Bioorganic & medicinal chemistry letters

Publications in this journal

• Article: Synthesis and biological evaluation of a novel (99m)Tc labeled 2-nitroimidazole derivative as a potential agent for imaging tumor hypoxia.

  Yoann Joyard, Vadim Le Joncour, Hélène Castel, Chérif Bounana Diouf, Laurent Bischoff, Cyril Papamicaël, Vincent Levacher, Pierre Vera, Pierre Bohn
  [show abstract] [hide abstract]
  ABSTRACT: Tumor hypoxia plays a major role in reducing the efficacy of therapeutic modalities like chemotherapy and radiation therapy in combating cancer. In order to target hypoxic tissues, a tripeptide ligand having a 2-nitroimidazole moiety, as a bioreductive species, was synthesized. The latter was radiolabeled with (99m)Tc for imaging hypoxic regions of tumors and was characterized by means of its rhenium analogue. The biodistribution and scintigraphic image of the corresponding (99m)Tc-complex showed accumulation in tumor and these results suggest that it could be a marker for imaging tumor hypoxia.
  Bioorganic & medicinal chemistry letters 05/2013;
• Article: Activity-lipophilicity relationship studies on P-gp ligands designed as simplified tariquidar bulky fragments.

  Marialessandra Contino, Laura Zinzi, Mariangela Cantore, Maria Grazia Perrone, Marcello Leopoldo, Francesco Berardi, Roberto Perrone, Nicola Antonio Colabufo
  [show abstract] [hide abstract]
  ABSTRACT: A series of alkyloxyquinoline derivatives has been developed to evaluate the relationship between P-gp potency and lipophilicity. The results show a satisfactory lipophilicity-activity correlation although a series of derivatives showing higher P-gp potency is needed in order to confirm this hypothesis.
  Bioorganic & medicinal chemistry letters 05/2013;
• Article: Synthesis and biological evaluation of nonsymmetrical aromatic disulfides as novel inhibitors of acetohydroxyacid synthase.

  Zai-Shun Li, Wei-Min Wang, Wei Lu, Cong-Wei Niu, Yong-Hong Li, Zheng-Ming Li, Jian-Guo Wang
  [show abstract] [hide abstract]
  ABSTRACT: 46 Novel nonsymmetrical aromatic disulfides containing [1,3,4]thiadiazole or [1,3,4]oxadiazole groups were synthesized and their biological activities were evaluated as inhibitors of acetohydroxyacid synthase (AHAS, EC 2.2.1.6). Besides their strong in vitro inhibition against plant AHAS, compounds 3e and 3f also display 80-100% post-emergence herbicidal activities in greenhouse bioassay at 1500g/ha dosage. The assay of exogenous branched-chain amino acids supplementation on rape root growth of 3e suggests that the herbicidal activity has relationship with AHAS inhibition.
  Bioorganic & medicinal chemistry letters 05/2013;
• Article: Synthesis and neuroprotective effect of E-3,4-dihydroxy styryl aralkyl ketones derivatives against oxidative stress and inflammation.

  Xianling Ning, Ying Guo, Xiaoyan Ma, Renzong Zhu, Chao Tian, Xiaowei Wang, Zhizhong Ma, Zhili Zhang, Junyi Liu
  [show abstract] [hide abstract]
  ABSTRACT: E-3,4-Dihydroxy styryl aralkyl ketones as well as their 3,4-diacetylated derivatives as the analogues of neuroprotective agent CAPE were designed and synthesized for improving stability and lipid solubility. The neuroprotective activities of target compounds 10a-g and 11a-g were tested by three models in vitro, including 1,1-diphenyl-2-picrylhydrazyl radical scavenging capacity, neuronal protecting effect against damage induced by H2O2 in PC12 cells and nitric oxide suppression effect in BV2 microglial cells. The results demonstrated that compounds 10f and 11f exhibited the most potent neuroprotective effect against oxidative stress and inflammation, which is higher than that of the lead compound CAPE.
  Bioorganic & medicinal chemistry letters 05/2013;
• Article: Hydroxyethylamine-based inhibitors of BACE1: P1-P3 macrocyclization can improve potency, selectivity, and cell activity.

