Description

ChemMedChem is intended to become a premier European journal at the interface of chemistry, biology and medicine. ChemMedChem will be made in Europe, but will publish primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies - to name just a few topics. ChemMedChem replaces Il Farmaco - An International Journal of Medicinal Chemistry and Pharmaceutical Chemistry, which will be published by the Società Chimica Italiana until the end of 2005 and generously given up in order to limit the crowding of journals in these sciences.

Publisher details

John Wiley & Sons

Publications in this journal

• Predicting Drug Metabolism by Cytochrome P450 2C9: Comparison with the 2D6 and 3A4 Isoforms.

  Authors: Patrik Rydberg, Lars Olsen

  ChemMedChem.

  By the use of knowledge gained through modeling of drug metabolism mediated by the cytochrome P450 2D6 and 3A4 isoforms, we constructed a 2D-based model for site-of-metabolism prediction for theBy the use of knowledge gained through modeling of drug metabolism mediated by the cytochrome P450 2D6 and 3A4 isoforms, we constructed a 2D-based model for site-of-metabolism prediction for the cytochrome P450 2C9 isoform. The similarities and differences between the models for the 2C9 and 2D6 isoforms are discussed through structural knowledge from the X-ray crystal structures and trends in experimental data. The final model was validated on an independent test set, resulting in an area under the curve value of 0.92, and a site of metabolism was found among the top two ranked atoms for 77 % of the compounds.

• Discovery of 3H-Imidazo[4,5-b]pyridines as Potent c-Met Kinase Inhibitors: Design, Synthesis, and Biological Evaluation.

  Authors: Danqi Chen, Ying Wang, Yuchi Ma, Bing Xiong, Jing Ai, Yi Chen, Meiyu Geng, Jingkang Shen

  ChemMedChem.

  To identify novel c-Met inhibitors, sequences and crystal structures of the human kinome were analyzed to find interesting hinge binders that have been underexplored within the tyrosine kinaseTo identify novel c-Met inhibitors, sequences and crystal structures of the human kinome were analyzed to find interesting hinge binders that have been underexplored within the tyrosine kinase subfamily. Through this study, the imidazolopyridine ring was selected as a novel c-Met hinge-binding inhibitor scaffold. A series of derivatives was prepared, and the structure-activity relationships were studied. Among these, one compound in particular showed excellent activities in enzymatic and cellular assays, good in vitro metabolic stability, and favorable pharmacokinetic parameters. When administered orally, the compound inhibited tumor growth in an NIH-3T3/TPR-Met xenograft model and did not show adverse effects on body weight. The present work not only conceptually demonstrates a new route for designing novel kinase inhibitors by using known structural information of ligand-hinge interactions but also provides a series of imidazolopyridine derivatives as potent c-Met inhibitors.

• The Prospect of FKBP51 as a Drug Target.

  Authors: Mathias V Schmidt, Marcelo Paez-Pereda, Florian Holsboer, Felix Hausch

  ChemMedChem.

  The FK506 binding protein 51 (FKBP51) is best known as an Hsp90-associated co-chaperone that regulates the responsiveness of steroid hormone receptors. In human genetic association studies, FKBP51The FK506 binding protein 51 (FKBP51) is best known as an Hsp90-associated co-chaperone that regulates the responsiveness of steroid hormone receptors. In human genetic association studies, FKBP51 has repeatedly been associated with emotion processing and numerous stress-related affective disorders. It has also been implicated in contributing to the glucocorticoid hyposensitivity observed in New World primates. More recently, several research groups have consistently shown a protective effect of FKBP51 knockout or knockdown on stress endocrinology and stress-coping behavior in animal models of depression and anxiety. The principal druggability of FKBP51 is exemplified by the prototypic FKBP ligands FK506 and rapamycin. Moreover, FKBP51 is highly suited for X-ray co-crystallography, which should facilitate the rational drug design of improved FKBP51 ligands. In summary, FKBP51 has emerged as a promising new drug target for stress-related disorders that should be amenable to drug discovery.

• Synthesis and Structure-Activity Relationship Studies of HIV-1 Virion Infectivity Factor (Vif) Inhibitors that Block Viral Replication.

  Authors: Akbar Ali, Jinhua Wang, Robin S Nathans, Hong Cao, Natalia Sharova, Mario Stevenson, Tariq M Rana

  ChemMedChem.

