Protein–protein interactions in bacteria: a promising and challenging avenue towards the discovery of new antibiotics

• Laura Carro

Beilstein J. Org. Chem. 2018, 14, 2881–2896, doi:10.3762/bjoc.14.267

• , PPIs, unlike the previous examples, do not have a small natural ligand which can be used as a lead in a standard drug development programme [15][16]. Despite the binding surfaces being large, it is well known that not all the amino acid residues at the interface contribute equally to the binding, but

• (SSB and sliding clamp), division (FtsZ) and transcription (NusB/NusE interaction). It is hoped that the knowledge acquired in both discovering and developing these inhibitors will lay the foundation for future antibacterial drug development pipelines. Given that the protein interactions systems

Drug targeting to decrease cardiotoxicity – determination of the cytotoxic effect of GnRH-based conjugates containing doxorubicin, daunorubicin and methotrexate on human cardiomyocytes and endothelial cells

• Livia Polgár,
• Eszter Lajkó,
• Pál Soós,
• Orsolya Láng,
• Marilena Manea,
• Béla Merkely,
• Gábor Mező and
• László Kőhidai

Beilstein J. Org. Chem. 2018, 14, 1583–1594, doi:10.3762/bjoc.14.136

• cardiomyocytes. The rate of cytotoxicity (antitumor effect) vs cardiotoxicity (toxic effects on cardiomyocytes and vascular endothelium) is an important factor for efficient drug development for targeted tumor therapy with minimized side effects. The technique used in this work – impedimetry – is a dedicated one

Design and biological characterization of novel cell-penetrating peptides preferentially targeting cell nuclei and subnuclear regions

• Anja Gronewold,
• Mareike Horn and
• Ines Neundorf

Beilstein J. Org. Chem. 2018, 14, 1378–1388, doi:10.3762/bjoc.14.116

• [4]. Selective inhibition of the ribosomal machinery has been shown to be an effective anticancer therapeutic strategy [5]. That is why selective drug transport to the nucleoli has emerged a potent new strategy in anticancer drug development [6][7]. Based on these homing domains, a substantial number

Oligonucleotide analogues with cationic backbone linkages

• Melissa Meng and
• Christian Ducho

Beilstein J. Org. Chem. 2018, 14, 1293–1308, doi:10.3762/bjoc.14.111

• biological mechanisms via sequence-specific molecular recognition makes them highly attractive candidates for drug development. However, their pharmacokinetic properties are problematic and represent a significant hurdle for their therapeutic application. First, the high polarity of ONs, mainly caused by

Hypervalent iodine-mediated Ritter-type amidation of terminal alkenes: The synthesis of isoxazoline and pyrazoline cores

• Sang Won Park,
• Soong-Hyun Kim,
• Jaeyoung Song,
• Ga Young Park,
• Darong Kim,
• Tae-Gyu Nam and
• Ki Bum Hong

Beilstein J. Org. Chem. 2018, 14, 1028–1033, doi:10.3762/bjoc.14.89

• Sang Won Park Soong-Hyun Kim Jaeyoung Song Ga Young Park Darong Kim Tae-Gyu Nam Ki Bum Hong Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do 15588, Republic of Korea New Drug Development Center (NDDC), Daegu-Gyeongbuk Medical

On the design principles of peptide–drug conjugates for targeted drug delivery to the malignant tumor site

• Eirinaios I. Vrettos,
• Gábor Mező and
• Andreas G. Tzakos

Beilstein J. Org. Chem. 2018, 14, 930–954, doi:10.3762/bjoc.14.80

• toxicity present in healthy tissues. It is estimated that about 30% of the clinical trials on ClinicalTrials.gov are related to cancer, while only 10% of them eventually gain market approval [3], rendering the drug development, especially in this therapeutic direction, costly and inefficient. Specifically

A stereoselective and flexible synthesis to access both enantiomers of N-acetylgalactosamine and peracetylated N-acetylidosamine

• Bettina Riedl and
• Walther Schmid

Beilstein J. Org. Chem. 2018, 14, 856–860, doi:10.3762/bjoc.14.71

• gastric tissues [8]. Furthermore, the TF-antigen region serves as the core region for the ABO and Lewis blood group determinants [9]. The high importance of GalNAc in diverse biological processes, together with its notable role in drug development, turns this compound into an interesting synthetic target

Fluorogenic PNA probes

• Tirayut Vilaivan

Beilstein J. Org. Chem. 2018, 14, 253–281, doi:10.3762/bjoc.14.17

• to specific biomolecular targets, including nucleic acids as well as non-nucleic acid targets, such as proteins and small molecules, have applications in various important areas. These include diagnostics, drug development and as tools for studying biomolecular interactions in situ and in real time

Aminomethylation/hydrogenolysis as an alternative to direct methylation of metalated isoquinolines – a novel total synthesis of the alkaloid 7-hydroxy-6-methoxy-1-methylisoquinoline