  Lewis D Pennington, Douglas A Whittington, Michael D Bartberger, Steven R Jordan, Holger Monenschein, Thomas T Nguyen, Bryant H Yang, Qiufen M Xue, Filisaty Vounatsos, Robert C Wahl, Kui Chen, Stephen Wood, Martin Citron, Vinod F Patel, Stephen A Hitchcock, Wenge Zhong
  [show abstract] [hide abstract]
  ABSTRACT: We describe a systematic study of how macrocyclization in the P1-P3 region of hydroxyethylamine-based inhibitors of β-site amyloid precursor protein (APP)-cleaving enzyme (BACE1) modulates in vitro activity. This study reveals that in a number of instances macrocyclization of bis-terminal dienes leads to improved potency toward BACE1 and selectivity against cathepsin D (CatD), as well as greater amyloid β-peptide (Aβ)-lowering activity in HEK293T cells stably expressing APPSW. However, for several closely related analogs the benefits of macrocyclization are attenuated by the effects of other structural features in different regions of the molecules. X-ray crystal structures of three of these novel macrocyclic inhibitors bound to BACE1 revealed their binding conformations and interactions with the enzyme.
  Bioorganic & medicinal chemistry letters 05/2013;
• Article: Discovery of TD-8954, a clinical stage 5-HT4 receptor agonist with gastrointestinal prokinetic properties.

  R Murray McKinnell, Scott R Armstrong, David T Beattie, Paul R Fatheree, Daniel D Long, Daniel G Marquess, Jeng-Pyng Shaw, Ross G Vickery
  [show abstract] [hide abstract]
  ABSTRACT: The discovery of a series of 5-HT4 receptor agonists based on a novel 2-alkylbenzimidazole aromatic core is described. Optimization of the 2-substituent of the benzimidazole ring led to a series of agonists with subnanomolar binding affinity and moderate-to-high intrinsic activity relative to that of 5-HT. Consistent with our previously described multivalent design approach to this target, subsequent optimization of the linker and secondary binding group regions of the series afforded compound 18 (TD-8954), a potent and selective 5-HT4 receptor agonist in vitro with demonstrated prokinetic activity in multiple species.
  Bioorganic & medicinal chemistry letters 05/2013;
• Article: Macrocyclic inhibitors of 3C and 3C-like proteases of picornavirus, norovirus, and coronavirus.

  Sivakoteswara Rao Mandadapu, Pathum M Weerawarna, Allan M Prior, Roxanne Adeline Z Uy, Sridhar Aravapalli, Kevin R Alliston, Gerald H Lushington, Yunjeong Kim, Duy H Hua, Kyeong-Ok Chang, William C Groutas
  [show abstract] [hide abstract]
  ABSTRACT: The design, synthesis, and in vitro evaluation of the first macrocyclic inhibitor of 3C and 3C-like proteases of picornavirus, norovirus, and coronavirus are reported. The in vitro inhibitory activity (50% effective concentration) of the macrocyclic inhibitor toward enterovirus 3C protease (CVB3 Nancy strain), and coronavirus (SARS-CoV) and norovirus 3C-like proteases, was determined to be 1.8, 15.5 and 5.1μM, respectively.
  Bioorganic & medicinal chemistry letters 05/2013;
• Article: Synthesis and in vitro evaluation of [(18)F]BMS-754807: A potential PET ligand for IGF-1R.