  The human immunodeficiency virus 1 (HIV-1) virion infectivity factor (Vif) protein, essential for in vivo viral replication, protects the virus from innate antiviral cellular factor apolipoprotein BThe human immunodeficiency virus 1 (HIV-1) virion infectivity factor (Vif) protein, essential for in vivo viral replication, protects the virus from innate antiviral cellular factor apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3G (APOBEC3G; A3G) and is an attractive target for the development of novel antiviral therapeutics. We have evaluated the structure-activity relationships of N-(2-methoxyphenyl)-2-((4-nitrophenyl)thio)benzamide (RN-18), a small molecule recently identified as an inhibitor of Vif function that blocks viral replication only in nonpermissive cells expressing A3G, by inhibiting Vif-A3G interactions. Microwave-assisted cross-coupling reactions were developed to prepare a series of RN18 analogues with diverse linkages and substitutions on the phenyl rings. A dual cell-based assay system was used to assess antiviral activity against wild-type HIV-1 in both nonpermissive (H9) and permissive (MT4) cells that also allowed evaluation of specificity. In general, variations of phenyl substitutions were detrimental to antiviral potency and specificity, but isosteric replacements of amide and ether linkages were relatively well tolerated. These structure-activity relationship data define structural requirements for Vif-specific activity, identify new compounds with improved antiviral potency and specificity, and provide leads for further exploration to develop new antiviral therapeutics.

• Exploration and Optimization of Structure-Activity Relationships in Drug Design using the Taguchi Method.

  Authors: Wee Kiang Yeo, Kheng Lin Tan, Siang Boon Koh, Matiullah Khan, Shahul Nilar, Mei Lin Go

  ChemMedChem.

  From engineering to drug design: Use of the Taguchi method to predict the optimal compound from a dataset could potentially allow the identification of the most biologically active compound withoutFrom engineering to drug design: Use of the Taguchi method to predict the optimal compound from a dataset could potentially allow the identification of the most biologically active compound without the synthesis of a full combinatorial library of derivatives. Our results show that the method achieved favorable outcomes for biological activities that are measured against specific target proteins. However, limitations were observed when the method was applied to data derived from a cell-based system.

• Discovery, Synthesis, and in vitro Evaluation of West Nile Virus Protease Inhibitors Based on the 9,10-Dihydro-3H,4aH-1,3,9,10a-tetraazaphenanthren-4-one Scaffold.

  Authors: Sanjay Samanta, Taian Cui, Yulin Lam

  ChemMedChem.

  West Nile virus (WNV), a member of the Flaviviridae family, is a mosquito-borne pathogen that causes a great number of human infections each year. Neither vaccines nor antiviral therapies areWest Nile virus (WNV), a member of the Flaviviridae family, is a mosquito-borne pathogen that causes a great number of human infections each year. Neither vaccines nor antiviral therapies are currently available for human use. In this study, a WNV NS2B-NS3 protease inhibitor with a 9,10-dihydro-3H,4aH-1,3,9,10a-tetraazaphenanthren-4-one scaffold was identified by screening a small library of non-peptidic compounds. This initial hit was optimized by solution-phase synthesis and screening of a focused library of compounds bearing this scaffold. This led to the identification of a novel, uncompetitive inhibitor (1a40, IC(50) =5.41±0.45 μM) of WNV NS2B-NS3 protease. Molecular docking of this chiral compound onto the WNV protease indicates that the S enantiomer of 1a40 appears to interfere with the productive interactions between the NS2B cofactor and the NS3 protease domain; (S)-1a40 is a preferred isomer for inhibition of WNV NS3 protease.

• Evaluation of Bis-Alkylamidoxime O-Alkylsulfonates as Orally Available Antimalarials.

  Authors: Mélissa Degardin, Sharon Wein, Smitha Gouni, Christophe Tran Van Ba, Jean-Frédéric Duckert, Thierry Durand, Roger Escale, Henri Vial, Yen Vo-Hoang

  ChemMedChem.

  The main threat to controlling malaria is the emerging multidrug resistance of Plasmodium sp. parasites. Bis-alkylamidines were developed as a potential new chemotherapy that targets plasmodialThe main threat to controlling malaria is the emerging multidrug resistance of Plasmodium sp. parasites. Bis-alkylamidines were developed as a potential new chemotherapy that targets plasmodial phospholipid metabolism. Unfortunately, these compounds are not orally available. To solve this absorption issue, we investigated a prodrug strategy based on sulfonate derivatives of alkylamidoximes. A total of 25 sulfonates were synthesized as prodrug candidates of one bis-N-alkylamidine and of six N-substituted bis-C-alkylamidines. Their antimalarial activities were evaluated in vitro against P. falciparum and in vivo against P. vinckei in mice to define structure-activity relationships. Small alkyl substituents on the sulfonate group of both C-alkyl- and N-alkylamidines led to the best oral antimalarial activities; alkylsulfonate derivatives are chemically transformed into the corresponding alkylamidines.

• Development of an (S)-1-{2-[Tris(4-methoxyphenyl)methoxy]ethyl}piperidine-3-carboxylic acid [(S)-SNAP-5114] Carba Analogue Inhibitor for Murine γ-Aminobutyric Acid Transporter Type 4.

  Authors: Jörg Pabel, Mark Faust, Cornelia Prehn, Babette Wörlein, Lars Allmendinger, Georg Höfner, Klaus T Wanner

  ChemMedChem.