• Benedikt C. Melzer,
• Jan G. Felber and
• Franz Bracher

Beilstein J. Org. Chem. 2018, 14, 130–134, doi:10.3762/bjoc.14.8

• products and in drug development and hence, effective synthetic approaches are required. Here we present a novel method for the introduction of a methyl group at C1 of isoquinolines. This is exemplified by a new total synthesis of the alkaloid 7-hydroxy-6-methoxy-1-methylisoquinoline. Direct metalation of

• considerable relevance in drug development, since it is found in both complex [1] and “simple” alkaloids (variously substituted derivatives of the native isoquinoline) isolated from different plants [2], and antiviral and antimicrobial activities have been found for numerous isoquinoline alkaloids [3]. Further

Preparation of imidazo[1,2-a]-N-heterocyclic derivatives with gem-difluorinated side chains

• Layal Hariss,
• Kamal Bou Hadir,
• Mirvat El-Masri,
• Thierry Roisnel,
• René Grée and
• Ali Hachem

Beilstein J. Org. Chem. 2017, 13, 2115–2121, doi:10.3762/bjoc.13.208

• widely recognized as a general strategy toward drug development in pharmaceutical research. This is connected to fluorine's electronegativity, size, and lipophilicity [15][16], which can strongly improve the biological properties of molecules through, for instance, increase of metabolic stability and

Solid-state mechanochemical ω-functionalization of poly(ethylene glycol)

• Michael Y. Malca,
• Pierre-Olivier Ferko,
• Tomislav Friščić and
• Audrey Moores

Beilstein J. Org. Chem. 2017, 13, 1963–1968, doi:10.3762/bjoc.13.191

• manufacturing, drug development and nanotechnology. PEG derivatives are being increasingly used to covalently modify small molecule and peptide drugs, as well as bioactive nanomaterials in order to improve solubility in biological serum, reduce immunogenicity, and enhance pharmacokinetic profiles. Herein we

• , modification of bioactive substrates with PEG is well established in drug development, and is also becoming important in the purification of proteins and nucleic acids [1]. Since the first demonstration of PEGylated proteins with altered immunogenicity [2][3], PEG has been heavily investigated for affording

• because of their versatile applicability to covalent conjugation onto various substrates and metal-based nanomaterials. Results and Discussion For this study, we focused on the functionalization of mPEG, which allows the simple mono-functionalization of the polymer, for useful applications to drug

Synthesis of novel 13α-estrone derivatives by Sonogashira coupling as potential 17β-HSD1 inhibitors

• Ildikó Bacsa,
• Rebeka Jójárt,
• János Wölfling,
• Gyula Schneider,
• Bianka Edina Herman,
• Mihály Szécsi and
• Erzsébet Mernyák

Beilstein J. Org. Chem. 2017, 13, 1303–1309, doi:10.3762/bjoc.13.126

• compounds may provide promising candidates for drug development in order to get nanomolar inhibitors. Syntheses of 2- or 4-phenethynyl-13α-estrones (8–11) by Sonogashira coupling. Partial or full hydrogenation of compounds 8c–11c. 17β-HSD1 inhibition data of Sonogashira coupled compounds and their

Biomimetic molecular design tools that learn, evolve, and adapt

• David A Winkler

Beilstein J. Org. Chem. 2017, 13, 1288–1302, doi:10.3762/bjoc.13.125

• Adam and Eve that automate drug development via cycles of quantitative structure–activity relationship (QSAR) learning and biological testing (Figure 3) [16][17][18]. Eve’s selection of compounds was more cost efficient than standard drug screening, and the robotic scientist has identified several new

Aqueous semisynthesis of C-glycoside glycamines from agarose

• Juliana C. Cunico Dallagnol,
• Alexandre Orsato,
• Diogo R. B. Ducatti,
• Miguel D. Noseda,
• Maria Eugênia R. Duarte and
• Alan G. Gonçalves

Beilstein J. Org. Chem. 2017, 13, 1222–1229, doi:10.3762/bjoc.13.121

• available, these polysaccharides are far little explored as sources of chemical platforms for drug development. The rare monosaccharide 3,6-anhydro-α-L-galactopyranose (AnGal), naturally present in the agarose structure, is a valuable scaffold since it is a highly functionalized and a chiral-rich monomer

Biosynthetic origin of butyrolactol A, an antifungal polyketide produced by a marine-derived Streptomyces

• Enjuro Harunari,
• Hisayuki Komaki and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2017, 13, 441–450, doi:10.3762/bjoc.13.47

• /carbohydrate/nucleic acid derivatives [1][2]. One of the largest groups of bacterial secondary metabolites is polyketide from which a range of clinically used drugs have been developed. Polyketides still remain in the focus of drug development because of their structural complexity that can provide attractive

A chemoselective and continuous synthesis of m-sulfamoylbenzamide analogues

• Arno Verlee,
• Thomas Heugebaert,
• Tom van der Meer,
• Pavel I. Kerchev,
• Frank Van Breusegem and
• Christian V. Stevens

Beilstein J. Org. Chem. 2017, 13, 303–312, doi:10.3762/bjoc.13.33

• molecules are commonly used for their ability to regulate or assist in different biological processes. Typically, drug development starts with the screening of large libraries of relatively similar compounds, where only milligrams of material are needed for primary testing. Upon identification of a primary

