Synthesis and biological evaluation of truncated derivatives of abyssomicin C as antibacterial agents

• Leticia Monjas,
• Peter Fodran,
• Johanna Kollback,
• Carlo Cassani,
• Thomas Olsson,
• Maja Genheden,
• D. G. Joakim Larsson and
• Carl-Johan Wallentin

Beilstein J. Org. Chem. 2019, 15, 1468–1474, doi:10.3762/bjoc.15.147

• structure–activity relationship studies towards novel antibiotics targeting 4-amino-4-deoxychorismate (ADC) synthase. Specifically, it is demonstrated that the synthetically challenging bicyclic motif is essential for activity towards methicillin-resistant Staphylococcus aureus (MRSA). Keywords

Steroid diversification by multicomponent reactions

• Leslie Reguera,
• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Daniel G. Rivera

Beilstein J. Org. Chem. 2019, 15, 1236–1256, doi:10.3762/bjoc.15.121

• targeting steroid-fused pyrimidines, Boruah’s group developed a solid-phase MCR between 2-hydroxymethylene-3-ketosteroids, aromatic aldehydes and ammonium acetate [46]. As shown in Scheme 15, the reaction was carried out with steroid 49 and different aldehydes to furnish the set of compounds 50 in good to

A chemically contiguous hapten approach for a heroin–fentanyl vaccine

• Yoshihiro Natori,
• Candy S. Hwang,
• Lucy Lin,
• Lauren C. Smith,
• Bin Zhou and
• Kim D. Janda

Beilstein J. Org. Chem. 2019, 15, 1020–1031, doi:10.3762/bjoc.15.100

• respiratory depression. Indeed, anti-drug vaccines for individual conjugate vaccines of fentanyl and heroin have already exhibited protection in several animal models [3][4][5][6][7][8]. Antidrug vaccines targeting multiple, structurally distinct species are not common and have utilized two tactics: 1) mixing

Mechanistic investigations on multiproduct β-himachalene synthase from Cryptosporangium arvum

• Jan Rinkel and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2019, 15, 1008–1019, doi:10.3762/bjoc.15.99

• into (E)-β-farnesene (19, I = 1460 (HP-5MS), Lit: I = 1459 (HP-5MS) [42]). The same outcome regarding the formation of (Z)-γ-bisabolene from (R)-NPP and FPP, but of 19 from (S)-NPP was recently also observed for BbS [13]. Targeting the stereochemical course of the 1,11-cyclisation of (R)-NPP to cation

• with (E)- and (Z)-(4-13C,4-2H)IPP, DMAPP, FPPS and HcS targeting the positions C-3 and C-7 (Figure S11, Supporting Information File 1), using published NMR data for 7 [44]. The stereochemical fate for the hydrogens at C-1 was then targeted by the incubation of (1R)- and (1S)-(1-13C,1-2H)FPP [28] with

New terpenoids from the fermentation broth of the edible mushroom Cyclocybe aegerita

• Frank Surup,
• Florian Hennicke,
• Nadine Sella,
• Maria Stroot,
• Steffen Bernecker,
• Sebastian Pfütze,
• Marc Stadler and
• Martin Rühl

Beilstein J. Org. Chem. 2019, 15, 1000–1007, doi:10.3762/bjoc.15.98

• strains, targeting both volatile and non-volatile compounds. The present paper will describe the discovery of one known and three new non-volatile terpenoids (Figure 1) that were isolated from liquid cultures of C. aegerita and their physicochemical and preliminary biological characterisation. Results and

Azologization of serotonin 5-HT₃ receptor antagonists

• Karin Rustler,
• Galyna Maleeva,
• Piotr Bregestovski and
• Burkhard König

Beilstein J. Org. Chem. 2019, 15, 780–788, doi:10.3762/bjoc.15.74

• 1990s, the range of highly selective and potent drugs expanded based on various chemical structures. Nevertheless, on-off-targeting of a pharmacophore’s activity with high spatiotemporal resolution as provided by photopharmacology remains an unsolved challenge bearing additionally the opportunity for

• release [21][22]. Besides targeting of 5-HT3Rs for the treatment of psychiatric disorders, they are object to counteract postoperative nausea and chemo-/radiotherapy provoked emesis [26][27][28][29]. In the early 1990s, the first potent and selective 5-HT3 receptor antagonist ondansetron was initially

