Highlights from ASMC'13 – Advances in Synthetic and Medicinal Chemistry – May 5–8 2013, Moscow, Russia

Edmond Differding

doi:10.1039/C3MD90017G

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DOI: 10.1039/C3MD90017G (Conference Report) Med. Chem. Commun., 2013, 4, 1138-1144

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Highlights from ASMC'13 – Advances in Synthetic and Medicinal Chemistry – May 5–8 2013, Moscow, Russia

Edmond Differding
EFMC & Differding Consulting, Route de Blocry 55, 1348 Louvain-la-Neuve, Belgium. E-mail: edmond@differding.com

Received 14th June 2013 , Accepted 14th June 2013

First published on 18th July 2013

Abstract

ASMC'13 Moscow (May 5–8, 2013) focused on new synthetic methodologies and aimed at expanding the drug discovery space from small to large molecules, including carbohydrates, novel protein scaffolds, dendrimers, and genes.

ASMC'13 Moscow has been organized by the European Federation for Medicinal Chemistry (EFMC) and ChemBridge Corporation, on May 5–8 in Moscow, Russia, with a programme assembled by the symposium co-chairmen, Peter Seeberger (Max Planck Institute of Colloids and Interfaces, Germany) and Alan Palkowitz (Eli Lilly & Company, United States). The symposium was held at the “Crowne Plaza Moscow World Trade Centre Hotel”, overlooking the Moskva river, and situated within walking distance of the historical heart of the city. About 250 participants from 28 countries, half from industry, half from academia, attended the meeting and participated in the lively discussions.

The main topics of this symposium included new synthetic methodologies, total synthesis of natural products and heterocyclic chemistry, as well as medicinal chemistry and drug discovery and development. Beyond key lectures in synthetic and catalytic chemistry, as well as recent case studies in medicinal chemistry, the symposium aimed at expanding the chemical space from small to large molecules, including carbohydrates, novel protein scaffolds, dendrimers, and genes.

After a welcome reception on Sunday evening, the meeting was opened on Monday morning by Peter Seeberger, who highlighted the scientific breadth of the topics covered in the meeting with 24 invited plenary lectures from academia and from the pharmaceutical and biotech industry in Europe, USA and former USSR countries, 2 EFMC Prize lectures, 10 short oral communications selected from the submitted abstracts, and a poster session.

He was followed by Uli Stilz (Sanofi, Germany), EFMC President, who stressed the Federation's objectives of promoting medicinal chemistry and of building bridges between disciplines and scientists worldwide, by organizing scientific meetings, courses and schools, by participating in publishing a journal, MedChemComm, and by conferring EFMC Awards and Prizes.¹

Gene Vaisberg, CEO ChemBridge Corporation concluded the introduction by highlighting the history and background of ASMC, a series of symposia which started with ASMC'04 Moscow, followed by two editions in St. Petersburg (ASMC'07, ASMC'11) and one in Kiev (ASMC'09).

The scientific programme started with a session chaired by Peter Seeberger, and the inaugural lecture by Andrew Hamilton (Oxford University, United Kingdom), who stressed the importance of creating novel chemical microenvironments using designed proteomimetics to tackle targets such as protein–protein interactions (PPIs). He focused on three increasingly difficult challenges in protein mimicry: targeting binding pockets with peptidomimetics and β-strand mimetics (e.g. acetylene linked 2,2-disubstituted-indolin-3-one oligomers²), shallow clefts with helix mimetics (e.g. oligophenylenes targeting Bcl-xL/Bak complexes), and large protein interfaces by surface mimetics (e.g. β-sheet mimetics by ‘stitching’ together β-strands via acetylenic linkers).

Petra Johannesson (AstraZeneca, Sweden) followed with a talk on the discovery of a new series of pyrazinecarboxamide inhibitors of diglyceride acyltransferase-1 (DGAT1) for the treatment of obesity and metabolic syndrome. Rational design and optimization of this series led to the discovery of AZD7687, which met the project objectives for potency, selectivity, in particular over acetyl-CoA acetyltransferase-1 (ACAT1), solubility, and preclinical PK profile.³ This compound showed the anticipated excellent pharmacokinetic properties in human volunteers (Fig. 1).