  A series of GABA uptake inhibitors related to (S)-1-{2-[tris(4-methoxyphenyl)methoxy]ethyl}piperidine-3-carboxylic acid [(S)-SNAP-5114], the most potent mGAT4 inhibitor known so far, were synthesizedA series of GABA uptake inhibitors related to (S)-1-{2-[tris(4-methoxyphenyl)methoxy]ethyl}piperidine-3-carboxylic acid [(S)-SNAP-5114], the most potent mGAT4 inhibitor known so far, were synthesized and biologically evaluated for their inhibitory potency at the four GABA uptake transporters mGAT1-4 stably expressed in HEK-293 cell lines. New analogues were developed with potencies that are similar to or slightly higher than those of current mGAT4 inhibitors, but with distinctly improved chemical stability. (S)-Nipecotic acid derivatives possessing a 2-[1-(4-methoxy-2-methylphenyl)-1,1-bis(4-methoxyphenyl)methoxy]ethyl (DDPM-859) or a 4,4,4-tris(4-methoxyphenyl)but-2-en-1-yl moiety (DDPM-1457) were found to exhibit pIC(50) values of 5.78 and 5.87, respectively. Thus, as mGAT4 inhibitors, these compounds compare well with (S)-SNAP-5114 (pIC(50) =5.71), but are far more stable than the latter. Moreover, DDPM-859 displays a more favorable subtype selectivity for mGAT4 versus mGAT3 than does (S)-SNAP-5114.

• Pentacycloundecane-diol-Based HIV-1 Protease Inhibitors: Biological Screening, 2D NMR, and Molecular Simulation Studies.

  Authors: Bahareh Honarparvar, Maya M Makatini, Sachin A Pawar, Katja Petzold, Mahmoud E S Soliman, Per I Arvidsson, Yasien Sayed, Thavendran Govender, Glenn E M Maguire, Hendrik G Kruger

  ChemMedChem.

  Novel compounds incorporating a pentacycloundecane (PCU) diol moiety were designed, synthesized, and evaluated as inhibitors of the wild-type C-South African (C-SA) HIV-1 protease. Seven compoundsNovel compounds incorporating a pentacycloundecane (PCU) diol moiety were designed, synthesized, and evaluated as inhibitors of the wild-type C-South African (C-SA) HIV-1 protease. Seven compounds are reported herein, three of which displayed IC(50) values in the 0.5-0.6 μM range. The cytotoxicity of PCU cage peptides toward human MT-4 cells appears to be several orders of magnitude less toxic than the current antiviral medications ritonavir and lopinavir. NMR studies based on the observed through-space (1) H,(1) H distances/contacts in the EASY-ROESY spectra of three of the considered PCU peptide inhibitors enabled us to describe their secondary solution structure. Conserved hydrogen bonding interactions were observed between the hydroxy group of the PCU diol inhibitors and the catalytic triad (Asp25, Ile26, Gly27) of HIV protease in docking and molecular dynamics simulations. The biological significance and possible mode of inhibition by PCU-based HIV protease inhibitors discussed herein facilitates a deeper understanding of this family of inhibitors and their potential application to a vast number of alternative diseases related to proteases.

• O-Linked Triazolotriazines: Potent and Selective c-Met Inhibitors.

  Authors: Fang Chen, Ying Wang, Jing Ai, Zhengsheng Zhan, Yongcong Lv, Zhongjie Liang, Cheng Luo, Desheng Mei, Meiyu Geng, Wenhu Duan

  ChemMedChem.

  The HGF/c-Met signaling pathway mediates a variety of important biological activities, but dysregulation of the pathway is also closely associated with poor prognosis in a wide range of humanThe HGF/c-Met signaling pathway mediates a variety of important biological activities, but dysregulation of the pathway is also closely associated with poor prognosis in a wide range of human cancers. c-Met is considered to be among the most promising therapeutic targets for anticancer drug discovery. Herein we report the discovery of a series of O-linked triazolotriazines that show sub-nanomolar inhibition of c-Met activity. Among these new compounds, 6 a exhibits high c-Met inhibitory potency in both enzymatic and cellular assays with great selectivity.

• Synthesis, Structure Analysis, and Antitumor Evaluation of 3,6-Dimethyl-1,2,4,5-tetrazine-1,4-dicarboxamide Derivatives.

  Authors: Guo-Wu Rao, Yan-Mei Guo, Wei-Xiao Hu

  ChemMedChem.