  Vattoly J Majo, Victoria Arango, Norman R Simpson, Jaya Prabhakaran, Suham A Kassir, Mark D Underwood, Mihran Bakalian, Peter Canoll, J John Mann, J S Dileep Kumar
  [show abstract] [hide abstract]
  ABSTRACT: Radiosynthesis and in vitro evaluation of [(18)F](S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide ([(18)F]BMS-754807 or [(18)F]1) a specific IGF-1R inhibitor was performed. [(18)F]1 demonstrated specific binding in vitro to human cancer tissues. Synthesis of reference standard 1 and corresponding bromo derivative (1a), the precursor for radiolabeling were achieved from 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (4) in three steps with 50% overall yield. The radioproduct was obtained in 8% yield by reacting 1a with [(18)F]TBAF in DMSO at 170°C at high radiochemical purity and specific activity (1-2Ci/μmol, N=10). The proof of concept of IGF-IR imaging with [(18)F]1 was demonstrated by in vitro autoradiography studies using pathologically identified surgically removed grade IV glioblastoma, breast cancer and pancreatic tumor tissues. These studies indicate that [(18)F]1 can be a potential PET tracer for monitoring IGF-1R.
  Bioorganic & medicinal chemistry letters 05/2013;
• Article: Affinity-based screening of MDM2/MDMX-p53 interaction inhibitors by chemical array: Identification of novel peptidic inhibitors.

  Taro Noguchi, Shinya Oishi, Kaori Honda, Yasumitsu Kondoh, Tamio Saito, Tatsuhiko Kubo, Masato Kaneda, Hiroaki Ohno, Hiroyuki Osada, Nobutaka Fujii
  [show abstract] [hide abstract]
  ABSTRACT: MDM2 and MDMX are oncoproteins that negatively regulate the activity and stability of the tumor suppressor protein p53. The inhibitors of protein-protein interactions (PPIs) of MDM2-p53 and MDMX-p53 represent potential anticancer agents. In this study, a novel approach for identifying MDM2-p53 and MDMX-p53 PPI inhibitor candidates by affinity-based screening using a chemical array has been established. A number of compounds from an in-house compound library, which were immobilized onto a chemical array, were screened for interaction with fluorescence-labeled MDM2 and MDMX proteins. The subsequent fluorescent polarization assay identified several compounds that inhibited MDM2-p53 and MDMX-p53 interactions.
  Bioorganic & medicinal chemistry letters 05/2013;
• Article: Construction and functionalization of pyranone ring fused with pyran moiety: Design and synthesis of novel pyrano[4,3-b]pyran-5(4H)-ones as potential inhibitors of sirtuins.

  Ali Nakhi, Md Shafiqur Rahman, Sivakumar Archana, Ravada Kishore, G P K Seerapu, K Lalith Kumar, Devyani Haldar, Manojit Pal
  [show abstract] [hide abstract]
  ABSTRACT: Novel pyrano[4,3-b]pyran-5(4H)-one based small molecules were designed as potential inhibitors of sirtuins (i.e., yeast sir2, a homolog of human SIRT1). Elegant synthesis of these compounds was performed via a multi-step sequence consisting of MCR, Sandmeyer type iodination, Sonogashira type coupling followed by iodocyclization and then Pd-mediated various C-C bond forming reactions. The overall strategy involved the construction of a pyran ring followed by the fused pyranone moiety and subsequent functionalization at C-8 position of the resultant core pyrano[4,3-b]pyran-5(4H)-one framework. The crystal structure analysis of a representative iodolactonized product (6d) is presented. Some of the synthesized compounds showed promising inhibitory activities when tested against yeast sir2 in vitro. The compound 6g showed dose dependent inhibition (IC50=78.05μM) of yeast sir2 and good interactions with this protein in silico.
  Bioorganic & medicinal chemistry letters 05/2013;
• Article: Synthesis and antiprotozoal activity of novel 2-{[2-(1H-imidazol-1-yl)ethyl]sulfanyl}-1H-benzimidazole derivatives.

  Jaime Pérez-Villanueva, Alicia Hernández-Campos, Lilián Yépez-Mulia, Carlos Méndez-Cuesta, Oscar Méndez-Lucio, Francisco Hernández-Luis, Rafael Castillo
  [show abstract] [hide abstract]
  ABSTRACT: A series of 19 new 2-{[2-(1H-imidazol-1-yl)ethyl]sulfanyl}-1H-benzimidazole derivatives was synthesized starting from the properly substituted 1,2-phenylendiamine. These compounds have hydrogen or methyl at position 1; while hydrogen, chlorine, ethoxy or methoxycarbonyl group is at position 5 and/or 6. The novel compounds were tested against protozoa Trichomonas vaginalis, Giardia intestinalis and Entamoeba histolytica. Experimental evaluations revealed strong activity for all tested compounds, having IC50 values in the nanomolar range, which were even better than metronidazole, the drug of choice for these parasites.
  Bioorganic & medicinal chemistry letters 05/2013;
• Article: Heterocyclic modification of a novel bicyclo[3.1.0]hexane NPY1 receptor antagonist.