	Fig. 1 AZD7687, a DGAT1 inhibitor for the treatment of obesity and metabolic syndrome (AstraZeneca).

María del Mar Martín-Fontecha (Complutense University of Madrid, Spain) described in an oral communication her group's approach to targeting cancer with new inhibitors of the enzyme isoprenylcysteine carboxyl methyltransferase (ICMT). Rational design based on a 3D-pharmacophore model refined with the information from the recently described crystal structure of a prokaryotic ICMT ortholog, or alternatively starting with analogs of cysmethynil, led to hits with interesting ICMT inhibitory activities and good preliminary pharmacokinetic properties.

The tremendous progress made in the synthesis of DNA and RNA was highlighted by Marvin Carruthers (University of Colorado, United States), a pioneer in the domain, in his talk entitled “Oligonucleotide synthesis interfaced with molecular biology and nanotechnology”. He focused first on the chemistry his group developed over the past decades to synthesize DNA on a glass chip, which culminated in an automated flow reactor and the simultaneous DNA synthesis of 12 chips on a glass wafer. After optimization of coupling, oxidation and deprotection steps, the synthesis of 150–300 mers has been made possible with a fidelity of 65% (150 mers) and 45% (300 mers). With the current automated synthesis equipment in his lab (5 platforms, 244 [thin space (1/6-em)] 000 DNA features/chip), the equivalent of the entire human genome can be performed every day (3 billion base pairs or 6 billion internucleotide synthetic steps). Similarly, the optimization of reaction conditions for RNA synthesis on a chip⁴ leads to RNA microarrays with numerous applications, including RNA–nucleic acid interactions, RNA–protein interactions, RNA–ligand binding, or RNA sequence/structure–activity relationships. The talk concluded with the synthesis of DNAs having triazoylphosphonate, boranephosphamidate, boranealkylphosphine and boranephosphonate internucleotide linkages, which display unique biological properties while those having borane reduce metals.

In her talk “BETting on Epigenetic Targets: From Phenotypic Discovery to First Time in Man”, Chun-wa Chung (GlaxoSmithKline, United Kingdom) described how the serendipitous discovery and subsequent molecular characterisation of potent small molecule inhibitors that disrupt the function of the BET family of bromodomains, an epigenetic reader class, led to potent compounds that bind within an acetylated lysine recognition pocket and antagonize the PPI between the bromodomain and chromatin, thus offering new treatment opportunities for cancer and inflammation (Fig. 2).⁵


	Fig. 2 Potent inhibitor that disrupts the function of the BET family of bromodomains (GSK).

Vladimir Poroikov (Institute of Biomedical Chemistry of the Russian Academy of Sciences, Russia) followed with a presentation on virtual screening and the design of new pharmaceutical agents using PASS (Prediction of Activity Spectra for Substances), a software his group has been developing since the early 1990s.⁶ PASS aims at predicting the biological activities of drug-like compounds based on the analysis of structure–activity relationships, and recently led to several applications, including the discovery of novel anticancer agents which demonstrated a synergistic activity with the known p53 reactivator RITA.

The Monday afternoon session, chaired by Laurent Provins (UCB, Belgium), started with Kevin Booker-Milburn (University of Bristol, United Kingdom) on “Synthetic Organic Photochemistry in Batch and Flow”, discussing his group's contributions to synthetic organic photochemistry which have involved the development of novel cycloaddition reactions, and the development of novel flow reactors⁷ and their application to the scale-up of synthetic photochemistry.