  3,6-Dimethyl-1,2,4,5-tetrazine-1,4-dicarboxamide derivatives were synthesized, and their structures were confirmed by single-crystal X-ray diffraction. This reaction yields the 1,4-dicarboxamide3,6-Dimethyl-1,2,4,5-tetrazine-1,4-dicarboxamide derivatives were synthesized, and their structures were confirmed by single-crystal X-ray diffraction. This reaction yields the 1,4-dicarboxamide derivatives rather than the 1,2-dicarboxamide derivatives. Their in vitro antitumor activities were evaluated against SGC-7901, HO-8910, MCF-7, and A-549 cells. The results showed several compounds to be endowed with cytotoxicity in the low micromolar range. One compound (IC(50) =0.57 μM) was further evaluated in vivo against an A-549 xenograft in BALB/cA nude mice; it effected 76.4 % inhibition of tumor weight through intraperitoneal (i.p.) administration of 40 mg kg(-1) body weight. Moreover, its acute toxicity was evaluated, and the i.p. LD(50) value was 325 mg kg(-1) in mice.

• Kinase Inhibitor Scaffolds against Neurodegenerative Diseases from a Southern Australian Ascidian, Didemnum sp.

  Authors: Fabien Plisson, Melissa Conte, Zeinab Khalil, Xiao-Cong Huang, Andrew M Piggott, Robert J Capon

  ChemMedChem.

  Screening a library of Southern Australian and Antarctic marine invertebrates and algae for inhibitors of neurodegenerative disease kinase targets casein kinase 1 (CK1δ), cyclin-dependent kinase 5Screening a library of Southern Australian and Antarctic marine invertebrates and algae for inhibitors of neurodegenerative disease kinase targets casein kinase 1 (CK1δ), cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3β) identified a Western Australian Didemnum species (CMB-02127) as a high-priority specimen. Chemical fractionation returned the known aromatic alkaloids ningalins B-D as the major metabolites, together with six minor metabolites, the new ningalins E-G and the known hexacyclic pyrrole alkaloids lamellarins Z, G and A6. All structures were assigned by detailed spectroscopic analysis and literature comparisons, and the structural assignments were supported by biosynthetic considerations. The ningalins showed potent and broad inhibition across the three kinases, while the lamellarins were generally more selective for CDK5. Docking studies using published X-ray crystal structures of CDK5 revealed both scaffolds target the ATP binding pocket.

• Structure-Activity Relationships and Mechanism of Action of Eph-ephrin Antagonists: Interaction of Cholanic Acid with the EphA2 Receptor.

  Authors: Massimiliano Tognolini, Matteo Incerti, Iftiin Hassan-Mohamed, Carmine Giorgio, Simonetta Russo, Renato Bruni, Barbara Lelli, Luisa Bracci, Roberta Noberini, Elena B Pasquale, Elisabetta Barocelli, Paola Vicini, Marco Mor, Alessio Lodola

  ChemMedChem.

  The Eph-ephrin system, including the EphA2 receptor and the ephrinA1 ligand, plays a critical role in tumor and vascular functions during carcinogenesis. We previously identifiedThe Eph-ephrin system, including the EphA2 receptor and the ephrinA1 ligand, plays a critical role in tumor and vascular functions during carcinogenesis. We previously identified (3α,5β)-3-hydroxycholan-24-oic acid (lithocholic acid) as an Eph-ephrin antagonist that is able to inhibit EphA2 receptor activation; it is therefore potentially useful as a novel EphA2 receptor-targeting agent. Herein we explore the structure-activity relationships of a focused set of lithocholic acid derivatives based on molecular modeling investigations and displacement binding assays. Our exploration shows that while the 3-α-hydroxy group of lithocholic acid has a negligible role in recognition of the EphA2 receptor, its carboxylate group is critical for disrupting the binding of ephrinA1 to EphA2. As a result of our investigation, we identified (5β)-cholan-24-oic acid (cholanic acid) as a novel compound that competitively inhibits the EphA2-ephrinA1 interaction with higher potency than lithocholic acid. Surface plasmon resonance analysis indicates that cholanic acid binds specifically and reversibly to the ligand binding domain of EphA2, with a steady-state dissociation constant (K(D) ) in the low micromolar range. Furthermore, cholanic acid blocks the phosphorylation of EphA2 as well as cell retraction and rounding in PC3 prostate cancer cells, two effects that depend on EphA2 activation by the ephrinA1 ligand. These findings suggest that cholanic acid can be used as a template structure for the design of effective EphA2 antagonists, and may have potential impact in the elucidation of the role played by this receptor in pathological conditions.

• Development of Selective Estrogen Receptor Modulator (SERM)-Like Activity Through an Indirect Mechanism of Estrogen Receptor Antagonism: Defining the Binding Mode of 7-Oxabicyclo[2.2.1]hept-5-ene Scaffold Core Ligands.

  Authors: Yangfan Zheng, Manghong Zhu, Sathish Srinivasan, Jerome C Nwachukwu, Valerie Cavett, Jian Min, Kathryn E Carlson, Pengcheng Wang, Chune Dong, John A Katzenellenbogen, Kendall W Nettles, Hai-Bing Zhou

  ChemMedChem.