Computational methods in drug discovery

• Sumudu P. Leelananda and
• Steffen Lindert

Beilstein J. Org. Chem. 2016, 12, 2694–2718, doi:10.3762/bjoc.12.267

• ; machine learning; pharmacophore; QSAR; SBDD; scoring; target flexibility; Introduction Bringing a pharmaceutical drug to the market is a long term process that costs billions of dollars. In 2014, the Tufts Center for the Study of Drug Development estimated that the cost associated with developing and

Enduracididine, a rare amino acid component of peptide antibiotics: Natural products and synthesis

• Darcy J. Atkinson,
• Briar J. Naysmith,
• Daniel P. Furkert and
• Margaret A. Brimble

Beilstein J. Org. Chem. 2016, 12, 2325–2342, doi:10.3762/bjoc.12.226

• synthetic routes to enduracididine. However, current syntheses are cumbersome and inefficient. A robust and scalable synthetic route to an orthogonally protected enduracididine derivative suitable for solid phase peptide synthesis would greatly facilitate antibiotic drug development focused on a teixobactin

Is conformation a fundamental descriptor in QSAR? A case for halogenated anesthetics

• Maria C. Guimarães,
• Mariene H. Duarte,
• Josué M. Silla and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2016, 12, 760–768, doi:10.3762/bjoc.12.76

• requirements for drug development. Multivariate Image Analysis applied to QSAR (MIA-QSAR) is a genuine 2D method, since descriptors are pixels of molecular projections drawn as black and white wireframes [10] and, more recently, as colored 2D-images (chemical structures) with spheres representing atoms with

From steroids to aqueous supramolecular chemistry: an autobiographical career review

• Bruce C. Gibb

Beilstein J. Org. Chem. 2016, 12, 684–701, doi:10.3762/bjoc.12.69

• the potential to save the pharmaceutical industry billions of dollars in drug development. Collaboration with my former colleague Steven Rick has provided considerable insight into the solvation of octa-acid. Briefly, this work showed that between 0–7 (~4.5 on average) water molecules can be found

Natural products from microbes associated with insects

• Christine Beemelmanns,
• Huijuan Guo,
• Maja Rischer and
• Michael Poulsen

Beilstein J. Org. Chem. 2016, 12, 314–327, doi:10.3762/bjoc.12.34

• synthetic compound libraries to counteract a declining number of new antibiotic entities in the drug development pipeline has largely failed [3], and the current poor repertoire represents a ”ticking time bomb”. Societies face, as a consequence of the rapid globalization and intensive use of antibiotics, an

Towards inhibitors of glycosyltransferases: A novel approach to the synthesis of 3-acetamido-3-deoxy-D-psicofuranose derivatives

• Maroš Bella,
• Miroslav Koóš and
• Chun-Hung Lin

Beilstein J. Org. Chem. 2015, 11, 1547–1552, doi:10.3762/bjoc.11.170

• are involved in these disease processes, inhibitors of GTs are of great therapeutic potential and attract remarkable interest for drug development. Although the mechanism of reactions catalyzed by glycosyltransferases has been investigated thoroughly, many aspects of the catalytic mechanism remain

Synthesis of alpha-tetrasubstituted triazoles by copper-catalyzed silyl deprotection/azide cycloaddition

• Zachary L. Palchak,
• Paula T. Nguyen and
• Catharine H. Larsen

Beilstein J. Org. Chem. 2015, 11, 1425–1433, doi:10.3762/bjoc.11.154

• ; copper catalysis; multicomponent reactions; tetrasubstituted carbon; triazole; Introduction 1,2,3-Triazoles demonstrate wide spread application in biological systems and drug development [1][2][3][4][5][6][7][8][9][10][11][12]. Copper-catalyzed azide–alkyne cycloadditions (CuAAC) regioselectively

Pd(OAc)₂-catalyzed dehydrogenative C–H activation: An expedient synthesis of uracil-annulated β-carbolinones

• Biplab Mondal,
• Somjit Hazra,
• Tarun K. Panda and
• Brindaban Roy

Beilstein J. Org. Chem. 2015, 11, 1360–1366, doi:10.3762/bjoc.11.146

• ]. For example, SL651498 was documented as a potential drug development candidate in a research program designed to discover subtype-selective GABAA receptor agonists for the treatment of muscle spasms and generalized anxiety disorder [13]. β-Carbolinones such as strychnocarpine, the alkaloid from

Chemoselective O-acylation of hydroxyamino acids and amino alcohols under acidic reaction conditions: History, scope and applications

• Tor E. Kristensen

Beilstein J. Org. Chem. 2015, 11, 446–468, doi:10.3762/bjoc.11.51

• recognized procedure for large-scale preparation of many useful side-chain derivatives of hydroxyamino acids and related compounds. Such derivatives are useful in peptide chemistry and drug development, as amino acid amphiphiles for asymmetric catalysis, and as amino acid acrylic precursors for preparation