Michael Rowley (MSD, Switzerland), gave a talk on “The Discovery of the Macrocyclic Hepatitis C Virus (HCV) NS3/4A Protease Inhibitor MK-5172”.⁸ Starting from analogs of BILN-2061, a known inhibitor developed by Boehringer-Ingelheim, and using a novel P2–P4 macrocyclization strategy together with constrained linkers, highly potent protease inhibitors were obtained which led to two clinical candidates, first Vaniprevir, and subsequently MK-5172 displaying enhanced cross genotype activity, coverage of NS3/4A resistance mutations, and good pharmacokinetic and physicochemical properties. In Phase 2 trials, MK-5172 showed high efficacy and improved tolerability over first generation HCV Protease Inhibitors. The compound is currently undergoing Phase 3 studies.

An approach to treating a fatal neurodegenerative disease by targeting misfolded superoxide dismutase-1 (SOD-1) was presented in an oral communication by Arie-Lev Gruzman (Bar Ilan University, Israel) entitled “Novel Synthetic Chemical Chaperones as a New Basis for Amyotrophic Lateral Sclerosis (ALS) Treatment”. It is based on connecting existing small molecule chaperones such as 4-phenylbutyric acid or tauroursodeoxycholic acid with a variety of linkers to moieties targeting intracellular organelles such as the lysosome, mitochondria or the Golgi complex.

Jean Quancard (Novartis Pharma, Switzerland) followed with an oral communication on the discovery of highly potent sphingosine-1-phosphate receptor (S1P₁) antagonists, including NIBR-0213 for the treatment of multiple sclerosis (Fig. 3).⁹


	Fig. 3 NIBR-0213, a highly potent S1P₁ antagonist (Novartis).

A new approach to tuberculosis research was presented by Philip A. Hipskind (Eli Lilly & Co., United States) with an overview of “The Lilly TB Drug Discovery Initiative (LTI)”. Initiated in 2007, this non-profit partnership with the Infectious Disease Research Institute (IDRI-Seattle), and the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health (NIAID/NIH) and other partners draws on resources globally from leading TB and infectious disease drug researchers.¹⁰

The day ended with a presentation by Martin D. Burke (University of Illinois, United States) on “Molecular Prosthetics”, small molecules that perform higher-order, protein-like functions, having the potential to serve as substitutes for missing or dysfunctional proteins that underlie human diseases. This required the development of a new synthesis strategy, dubbed iterative cross-coupling, which aims to make the process of complex small molecule synthesis as simple, efficient, flexible as possible, and amenable to automation, similar to modern peptide synthesis, involving the simple iterative coupling of bifunctional building blocks. This has been achieved using MIDA boronates, of which more than 140 are now commercially available.¹¹

Day two started with a session chaired by Uli Stilz, and a talk by Janine Cossy (ESPCI ParisTech, France) on “Versatile Synthetic Methods: Access to Bioactive Molecules”. This included new synthetic approaches to five-membered, chiral lactones such as nephrosteranic acid and androccelaric acid using Pd catalysis,¹² to complex molecules including a spiroketal moiety using ferric ion catalysis of alkyl halide and vinyl Grignard cross-coupling reactions, to 2,6-disubstituted pyrans using cobalt-catalyzed cross-coupling reactions between Grignard reagents and glycosyl halides, and to 3-amino piperidines using acid-catalyzed rearrangements of 2-hydroxymethyl pyrrolidines.

This was followed by a little ceremony during which Uli Stilz, as EFMC President, handed over this year's ‘EFMC Prizes for Young Scientists’ (Picture), followed by the Prize winners talks.


	Plate1 EFMC President U. Stilz with EFMC Prize Winners G. Bernardes (left) and F. Goldberg (right).