  Previously, we discovered estrogen receptor (ER) ligands with a novel three-dimensional oxabicyclo[2.2.1]heptene core scaffold and good ER binding affinity act as partial agonists via small alkylPreviously, we discovered estrogen receptor (ER) ligands with a novel three-dimensional oxabicyclo[2.2.1]heptene core scaffold and good ER binding affinity act as partial agonists via small alkyl ester substitutions on the bicyclic core that indirectly modulate the critical switch helix in the ER ligand binding domain, helix 12, by interactions with helix 11. This contrasts with the mechanism of action of tamoxifen, which directly pushes helix 12 out of the conformation required for gene activation. We now report that a much larger substitution can be tolerated at this position of the bicyclic core scaffold, namely a phenyl sulfonate group, which defines a novel binding epitope for the estrogen receptor. We prepared an array of 14 oxabicycloheptene sulfonates, varying the phenyl sulfonate group. As with the parent compound, 5,6-bis-(4-hydroxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonic acid phenyl ester (OBHS), these compounds showed preferential affinity for ERα, and the disposition and size of the phenyl substituents were important determinants of the binding affinity and selectivity of these compounds, with those having ortho substituents giving the highest, and para substituents the lowest affinities for ERα. A few analogues exhibit ERα binding affinities that are comparable to or, in the case of the ortho-chloro analogue, higher than that of OBHS itself. In cell-based studies, we found several compounds with activity profiles comparable to tamoxifen, but acting entirely as indirect antagonists, allosterically interfering with recruitment of coactivator proteins to the receptor. Thus, the OBHS binding epitope represents a novel approach to the development of estrogen receptor antagonists via an indirect mechanism of antagonism.

• Docetaxel Nanotechnology in Anticancer Therapy.

  Authors: Pengxiang Zhao, Didier Astruc

  ChemMedChem.

  Taxanes have been recognized as a family of very efficient anticancer drugs, but the formulation in use for the two main taxanes-Taxol for paclitaxel and Taxotere for docetaxel-have shown dramaticTaxanes have been recognized as a family of very efficient anticancer drugs, but the formulation in use for the two main taxanes-Taxol for paclitaxel and Taxotere for docetaxel-have shown dramatic side effects. Whereas several new formulations for paclitaxel have recently appeared, such as Abraxane and others currently in various phases of clinical trials, there is no new formulation in clinical trials for the other main taxane, docetaxel, except BIND-014, a polymeric nanoparticle, which recently entered phase I clinical testing. Therefore, we review herein the state of the art and recent abundance in published results of academic approaches toward nanotechnology-based drug-delivery systems containing nanocarriers and targeting agents for docetaxel formulations. These efforts will certainly enrich the spectrum of docetaxel treatments in the near future. Taxotere's systemic toxicity, low water solubility, and other side effects are significant problems that must be overcome. To avoid the limitations of docetaxel in clinical use, researchers have developed efficient drug-delivery assemblies that consist of a nanocarrier, a targeting agent, and the drug. A wide variety of such engineered nanosystems have been shown to transport and eventually vectorize docetaxel more efficiently than Taxotere in vitro, in vivo, and in pre-clinical administration. Recent progress in drug vectorization has involved a combined therapy and diagnostic ("theranostic") approach in a single drug-delivery vector and could significantly improve the efficiency of such an anticancer drug as well as other drug types.

• Synthesis, Anti-HIV Activity Studies, and in silico Rationalization of Cyclobutane-Fused Nucleosides.

  Authors: Antoni Figueras, Rosa Miralles-Llumà, Ramon Flores, Albert Rustullet, Félix Busqué, Marta Figueredo, Josep Font, Ramon Alibés, Jean-Didier Maréchal

  ChemMedChem.

  The present work describes some recent approaches to novel 3-oxabicyclo[3.2.0]heptane-type nucleosides structurally similar to the potent anti-HIV agent stavudine (d4T). To gain knowledge at theThe present work describes some recent approaches to novel 3-oxabicyclo[3.2.0]heptane-type nucleosides structurally similar to the potent anti-HIV agent stavudine (d4T). To gain knowledge at the molecular level relevant for further synthetic designs, the lack of activity of these compounds was investigated by computational approaches accounting for three main physiological requirements of anti-HIV nucleosides: their drug-likeness, their activation process, and their subsequent interaction with HIV reverse transcriptase (HIV-RT). Our results show that the inclusion of the fused cyclobutane at the 2'- and 3'-positions of the sugar portion provides drug-like compounds. Nonetheless, the presence of this cyclobutane moiety prevents binding orientations consistent with the catalytic activation for at least one of the enzymes known to activate d4T. To the best of our knowledge, this is the first study to explicitly consider the simulation of the entire activation process to rationalize anti-HIV activities.

• Bicyclic Peptides with Optimized Ring Size Inhibit Human Plasma Kallikrein and its Orthologues While Sparing Paralogous Proteases.