  Guanglin Luo, Ling Chen, Shuanghua Hu, Yazhong Huang, Gail Mattson, Lawrence G Iben, John W Russell, Wendy J Clarke, John B Hogan, Ildiko Antal-Zimanyi, Graham S Poindexter
  [show abstract] [hide abstract]
  ABSTRACT: A convergent synthesis route for the heterocyclic modification of a novel bicyclo[3.1.0]hexane NPY1 antagonist 2 was developed and the structure activity relationship of these modifications on NPY1 binding is reported. Two heterocyclic analogs 9 and 10 showed comparable Y1 binding potency to 2, but with improved aqueous solubility. Compound 9 demonstrated reduced spontaneous nocturnal food intake in a rat model when dosed ip. Compound 9 was also shown to be orally bioavailable and brain penetrable.
  Bioorganic & medicinal chemistry letters 05/2013;
• Article: HS-1793, a recently developed resveratrol analogue protects rat heart against hypoxia/reoxygenation injury via attenuating mitochondrial damage.

  Seung Hun Jeong, Tran My Hanh, Hyoung Kyu Kim, Sung Ryul Lee, In-Sung Song, Su Jin Noh, Suhee Song, Hongsuk Suh, Nari Kim, Byoung Doo Rhee, Kyung Soo Ko, Jin Han
  [show abstract] [hide abstract]
  ABSTRACT: Resveratrol is known to exert a cardioprotective effect against hypoxia/reoxygenation (H/R) injury. HS-1793 is a novel, more stable resveratrol analog, but its cardioprotective effects were unknown. The present study aimed to test the cardioprotective effect of HS-1793 against H/R injury and investigate the role of mitochondria in Sprague Dawley rat heart damage using an ex vivo Langendorff system. HS-1793 ameliorated H/R-induced mitochondrial dysfunction by reducing mitochondrial reactive oxygen species production, improving mitochondrial oxygen consumption and suppressing mitochondrial calcium (Ca(2+)) overload during reperfusion. Moreover, HS-1793-treated rat heart showed reduced infarct size. Our data suggest that HS-1793 can protect cardiac against mitochondrial damage following H/R, thereby suppressing injury.
  Bioorganic & medicinal chemistry letters 05/2013;
• Article: Potent MCH-1 receptor antagonists from cis-1,4-diaminocyclohexane-derived indane analogs.

  Yimin Qian, Karin Conde-Knape, Shawn D Erickson, Fiorenza Falcioni, Paul Gillespie, Irina Hakimi, Francis Mennona, Yonglin Ren, Hamid Salari, Sung-Sau So, Jefferson W Tilley
  [show abstract] [hide abstract]
  ABSTRACT: Benzimidazole and indane are the two key fragments in our potent and selective MCH-1 receptor (MCHR1) antagonists. To identify novel linkers connecting the two fragments, we investigated diamino-cycloalkane-derived analogs and discovered highly potent antagonists with cis-1,4-diaminocyclohexane as a unique spacer in this chemical class. Structural overlay suggested that cis-1-substituted-4-aminocyclohexane functions as a bioisostere of 4-substituted-piperidine and that the active conformation adopts a U-shaped orientation.
  Bioorganic & medicinal chemistry letters 05/2013;
• Article: Synthesis and biological evaluation of pyrrolidine derivatives as novel and potent sodium channel blockers for the treatment of ischemic stroke.