Gonçalo Bernardes (University of Cambridge, United Kingdom & Instituto de Medicina Molecular, Portugal), this year's recipient of the ‘EFMC Prize for a Young Medicinal Chemist in Academia’ gave a talk on “Chemical Approaches to Biology and Therapeutics”, presenting his results on reaction engineering for chemical site-selective protein modification,¹³ the construction of homogeneous, vascular targeting antibody–drug conjugates for cancer therapy and the development of novel carbon monoxide (CO) releasing molecules for the delivery of therapeutic CO in vivo.¹⁴

Frederick Goldberg (AstraZeneca, Sweden), recipient of the ‘EFMC Prize for a Young Medicinal Chemist in Industry’, followed by giving a lecture on “Free-Wilson and Structural Approaches to Co-Optimising Human and Rodent Isoform Potency for 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitors” for the treatment of type II diabetes and the metabolic syndrome. Both a data-driven and a structure-based approach were used to rapidly identify compounds with good human/murine potencies, and good rodent pharmacokinetic properties (Fig. 4).¹⁵


	Fig. 4 11β-HSD1 inhibitor for the treatment of diabetes and metabolic disorders (AstraZeneca).

“Rapid Kinase SAR Generation: An Integrated Approach to Synthesis, Screening and Molecular Design”, by Dave Parry (Cyclofluidic, United Kingdom), illustrated his company's progress made in a continuous process, combining synthesis carried out in flow, product purification, analysis and reformatting prior to screening on an integrated platform (CyclOPs (Cyclofluidic Optimisation Platform)). The biological data is then incorporated into a continuously evolving activity model which allows the next molecule to be selected for synthesis, each iteration taking less than 2 hours, as illustrated by the discovery of novel Abl tyrosine kinase inhibitors.

Rainer Haag (Free University Berlin, Germany) introduced a paradigm shift in medicinal chemistry, by extending the range of target compounds from small molecules and biologics to synthetic polymers. In his talk on “Highly Anti-Inflammatory Dendritic Polyglycerol Sulfates – a Multiple Target Approach”, he reviewed the challenges and opportunities related to the use of dendritic polyglycerol scaffolds in biomedical applications.¹⁶ The variety of dendritic polyglycerol architectures combined with their low molecular weight dispersity, their functionality, their size-dependent cellular uptake and their good biocompatibility makes these compounds unique tools to mimic functional biomacromolecules. This has led among others to applications in the areas of cancer with e.g. tumor imaging agents and anti-tumor prodrugs, or in inflammation with polyanionic, dendritic polyglycerol sulfates, which strongly bind to cellular targets involved in the inflammatory process by inhibiting leukocyte infiltration, and are therefore suitable synthetic nanocarriers for inflammation-specific molecular imaging.

In his presentation entitled “Peptide Chemologics”, Lee Roberts (Pfizer, United States) gave a presentation which included novel stapled peptides that bind the co-activator peptide site of estrogen receptors,¹⁷ and CovX-Bodies, a novel class of biotherapeutic agents created by the fusion of a relatively small molecular weight payload (small molecule, peptide, protein) with an antibody, which provides an antibody-like pharmacokinetic and distribution profile.¹⁸

Simon Giroux (Vertex Pharmaceuticals, United States) described the “Discovery of Thienoimidazole-Based HCV NS5A Genotype 1a and 1b Inhibitors”. A novel method to synthesize the thienoimidazole [5,5]-bicyclic system, as a bioisostere of benzimidazole followed by coupling reactions using different linkers, allowed a detailed study of the structure–activity relationship (SAR) of the linkers which led to highly potent HCV NS5A inhibitors, such as VRT-546 (Fig. 5).¹⁹


	Fig. 5 VRT-546, a highly potent HCV NS5A inhibitor (Vertex).

The afternoon session started with a presentation by Cristina Nevado (University of Zurich, Switzerland) on “Organic Molecules as Biological Probes…an Exciting Journey”, which included the total synthesis of Frondosin A via gold-catalyzed propargylic rearrangement, the total synthesis and biological evaluation of Iriomoteolide-3a, and the use of computational tools in drug design which led to highly potent inhibitors of EphB4 as antiangiogenetic compounds.²⁰