Homo- and hetero-difunctionalized β-cyclodextrins: Short direct synthesis in gram scale and analysis of regiochemistry

• Gábor Benkovics,
• Mihály Bálint,
• Éva Fenyvesi,
• Erzsébet Varga,
• Szabolcs Béni,
• Konstantina Yannakopoulou and
• Milo Malanga

Beilstein J. Org. Chem. 2019, 15, 710–720, doi:10.3762/bjoc.15.66

• drug carriers, incorporating two different groups, for example a targeting unit and a prodrug, pseudoenantiomeric purity is not required, but the side-selective substitution has to be ensured. This has led us to develop a versatile and simple synthetic route towards difunctionalized β-CD, carrying non

• high selectivity towards the primary rim in monosubstitution of β-CD [22][23]. Our assumption was that targeting the disubstituted product with the same tosylating agent would preserve the side-selectivity and significantly reduce the number of possible regioisomers (6A,6B-, 6A,6C- and 6A,6D-ditosyl-β

Design of indole- and MCR-based macrocycles as p53-MDM2 antagonists

• Constantinos G. Neochoritis,
• Maryam Kazemi Miraki,
• Eman M. M. Abdelraheem,
• Ewa Surmiak,
• Tryfon Zarganes-Tzitzikas,
• Beata Łabuzek,
• Tad A. Holak and
• Alexander Dömling

Beilstein J. Org. Chem. 2019, 15, 513–520, doi:10.3762/bjoc.15.45

• ]. Herein, an indole-based macrocycle synthesis is reported in a one-pot fashion based on Ugi macrocyclization with readily available α,ω-amino acids. Moreover, in continuation of our efforts in the design and synthesis of macrocycles targeting the p53–MDM2 interaction demonstrating the potential of these

• postgenomic targets as it was demonstrated with the p53-MDM2 interaction. (A) Modeling of the macrocycle 2h (cyan sticks) and 2n (magenta sticks) into the MDM2 receptor (PDB ID: 1YCR); (B) 2D structure of 2h with the substituents targeting the subpockets of MDM2; (C) Analysis of the synthesized macrocycles

Olefin metathesis in multiblock copolymer synthesis

• Maria L. Gringolts,
• Yulia I. Denisova,
• Eugene Sh. Finkelshtein and
• Yaroslav V. Kudryavtsev

Beilstein J. Org. Chem. 2019, 15, 218–235, doi:10.3762/bjoc.15.21

• , IBI, and SIBIS multiblock copolymers, which include glassy, rubbery, and semicrystalline polymer segments and demonstrate peculiar mechanical behavior [57][58]. References [59] and [60] report on the preparation of fluorescent polymer nanoparticles for bioimaging and in vivo targeting of tumors and

• bioimaging and in vivo tumor targeting [60]. The multiblock copolymer capable of post-functionalization [76]. Multiblock copolymers synthesized by macromolecular cross metathesis. Changes in the DSC thermograms during MCM of PBD and polyesters (left) [84] and PNB–PCOE (right) mediated by Gr1 catalyst [89

Synthesis of a tubugi-1-toxin conjugate by a modulizable disulfide linker system with a neuropeptide Y analogue showing selectivity for hY1R-overexpressing tumor cells

• Rainer Kufka,
• Robert Rennert,
• Goran N. Kaluđerović,
• Lutz Weber,
• Wolfgang Richter and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2019, 15, 96–105, doi:10.3762/bjoc.15.11

• Pharmaceuticals GmbH, Leberstr. 20, A-1110 Vienna, Austria 10.3762/bjoc.15.11 Abstract Tubugi-1 is a small cytotoxic peptide with picomolar cytotoxicity. To improve its cancer cell targeting, it was conjugated using a universal, modular disulfide derivative. This allowed conjugation to a neuropeptide-Y (NPY

• )-inspired peptide [K4(C-βA-),F7,L17,P34]-hNPY, acting as NPY Y1 receptor (hY1R)-targeting peptide, to form a tubugi-1–SS–NPY disulfide-linked conjugate. The cytotoxic impacts of the novel tubugi-1–NPY peptide–toxin conjugate, as well as of free tubugi-1, and tubugi-1 bearing the thiol spacer (liberated from

