specific activity against some of the most problematic Gram-negative ESKAPE pathogens. This mini-review gives an up-date on recent developments.
      Graphical abstract image

      PubDate: 2018-05-17T15:58:02Z
      DOI: 10.1016/j.bmc.2017.08.006
       
  • Therapeutic peptides for CNS indications: Progress and challenges
    • Authors: Bruce H. Morimoto
      Pages: 2859 - 2862
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10
      Author(s): Bruce H. Morimoto
      Attacking neurodegeneration and promoting neuroprotection have been the holy grail in neurology for almost 20years 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: 2018-05-17T15:58:02Z
      DOI: 10.1016/j.bmc.2017.09.011
       
  • Peptide therapeutics for the treatment of gastrointestinal disorders
    • Authors: Angelika Fretzen
      Pages: 2863 - 2872
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10
      Author(s): Angelika Fretzen
      Graphical abstract image

      PubDate: 2018-05-17T15:58:02Z
      DOI: 10.1016/j.bmc.2017.11.007
       
  • Optimization of peptide-based polyagonists for treatment of diabetes and
           obesity
    • Authors: Patrick J. Knerr; Brian Finan; Vasily Gelfanov; Diego Perez-Tilve; Matthias H. Tschöp; Richard D. DiMarchi
      Pages: 2873 - 2881
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10
      Author(s): Patrick J. Knerr, Brian Finan, Vasily Gelfanov, Diego Perez-Tilve, Matthias H. Tschöp, Richard D. DiMarchi
      Graphical abstract image

      PubDate: 2018-05-17T15:58:02Z
      DOI: 10.1016/j.bmc.2017.10.047
       
  • Prospects of PASylation® for the design of protein and peptide
           therapeutics with extended half-life and enhanced action
    • Authors: Michaela Gebauer; Arne Skerra
      Pages: 2882 - 2887
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10
      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 in biopharmaceutical drug development today. Although PEGylation has become a widely applied methodology to furnish therapeutic proteins and peptides with prolonged plasma half-life, the immunogenicity and missing biodegradability 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: 2018-05-17T15:58:02Z
      DOI: 10.1016/j.bmc.2017.09.016
       
  • Nose-to-brain peptide delivery – The potential of nanotechnology
    • Authors: Eleni Samaridou; Maria José Alonso
      Pages: 2888 - 2905
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10
      Author(s): Eleni Samaridou, Maria José Alonso
      Nose-to-brain (N-to-B) delivery offers to protein and peptide drugs the possibility to reach the brain in a non-invasive way. This article is a comprehensive review of the state-of-the-art of this emerging peptide delivery route, as well as of the challenges associated to it. Emphasis is given on the potential of nanosized drug delivery carriers to enhance the direct N-to-B transport of protein or peptide drugs. In particular, polymer- and lipid- based nanocarriers are comparatively analyzed in terms of the influence of their physicochemical characteristics and composition on their in vivo fate and efficacy. The use of biorecognitive ligands and permeation enhancers in order to enhance their brain targeting efficiency is also discussed. The article concludes highlighting the early stage of this research field and its still unveiled potential. The final message is that more explicatory PK/PD studies are required in order to achieve the translation from preclinical to the clinical development phase.
      Graphical abstract image

      PubDate: 2018-05-17T15:58:02Z
      DOI: 10.1016/j.bmc.2017.11.001
       
  • Peroral peptide delivery: Peptidase inhibition as a key concept for
           commercial drug products
    • Authors: Martin Werle; Florian Föger
      Pages: 2906 - 2913
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10
      Author(s): Martin Werle, Florian Föger
      Graphical abstract image

      PubDate: 2018-05-17T15:58:02Z
      DOI: 10.1016/j.bmc.2017.08.028
       
  • Synthetic peptide API manufacturing: A mini review of current perspectives
           for peptide manufacturing
    • Authors: Jon H. Rasmussen
      Pages: 2914 - 2918
      Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10
      Author(s): Jon H. Rasmussen
      Graphical abstract image

      PubDate: 2018-05-17T15:58:02Z
      DOI: 10.1016/j.bmc.2018.01.018
       
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    • Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10


      PubDate: 2018-05-17T15:58:02Z
       
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    • Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10


      PubDate: 2018-05-17T15:58:02Z
       
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    • Abstract: Publication date: 1 June 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10