Positron emission tomography (PET) was the topic of “Discovery and Initial Clinical Results of [¹⁸F]-UCB-H, First PET Radiotracer Targeting Synaptic Vesicle 2A” by Anne Valade (UCB, Belgium). SV2 proteins are critical for proper nervous system function and have been demonstrated to be involved in vesicle trafficking. The SV2A subtype's role in epilepsy has been demonstrated with Levetiracetam and other SV2A ligands (e.g. Brivaracetam) but still little is known about its precise role in neurological diseases. Specific design efforts for preparing suitable radiotracers led to the identification of [¹⁸F]-UCB-H, a fluorine-18 radiolabelled PET imaging agent with a nanomolar affinity for the human SV2A protein. Preliminary clinical validation studies show that [¹⁸F]-UCB-H is a suitable PET tracer for human studies (Fig. 6).²¹


	Fig. 6 [¹⁸F]-UCB-H, a fluorine-18 radiolabelled PET imaging agent (UCB).

Frédéric Schmidt (Institut Curie, France) reported in an oral communication on “Self-Immolative Spacers in Prodrug/Profluorophore Strategies”. The determination of kinetic parameters for the release of single or multiple substrates has been achieved using a new strategy based on a photoactivation step leading to the release of the spacer in the form of a free phenol, and subsequent release of the drug after the self-immolation step.²²

Maria Volkova (Moscow State University, Russia) followed with an oral communication on the development of successful synthetic approaches to novel melatonin receptor ligands via indolic nitriles.

The resurgence of covalent drugs²³ was highlighted by Eric Schwartz (Celgene Avilomics Research, United States) with the “Design and Characterization of Targeted Covalent Inhibitors of Bruton's tyrosine kinase (Btk)”, a critical regulator of aberrant B-cell receptor signaling in a range of diseases including chronic lymphocytic leukemia, non-Hodgkin's lymphoma, rheumatoid arthritis and lupus. The design of selective inhibitors based on an analysis of the ATP-binding pocket of Btk with the identification of Cys481 as a target residue for covalent modification, led to the clinical candidate CC-292 (formerly AVL-292) (Fig. 7).²⁴


	Fig. 7 CC-292 (AVL-292), a covalent inhibitor of Btk (Celgene Avilomics).

Christa Müller (University of Bonn, Germany) concluded the day by giving a talk on “P2X Receptors: ATP-Gated Ion Channels as Novel Drug Targets”. Although nucleotide receptors are known to be difficult targets (many subtypes, highly polar anionic ligands and fast hydrolysis by ectonucleotidases), several new antagonist families have been identified by the Bonn group: anthraquinone compounds antagonizing P2X2,²⁵ and phenoxazine derivatives and polyoxometalates as allosteric P2X4 antagonists. Further developments led to VH 241 (structure not disclosed), a highly potent allosteric P2X4 modulator (IC50 value around 10 nM), which shows no species differences (human, rat, mouse), is selective vs. other P2X receptor subtypes and against 50 other targets, displays drug-like structure and properties, has no negative charge, and is highly active in a mouse model of neuropathic pain.

The third day of the symposium started with a session chaired by Rosa-Maria Rodriguez-Sarmiento (F. Hoffmann-La Roche, Switzerland), and a presentation by Peter Seeberger entitled “Preventing and Curing Infectious Diseases: Carbohydrate Vaccines and Continuous Flow Synthesis”. The first part focused on his group's approach to the development of carbohydrate vaccines to prevent severe diseases such as malaria, nosocomial infections, bacterial meningitis, or invasive pneumococcal diseases. Such vaccines have only been made possible with the tremendous progress made in recent years with the synthetic accessibility of carbohydrate antigens via automated oligosaccharide synthesis, which reduced the time required from years to hours.²⁶ The second part highlighted a continuous flow synthesis of artemisinin, currently the best available drug against malaria. Starting from dihydroartemisinic acid, a byproduct of the artemisinin extraction from the Artemisia annua plant, combined with flow photooxidation at low temperature (−20 °C) in toluene, followed by continuous purification is likely to reduce the cost of synthesis of this essential medicine.²⁷

Medicinal chemistry aspects and structural features of voltage-gated sodium channel (VGSC) inhibitors and structural biology of sodium channels were the topic of Antonio Nardi's (Grünenthal, Germany) overview on “Advances in Targeting (VGSC) with Small Molecules”.²⁸ He stressed the need for second generation sodium channel inhibitors, building on strategies that aim at identifying small molecules targeting either particular isoforms of sodium channels involved in specific diseases or anomalous sodium channel currents, irrespective of the isoform by which they have been generated.