• triple-negative breast cancer MDA-MB-468 cells. Keywords: drug targeting; neuropeptide Y; PDC; peptide–drug conjugate; targeted tumor therapy; tubugi; tubulysin A; Ugi reaction; Introduction Until recently, the medication of tumor diseases was primarily based on more or less unspecific

Repurposing the anticancer drug cisplatin with the aim of developing novel Pseudomonas aeruginosa infection control agents

• Mingjun Yuan,
• Song Lin Chua,
• Yang Liu,
• Daniela I. Drautz-Moses,
• Joey Kuok Hoong Yam,
• Thet Tun Aung,
• Roger W. Beuerman,
• May Margarette Santillan Salido,
• Stephan C. Schuster,
• Choon-Hong Tan,
• Michael Givskov,
• Liang Yang and
• Thomas E. Nielsen

Beilstein J. Org. Chem. 2018, 14, 3059–3069, doi:10.3762/bjoc.14.284

• targeting important components of the immune system, such as the type III secretion systems (T3SS), which was shown to be associated with poor clinic outcomes in patients with lower respiratory infections [8] and ventilator-associated pneumonia [9]. Identifying antimicrobial compounds which actively target

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

• reducing the burden of multidrug-resistant microorganisms. Protein–protein interactions (PPIs) are involved in a myriad of vital cellular processes and have become an attractive target to treat diseases. Therefore, targeting PPI networks in bacteria may offer a new and unconventional point of intervention

• in fact there are focal points (i.e., hot spots or hot segments) that contribute to the majority of the binding energy [17][18]. Targeting these “druggable” sites can therefore be used for the rational design of new therapeutic compounds that can disrupt those critical interactions. However, their

• ]. Similarly to the aforementioned sliding clamp, the structural arrangement of most bacterial SSBs differs significantly to its homolog in eukaryotic cells (replication protein A, RPA) [74]. This dissimilarity could be beneficial from a drug discovery perspective because it would enable selective targeting of

Synthesis of pyrrolidine-based hamamelitannin analogues as quorum sensing inhibitors in Staphylococcus aureus

• Jakob Bouton,
• Kristof Van Hecke,
• Reuven Rasooly and
• Serge Van Calenbergh

Beilstein J. Org. Chem. 2018, 14, 2822–2828, doi:10.3762/bjoc.14.260

• resistance problem need to be multifactorial. Next to disease prevention and the development of new antibiotics, it is essential to investigate innovative strategies to combat bacterial infections [3][4]. Recently, targeting bacterial virulence has gained a lot of attention [5][6][7]. It has been

Synthesis of α-D-GalpN₃-(1-3)-D-GalpN₃: α- and 3-O-selectivity using 3,4-diol acceptors

• Emil Glibstrup and
• Christian Marcus Pedersen

Beilstein J. Org. Chem. 2018, 14, 2805–2811, doi:10.3762/bjoc.14.258

• nucleophilicity and accessibility of the axial 4-OH versus the equatorial 3-OH [40], we wondered, if this could be used to simplify the synthesis of the α-D-GalpN3-(1-3)-D-GalpN3 unit. When consulting the literature, surprisingly few reports were describing diol glycosylations targeting the galacto-configured

Novel solid-phase strategy for the synthesis of ligand-targeted fluorescent-labelled chelating peptide conjugates as a theranostic tool for cancer

• Sagnik Sengupta,
• Mena Asha Krishnan,
• Premansh Dudhe,
• Ramesh B. Reddy,
• Bishnubasu Giri,
• Sudeshna Chattopadhyay and
• Venkatesh Chelvam

Beilstein J. Org. Chem. 2018, 14, 2665–2679, doi:10.3762/bjoc.14.244

• successfully designed and demonstrated a novel continuous process for assembling targeting ligands, peptidic spacers, fluorescent tags and a chelating core for the attachment of cytotoxic molecules, radiotracers, nanomaterials in a standard Fmoc solid-phase peptide synthesis in high yield and purity. The

• groups such as Trt (chlorotrityl), Mtt (4-methyltrityl), Mmt (4-methoxytrityl) are employed to synthesise the ligand targeted fluorescent tagged bioconjugates. Using this methodology, DUPA rhodamine B conjugate (DUPA = 2-[3-(1,3-dicarboxypropyl)ureido]pentanedioic acid), targeting prostate specific