      PubDate: 2018-05-17T15:58:02Z
       
  • Novel oxazolxanthone derivatives as a new type of α-glucosidase
           inhibitor: synthesis, activities, inhibitory modes and synergetic effect
    • Authors: Sen-Miao Ding; Tian Lan; Gao-Jie Ye; Jia-Jun Huang; You Hu; Yi-Ran Zhu; Bo Wang
      Abstract: Publication date: Available online 17 May 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Sen-Miao Ding, Tian Lan, Gao-Jie Ye, Jia-Jun Huang, You Hu, Yi-Ran Zhu, Bo Wang
      Xanthone derivatives have shown good α-glucosidase inhibitory activity and have drawn increased attention as potential anti-diabetic compounds. In this study, a series of novel oxazolxanthones were designed, synthesized, and investigated as α-glucosidase inhibitors. Inhibition assays indicated that compounds 4–21 bearing oxazole rings exhibited up to 30-fold greater inhibitory activity compared to their corresponding parent compound 1b. Among them, compounds 5–21 (IC50 = 6.3 ± 0.4–38.5 ± 4.6 μM) were more active than 1-deoxynojirimycin (IC50 = 60.2 ± 6.2 μM), a well-known α-glucosidase inhibitor. In addition, the kinetics of enzyme inhibition measured by using Lineweaver–Burk analysis shows that compound 4 is a competitive inhibitor, while compounds 15, 16 and 20 are non-competitive inhibitors. Molecular docking studies showed that compound 4 bound to the active site pocket of the enzyme while compounds 15, 16, and 20 did not. More interestingly, docking simulations reveal that some of the oxazolxanthone derivatives bind to different sites in the enzyme. This prediction was further confirmed by the synergetic inhibition experiment, and the combination of representative compounds 16 and 20 at the optimal ratio of 4:6 led to an IC50 value of 1.9 ± 0.7 μM, better than the IC50 value of 7.1 ± 0.9 μM for compound 16 and 8.6 ± 0.9 μM for compound 20.
      Graphical abstract image

      PubDate: 2018-05-17T15:58:02Z
      DOI: 10.1016/j.bmc.2018.05.008
       
  • Design, synthesis and molecular modeling of new 4-phenylcoumarin
           derivatives as tubulin polymerization inhibitors targeting MCF-7 breast
           cancer cells
    • Authors: Rasha Z. Batran; Asmaa F. Kassem; Eman M. Abbas; Samia A. El Seginy; Marwa M. Mounier
      Abstract: Publication date: Available online 16 May 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Rasha Z. Batran, Asmaa F. Kassem, Eman M. Abbas, Samia A. El Seginy, Marwa M. Mounier
      A new set of 4-phenylcoumarin derivatives was designed and synthesized aiming to introduce new tubulin polymerization inhibitors as anti-breast cancer candidates. All the target compounds were evaluated for their cytotoxic effects against MCF-7 cell line, where compounds 2f, 3a, 3b, 3 f, 7a and 7b, showed higher cytotoxic effect (IC50=4.3-21.2 μg/mL) than the reference drug doxorubicin (IC50= 26.1 μg/mL), additionally, compounds 1 and 6b exhibited the same potency as doxorubicin (IC50= 25.2 and 28.0 μg/mL, respectively). The thiazolidinone derivatives 3a, 3b and 3 f with potent and selective anticancer effects towards MCF-7 cells (IC50 = 11.1, 16.7 and 21.2 μg/mL) were further assessed for tubulin polymerization inhibition effects which showed that the three compounds were potent tubulin polymerization suppressors with IC50 values of 9.37, 2.89 and 6.13 μM, respectively, compared to the reference drug colchicine (IC50= 6.93 μM). The mechanistic effects on cell cycle progression and induction of apoptosis in MCF-7 cells were determined for compound 3a due to its potent and selective cytotoxic effects in addition to its promising tubulin polymerization inhibition potency. The results revealed that compound 3a induced cell cycle cessation at G2/M phase and accumulation of cells in pre-G1 phase and prevented its mitotic cycle, in addition to its activation of caspase-7 mediating apoptosis of MCF-7 cells. Molecular modeling studies for compounds 3a, 3b and 3 f were carried out on tubulin crystallography, the results indicated that the compounds showed binding mode similar to the co-crystalized ligand; colchicine. Moreover, pharmacophore constructed models and docking studies revealed that thiazolidinone, acetamide and coumarin moieties are crucial for the activity. Molecular dynamics (MD) studies were carried out for the three compounds over 100Ps. MD results of compound 3a showed that it reached the stable state after 30Ps which was in agreement with the calculated potential and kinetic energy of compound 3a.
      Graphical abstract image

      PubDate: 2018-05-17T15:58:02Z
      DOI: 10.1016/j.bmc.2018.05.022
       
 
 
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