  Authors: Vanessa Baeriswyl, Helen Rapley, Lisa Pollaro, Catherine Stace, Dan Teufel, Edward Walker, Shiyu Chen, Greg Winter, John Tite, Christian Heinis

  ChemMedChem.

  Picky push bikes! Bicyclic peptides with low to sub-nanomolar inhibitory activities towards the serine protease plasma kallikrein were developed. By modulating the size of the macrocyclic rings,Picky push bikes! Bicyclic peptides with low to sub-nanomolar inhibitory activities towards the serine protease plasma kallikrein were developed. By modulating the size of the macrocyclic rings, inhibitors with the desired specificity profile could be generated.

• Synthesis of Gd and (68) Ga Complexes in Conjugation with a Conformationally Optimized RGD Sequence as Potential MRI and PET Tumor-Imaging Probes.

  Authors: Leonardo Manzoni, Laura Belvisi, Daniela Arosio, Maria Paola Bartolomeo, Aldo Bianchi, Chiara Brioschi, Federica Buonsanti, Claudia Cabella, Cesare Casagrande, Monica Civera, Marilenia De Matteo, Lorenza Fugazza, Luciano Lattuada, Federico Maisano, Luigi Miragoli, Cristina Neira, Michael Pilkington-Miksa, Carlo Scolastico

  ChemMedChem.

  We report the synthesis of novel chelates of Gd and (68) Ga with DPTA, DOTA, HP-DOA3, as well as with AAZTA, a novel chelating agent developed by our research group. These chelating agents wereWe report the synthesis of novel chelates of Gd and (68) Ga with DPTA, DOTA, HP-DOA3, as well as with AAZTA, a novel chelating agent developed by our research group. These chelating agents were appropriately conjugated, prior to metal complexation, with DB58, an RGD peptidomimetic, conformationally constrained on an azabicycloalkane scaffold and endowed with high affinity for integrin α(ν) β(3) . Because α(ν) β(3) is involved in neo-angiogenesis in solid tumors and is also directly expressed in cancer cells (e.g. glioblastomas, melanomas) and ovarian, breast, and prostate cancers, these constructs could prove useful as molecular imaging probes in cancer diagnosis by MRI or PET techniques. Molecular modeling, integrin binding assays, and relaxivity assessments allowed the selection of compounds suitable for multiple expression on dendrimeric or nanoparticulate structures. These results also led us to an exploratory investigation of (68) Ga complexation for the promising (68) Ga-PET technique; the AAZTA complex 15((68) Ga) exhibited uptake in a xenograft model of glioblastoma, suggesting potentially useful developments with new probes with improved affinity.

• Molecular Recognition of T:G Mismatched Base Pairs in DNA as Studied by Electrospray Ionization Mass Spectrometry.

  Authors: Federico Riccardi Sirtori, Giancarlo Aldini, Maristella Colombo, Nicoletta Colombo, Jan Malyszko, Giulio Vistoli, Roberto D'Alessio

  ChemMedChem.

  Postreplicative mismatch repair (MMR) is a cellular system involved in the recognition and correction of DNA polymerase errors that escape detection in proofreading. Of the various mismatched bases,Postreplicative mismatch repair (MMR) is a cellular system involved in the recognition and correction of DNA polymerase errors that escape detection in proofreading. Of the various mismatched bases, T:G pairing in DNA is one of the more common mutations leading to the formation of tumors in humans. In addition, the absence of the MMR system can generate resistance to several chemotherapeutic agents, particularly DNA-damaging substances. The main purpose of this study was the setup and validation of an electrospray ionization (ESI) mass spectrometry method for the identification of small molecules that are able to recognize T:G mismatches in DNA targets. These findings could be useful for the discovery of new antitumor drugs. The analytical method is based on the ability of electrospray to preserve the noncovalent adducts present in solution and transfer them to the gas phase. Lexitropsin derivatives (polyimidazole compounds) have been previously described as selective for T:G mismatch binding by NMR and ITC studies. We synthesized and tested various polyimidazole derivatives, one of which in particular (NMS-057) showed a higher affinity for an oligonucleotide DNA sequence containing a T:G mismatched base pair. To rationalize these findings, molecular docking studies were performed using available NMR structures. Moreover, ESI-MS experiments, performed on an orbitrap mass spectrometer, highlighted the formation of heterodimeric complexes between DNA sequences, distamycin A, and polyimidazole compounds. Our results confirm that this ESI method could be a valuable tool for the identification of new molecules able to specifically recognize T:G mismatched base pairs.

• Comparative Molecular Profiling of the PPARα/γ Activator Aleglitazar: PPAR Selectivity, Activity and Interaction with Cofactors.

  Authors: Michel Dietz, Peter Mohr, Bernd Kuhn, Hans Peter Maerki, Peter Hartman, Armin Ruf, Jörg Benz, Uwe Grether, Matthew B Wright

  ChemMedChem.

  Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors that control the expression of genes involved in a variety of physiologic processes, throughPeroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors that control the expression of genes involved in a variety of physiologic processes, through heterodimerization with retinoid X receptor and complex formation with various cofactors. Drugs or treatment regimens that combine the beneficial effects of PPARα and γ agonism present an attractive therapeutic strategy to reduce cardiovascular risk factors. Aleglitazar is a dual PPARα/γ agonist currently in phase III clinical development for the treatment of patients with type 2 diabetes mellitus who recently experienced an acute coronary event. The potency and efficacy of aleglitazar was evaluated in a head-to-head comparison with other PPARα, γ and δ ligands. A comprehensive, 12-concentration dose-response analysis using a cell-based assay showed aleglitazar to be highly potent, with EC(50) values of 5 nM and 9 nM for PPARα and PPARγ, respectively. Cofactor recruitment profiles confirmed that aleglitazar is a potent and balanced activator of PPARα and γ. The efficacy and potency of aleglitazar are discussed in relation to other dual PPARα/γ agonists, in context with the published X-ray crystal structures of both PPARα and γ.

• Hydroxamic Acids as Potent Inhibitors of Fe(II) and Mn(II) E. coli Methionine Aminopeptidase: Biological Activities and X-ray Structures of Oxazole Hydroxamate-EcMetAP-Mn Complexes.

  Authors: Florian Huguet, Armelle Melet, Rodolphe Alves de Sousa, Aurélie Lieutaud, Jacqueline Chevalier, Laure Maigre, Patrick Deschamps, Alain Tomas, Nicolas Leulliot, Jean-Marie Pages, Isabelle Artaud

  ChemMedChem.

  New series of acids and hydroxamic acids linked to five-membered heterocycles including furan, oxazole, 1,2,4- or 1,3,4-oxadiazole, and imidazole were synthesized and tested as inhibitors against theNew series of acids and hydroxamic acids linked to five-membered heterocycles including furan, oxazole, 1,2,4- or 1,3,4-oxadiazole, and imidazole were synthesized and tested as inhibitors against the Fe(II) , Co(II) , and Mn(II) forms of E. coli methionine aminopeptidase (MetAP) and as antibacterial agents against wild-type and acrAB E. coli strains. 2-Aryloxazol-4-ylcarboxylic acids appeared as potent and selective inhibitors of the Co(II) MetAP form, with IC(50) values in the micromolar range, whereas 5-aryloxazol-2-ylcarboxylic acid regioisomers and 5-aryl-1,2,4-oxadiazol-3-ylcarboxylic acids were shown to be inefficient against all forms of EcMetAP. Regardless of the heterocycle, all the hydroxamic acids are highly potent inhibitors and are selective for the Mn(II) and Fe(II) forms, with IC(50) values between 1 and 2 μM. One indole hydroxamic acid that we previously reported as a potent inhibitor of E. coli peptide deformylase also demonstrated efficiency against EcMetAP. To gain insight into the positioning of the oxazole heterocycle with reversed substitutions at positions 2 and 5, X-ray crystal structures of EcMetAP-Mn complexed with two such oxazole hydroxamic acids were solved. Irrespective of the [metal]/[apo-MetAP] ratio, the active site consistently contains a dinuclear manganese center, with the hydroxamate as bridging ligand. Asp 97, which adopts a bidentate binding mode to the Mn2 site in the holoenzyme, is twisted in both structures toward the hydroxamate bridging ligand to favor the formation of a strong hydrogen bond. Most of the compounds show weak antibacterial activity against a wild-type E. coli strain. However, increased antibacterial activity was observed mainly for compounds with a 2-substituted phenyl group in the presence of the nonapeptide polymyxin B and phenylalanine-arginine-β-naphthylamide as permeabilizer and efflux pump blocker, respectively, which boost the intracellular uptake of the inhibitors.

• Selective Modification of the N-Terminal Structure of Polytheonamide B Significantly Changes its Cytotoxicity and Activity as an Ion Channel.

  Authors: Naoki Shinohara, Hiroaki Itoh, Shigeru Matsuoka, Masayuki Inoue

  ChemMedChem.

  Chemical point mutation: Polytheonamide B is a naturally occurring polypeptide containing 48 amino acids. It both displays potent cytotoxicity and acts as a monovalent cation channel in vitro.Chemical point mutation: Polytheonamide B is a naturally occurring polypeptide containing 48 amino acids. It both displays potent cytotoxicity and acts as a monovalent cation channel in vitro. Chemoselective methods to modify the 44th, N-, and C-terminal residues of the natural product have been developed, and evaluation of the resultant derivatives suggests that the intrinsic activities of the peptide can only be altered by switching its N-terminal substitution.

• Identification of Selective Inhibitors of the Potassium Channel Kv1.1-1.2((3)) by High-Throughput Virtual Screening and Automated Patch Clamp.

  Authors: Soeren J Wacker, Wiktor Jurkowski, Katie J Simmons, Colin W G Fishwick, A Peter Johnson, David Madge, Erik Lindahl, Jean-Francois Rolland, Bert L de Groot

  ChemMedChem.