Pavel Mykhailiuk (Enamine Ltd, Ukraine) followed with an oral communication on the application of fluorinated amino acids as labels to study membrane active peptides by solid state ¹⁹F NMR, which required the design and synthesis of suitable conformationally restricted amino acids bearing a CF3-reporter group, including analogs of polar amino acids (Fig. 8).²⁹


	Fig. 8 CF3-substituted analogue of serine and threonine (Enamine).

“Engineering of Small Non-Antibody Protein Scaffolds as Novel Biopharmaceuticals: from Anticalins to PASylation” by Arne Skerra (Technical University Munich, Germany) further expanded chemical and biological space. Anticalins are a novel class of small engineered proteins, usually derived from human plasma lipocalins, which offer potential as an alternative to antibodies.³⁰ They are much smaller than antibodies (160–180 residues), providing better tissue penetration, and comprise just a single polypeptide chain, thus offering the efficient preparation of fusion proteins and/or conjugation with payloads or enzymes. Their potential therapeutic application can be illustrated for instance with the VEGF-specific anticalin Angiocal which has completed Phase 1 trials for the treatment of solid tumors, or the anticalin directed against Hepcidin, which is currently undergoing late-stage preclinical studies. Another beneficial feature of the anticalins is their deep binding pocket, which enables the tight complexation of small molecule ligands such as fluorescein, digoxigenin, or metal–chelate complexes, and offers interesting applications in biomedical research, diagnostics as well as nuclear medicine. Finally, the group has shown that conformationally disordered polypeptide chains comprising the amino acid residues Pro, Ala, and Ser (PAS) offer simple fusion to a biological drug on the genetic level, and are able to tune the plasma half-life of biopharmaceuticals, including anticalins, offering significant advantages over chemical conjugation to polyethylene glycol (PEG).³¹

Emmanuel Pinard (F. Hoffmann-La Roche, Switzerland) presented an update on the clinical development of “Bitopertin (RG1678), a Potent and Selective Glycine Re-Uptake Inhibitor for the Treatment of Schizophrenia” (Fig. 9). Bitopertine³² has shown positive results in a phase 2 proof-of-concept study in patients with predominant negative symptoms, one of the highest unmet medical needs in schizophrenia. This proof-of-concept study provides clinical support for glycine reuptake inhibition, and thereby enhancement of NMDA receptor signaling, as a promising therapeutic approach for schizophrenia. Partial occupancy, optimally <60%, of the glycine transporter type 1 by bitopertin leads to efficacy in animal models and in patients with schizophrenia. A Phase 3 study is ongoing evaluating the additional benefit of bitopertin for negative and positive symptoms when added to a stable dose of an antipsychotic.


	Fig. 9 Bitopertin (RG1678), a glycine re-uptake inhibitor for the treatment of schizophrenia (Hoffmann-La Roche).

Tiziana Masini (University of Groningen, The Netherlands) concluded the morning session with an oral communication on fragment-based design of inhibitors of the antituberculosic target 1-deoxy-D-xylulose-5-phosphate synthase exploiting an innovative combination of NMR techniques.

The final symposium session was chaired by Owen Wallace (Eli Lilly & Co., United Kingdom), who was fortunately able to step in for Alan Palkowitz, who at the very last moment had to cancel his attendance, and opened with a presentation by James P. Morken (Boston College, United States), on “New Strategies in Organic Synthesis: Recent Advances Based on Catalytic Reactions of Boron Reagents”, which focused on Pt-catalyzed diboration of a panel of unsaturated molecules including dienes, 1-alkenes, or imines, giving synthetic access to natural products,³³ or important building blocks such as alpha-amino-boronic acids, or benzhydryl amines.