  Maki Seki, Osamu Tsuruta, Ryo Tatsumi, Aki Soejima
  [show abstract] [hide abstract]
  ABSTRACT: A novel series of pyrrolidine derivatives as Na(+) channel blockers was synthesized and evaluated for their inhibitory effects on neuronal Na(+) channels. Structure-activity relationship (SAR) studies of a pyrrolidine analogue 2 led to the discovery of 5e as a potent Na(+) channel blocker with a low inhibitory action against human ether-a-go-go-related gene (hERG) channels. Compound 5e showed remarkably neuroprotective activity in a rat transient middle cerebral artery occlusion (MCAO) model, suggesting that 5e would act as a neuroprotectant for ischemic stroke.
  Bioorganic & medicinal chemistry letters 05/2013;
• Article: Design, synthesis and evaluation of inhibitor of apoptosis protein (IAP) antagonists that are highly selective for the BIR2 domain of XIAP.

  Robert J Ardecky, Kate Welsh, Darren Finlay, Pooi San Lee, Marcos González-López, Santhi Reddy Ganji, Palaniyandi Ravanan, Peter D Mace, Stefan J Riedl, Kristiina Vuori, John C Reed, Nicholas D P Cosford
  [show abstract] [hide abstract]
  ABSTRACT: We recently reported the systematic ligand-based rational design and synthesis of monovalent Smac mimetics that bind preferentially to the BIR2 domain of the anti-apoptotic protein XIAP. Expanded structure-activity relationship (SAR) studies around these peptidomimetics led to compounds with significantly improved selectivity (>60-fold) for the BIR2 domain versus the BIR3 domain of XIAP. The potent and highly selective IAP antagonist 8q (ML183) sensitized TRAIL-resistant prostate cancer cells to apoptotic cell death, highlighting the merit of this probe compound as a valuable tool to investigate the biology of XIAP.
  Bioorganic & medicinal chemistry letters 05/2013;
• Article: Identification of cellular proteins interacting with octaarginine (R8) cell-penetrating peptide by photo-crosslinking.

  Yoshimasa Kawaguchi, Gen Tanaka, Ikuhiko Nakase, Miki Imanishi, Junya Chiba, Yasumaru Hatanaka, Shiroh Futaki
  [show abstract] [hide abstract]
  ABSTRACT: Octaarginine (R8) is a representative cell-penetrating peptide. Lanthionine synthetase component C-like protein 1 (LanCL1) was identified as a potential intracellular target of R8 by using a photo-crosslinking assay that utilized a phenyl-trifluoromethyl diazirine moiety and peptide mass fingerprinting. Increased cellular uptake of R8 by LanCL1-overexpressing cells was observed.
  Bioorganic & medicinal chemistry letters 05/2013;
• Article: Synthesis and antifungal activities of cyclic octa-lipopeptide burkholdine analogues.

  Hiroyuki Konno, Yusuke Otsuki, Kenta Matsuzaki, Kazuto Nosaka
  [show abstract] [hide abstract]
  ABSTRACT: Synthesis and antifungal activity of cyclic octapeptide derivatives of burkholdines are described. To construct cyclic octapeptides, the combination of Fmoc-SPPS and cyclization with DIC/HOBt in the solution phase was employed. Synthesized peptides were evaluated for antifungal activity with MIC values against Saccharomyces cerevisiae, Aspergillus oryzae, and Candida viswanathii. As a result, the lipid side chain and the stereochemistry of each amino acid of Bk-1097 analogues significantly affected antifungal activity.
  Bioorganic & medicinal chemistry letters 05/2013;
• Article: Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation.

  Pascal Furet, Vito Guagnano, Robin A Fairhurst, Patricia Imbach-Weese, Ian Bruce, Mark Knapp, Christine Fritsch, Francesca Blasco, Joachim Blanz, Reiner Aichholz, Jacques Hamon, Doriano Fabbro, Giorgio Caravatti
  [show abstract] [hide abstract]
  ABSTRACT: Phosphatidylinositol-3-kinase α (PI3Kα) is a therapeutic target of high interest in anticancer drug research. On the basis of a binding model rationalizing the high selectivity and potency of a particular series of 2-aminothiazole compounds in inhibiting PI3Kα, a medicinal chemistry program has led to the discovery of the clinical candidate NVP-BYL719.
  Bioorganic & medicinal chemistry letters 05/2013;