  Two voltage-dependent potassium channels, Kv1.1 (KCNA1) and Kv1.2 (KCNA2), are found to co-localize at the juxtaparanodal region of axons throughout the nervous system and are known to co-assemble inTwo voltage-dependent potassium channels, Kv1.1 (KCNA1) and Kv1.2 (KCNA2), are found to co-localize at the juxtaparanodal region of axons throughout the nervous system and are known to co-assemble in heteromultimeric channels, most likely in the form of the concatemer Kv1.1-1.2((3)) . Loss of the myelin sheath, as is observed in multiple sclerosis, uncovers the juxtaparanodal region of nodes of Ranvier in myelinated axons leading to potassium conductance, resulting in loss of nerve conduction. The selective blocking of these Kv channels is therefore a promising approach to restore nerve conduction and function. In the present study, we searched for novel inhibitors of Kv1.1-1.2((3)) by combining a virtual screening protocol and electrophysiological measurements on a concatemer Kv1.1-1.2((3)) stably expressed in Chinese hamster ovary K1 (CHO-K1) cells. The combined use of four popular virtual screening approaches (eHiTS, FlexX, Glide, and Autodock-Vina) led to the identification of several compounds as potential inhibitors of the Kv1.1-1.2((3)) channel. From 89 electrophysiologically evaluated compounds, 14 novel compounds were found to inhibit the current carried by Kv1.1-1.2((3)) channels by more than 80 % at 10 μM. Accordingly, the IC(50) values calculated from concentration-response curve titrations ranged from 0.6 to 6 μM. Two of these compounds exhibited at least 30-fold higher potency in inhibition of Kv1.1-1.2((3)) than they showed in inhibition of a set of cardiac ion channels (hERG, Nav1.5, and Cav1.2), resulting in a profile of selectivity and cardiac safety. The results presented herein provide a promising basis for the development of novel selective ion channel inhibitors, with a dramatically lower demand in terms of experimental time, effort, and cost than a sole high-throughput screening approach of large compound libraries.

• Elucidation of Mycobacterium tuberculosis Type II Dehydroquinase Inhibitors using a Fragment Elaboration Strategy.

  Authors: Anh Thu Tran, Nicholas P West, Warwick J Britton, Richard J Payne

  ChemMedChem.

  A library of novel Mycobacterium tuberculosis type II dehydroquinase (DHQase) inhibitors were discovered through the use of a fragment elaboration approach. Putative active site binding fragmentsA library of novel Mycobacterium tuberculosis type II dehydroquinase (DHQase) inhibitors were discovered through the use of a fragment elaboration approach. Putative active site binding fragments were initially assessed in silico which led to the selection of two small aromatic fragments for further investigation. Synthetic elaboration of the fragments provided a library of 34 inhibitors that exhibited low-micromolar inhibition of type II DHQase. A number of these inhibitors also showed antibacterial activity in the low-micromolar range in screens against M. tuberculosis in vitro; these now serve as lead compounds for further development of therapeutics for the treatment of tuberculosis.

• The Importance of the trans-Enamine Intermediate as a β-Lactamase Inhibition Strategy Probed in Inhibitor-Resistant SHV β-Lactamase Variants.

  Authors: Wei Ke, Elizabeth A Rodkey, Jared M Sampson, Marion J Skalweit, Anjaneyulu Sheri, Sundar Ram Reddy Pagadala, Michael D Nottingham, John D Buynak, Robert A Bonomo, Focco van den Akker

  ChemMedChem.

  The ability of bacteria to express inhibitor-resistant (IR) β-lactamases is stimulating the development of novel inhibitors of these enzymes. The 2'β-glutaroxypenicillinate sulfone, SA2-13, wasThe ability of bacteria to express inhibitor-resistant (IR) β-lactamases is stimulating the development of novel inhibitors of these enzymes. The 2'β-glutaroxypenicillinate sulfone, SA2-13, was previously designed to enhance the stabilization of the deacylation-refractory, trans-enamine inhibitory intermediate. To test whether this mode of inhibition can overcome different IR mutations, we determined the binding mode of SA2-13 through X-ray crystallography, obtaining co-crystals of the inhibitor-protein complex by soaking crystals of the IR sulfhydryl variable (SHV) β-lactamase variants S130G and M69V with the inhibitor. The 1.45 Å crystal structure of the S130G SHV:SA2-13 complex reveals that SA2-13 is still able to form the stable trans-enamine intermediate similar to the wild-type complex structure, yet with its carboxyl linker shifted deeper into the active site in the space vacated by the S130G mutation. In contrast, data from crystals of the M69V SHV:SA2-13 complex at 1.3 Å did not reveal clear inhibitor density indicating that this IR variant disfavors the trans-enamine conformation, likely due to a subtle shift in A237.

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