Simona Cotesta (Novartis, Switzerland) gave a lecture on “Identification of a Novel Series of Orexin Receptor Antagonists with a Distinct Effect on Sleep Architecture”. Orexin A and B are two neuropeptides produced in discretely localized neurons in the hypothalamus, activating two G-protein coupled receptors Ox1R and Ox2R. The orexin system plays an important role in the regulation of the sleep–wake cycle, feeding and reward seeking. Starting with a computational analysis of published orexin receptor antagonists, two novel series of orexin receptor antagonists with distinct profiles were identified by scaffold morphing.³⁴ Optimization yielded an Ox2R-selective antagonist, which induced an increase in total sleep time without affecting sleep architecture (Fig. 10).


	Fig. 10 Novel orexin receptor antagonist with a distinct effect on sleep architecture (Novartis).

Paul Polakis (Genentech, United States) focused on recent progress in “Antibody Drug Conjugates (ADCs) for the Treatment of Cancer”. ADCs are antibodies coupled via linkers to small biologically active molecules, and offer the potential to selectively deliver to tumor cells highly toxic compounds while reducing damage to normal tissues. Cell surface proteins highly specific to cancer cells were first identified using oligonucleotide microarrays and high through-put analysis of mRNA transcripts isolated from thousands of human tissue samples. Antibodies to several of these targets were generated and highly potent tubulin disrupting agents were appended to them to generate ADCs for a variety of cancer indications. These antibodies can be selectively functionalized by introducing cysteines into solvent-accessible areas of the protein backbone, leading to increased efficacy and safety.³⁵ Trastuzumab-DM1, an antibody–maytansinoid conjugate (ado-trastuzumab emtansine, trademark Kadcyla), targeting HER2-positive breast cancer, has recently been approved and is safer and more effective than current treatments. Eight other ADCs are in various phases of human clinical testing at Genentech. Anti-Muc16vcMMAE, targeting the membrane glycoprotein Muc-16 with monomethyl auristatin E (MMAE), using a valine–citrulline (vc) dipeptide as part of the linker, shows promise as a therapeutic for advanced ovarian cancer.

Marc Taillefer (ENSCM, France) gave a talk on “Metal Catalyzed Arylation of Nucleophiles”, illustrating how efficiently N-, O-, C- or S-arylations of nucleophiles with aromatic halides can occur with high yields using original copper and/or iron-based catalytic systems. Mild reaction conditions, low cost and simplicity make these reactions particularly well suited for industrial scale syntheses where financial and environmental issues are of greater concern.³⁶

The closing lecture was delivered by Dieter Seebach (ETH Zurich, Switzerland) on his journey “From Organic Synthesis to Biomedical Sciences – from Polyhydroxybutyrate (PHB) to Cell-Penetrating Peptides”. In his group's study of unnatural β-peptides, it was discovered that they form much more stable secondary structures (helices, turns, strands, sheets) than the natural counterparts, and that they are stable to proteolytic and metabolizing enzymes.³⁷ They can be designed to mimic natural peptides and proteins in their activities, as illustrated for neurotensin, interleukin-8, or MHC-binding peptides. More recently, cell-penetrating L-α-, D-α-, mixed L/D-α- and β-oligo-arginines and -oligo-prolines were developed as carriers for delivering fluorescence labels and antibiotics into prokaryotic and eukaryotic cells. Finally, the screening of numerous biological samples from forests or fields, from compost or sewer plants led to the identification of a unique β-amino-acid peptidase aminase (BapA), which cleaves only N-terminal β-amino acids.

The symposium's scientific programme was closed by conferring two best poster prizes, awarded to Gaël Le Douaron (Université Paris-Sud, France) and Tina Seifert (University of Gothenburg, Sweden), and by the announcement of the next edition of the symposium, ASMC'15, which will be organized in 2015 in Kiev, Ukraine.

ASMC'13 was brought to a close with a gala dinner at Yar Restaurant.

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