• membrane antigen (PSMA) expressed on prostate, breast, bladder and brain cancers and pteroate rhodamine B, targeting folate receptor positive cancers such as ovarian, lung, endometrium as well as inflammatory diseases have been synthesized. In vitro studies using LNCaP (PSMA +ve), PC-3 (PSMA −ve, FR −ve

Non-native autoinducer analogs capable of modulating the SdiA quorum sensing receptor in Salmonella enterica serovar Typhimurium

• Matthew J. Styles and
• Helen E. Blackwell

Beilstein J. Org. Chem. 2018, 14, 2651–2664, doi:10.3762/bjoc.14.243

• compounds represent new chemical tools for exploring the role of SdiA and QS in S. Typhimurium infections, for characterizing the mechanisms by which non-native AHLs interact with LuxR-type proteins, and for developing pathways toward novel antivirulence strategies targeting SdiA. Results and Discussion

• a small decrease in maximal activity to 80% (Figure 5B). These results support the conclusion that R8 inhibits SdiA activity by targeting SdiA directly. Itc-derivative 11 showed both competitive and non-competitive inhibition of OOHL (2) in the competition assay (Figure 5C): the EC50 increased from

The design and synthesis of an antibacterial phenothiazine–siderophore conjugate

• Abed Tarapdar,
• James K. S. Norris,
• Oliver Sampson,
• Galina Mukamolova and
• James T. Hodgkinson

Beilstein J. Org. Chem. 2018, 14, 2646–2650, doi:10.3762/bjoc.14.242

• achieved with beta-lactam-based siderophore conjugates targeting membrane associated penicillin binding proteins (PBPs) [7]. Cefiderocol (S-649266) is a beta-lactam–siderophore conjugate currently in phase III clinical trials which demonstrates enhanced potency against Gram-negative bacteria including

• multidrug resistant (MDR) Gram-negative pathogens [8]. One hypothesis for the success of siderophore conjugates targeting PBPs, in comparison to other antibiotic targets, is that PBPs are membrane associated and it is not necessary for the siderophore conjugate to cross into the bacterial cytoplasm [7

Targeting the Pseudomonas quinolone signal quorum sensing system for the discovery of novel anti-infective pathoblockers

• Christian Schütz and
• Martin Empting

Beilstein J. Org. Chem. 2018, 14, 2627–2645, doi:10.3762/bjoc.14.241

• been published based on the design and optimisation of pqs targeting QSI, which is the topic of this review. The biosynthetic cascade of the pqs QS system PQS is the abbreviation for Pseudomonas quinolone signal and actually refers to the signal molecule 2-heptyl-3-hydroxyquinolin-4(1H)-one (Figure 2

• cells in biofilms with anaerobic conditions [44]. Due to these important virulence mechanisms, which are under direct or indirect control of pqs QS, targeting this master regulatory system with small molecular compounds, thereby blocking P. aeruginosa pathogenicity, is very attractive. However, this

• attachment of a cell-penetrating peptide sequence [58]. One additional class, which did show cellular activity, was based on a catechol scaffold [59]. In analogy to the successful discovery of PqsD inhibitors starting from known FabH-targeting compounds (vide supra), ligands of another enzyme with high

Pathoblockers or antivirulence drugs as a new option for the treatment of bacterial infections

• Matthew B. Calvert,
• Varsha R. Jumde and
• Alexander Titz

Beilstein J. Org. Chem. 2018, 14, 2607–2617, doi:10.3762/bjoc.14.239

• current trends continue. To avoid this scenario, new classes of anti-infectives must urgently be developed. Antibiotics with new modes of action are needed, but other concepts are also currently being pursued. Targeting bacterial virulence as a means of blocking pathogenicity is a promising new strategy

• pioneering review by Clatworthy et al. in 2007, entitled ‘Targeting virulence: a new paradigm for antimicrobial therapy’ [8], which has been cited approximately 800 times. In sharp contrast to traditional antibiotics that kill or impair bacterial viability, this new approach aims to disarm the pathogen

• the aryl substitution resulted in a flat SAR with only little variation in potency among the substituents analyzed [30][36][37][38][39]. Just recently, in an attempt to search for new pharmacophores, Titz et al. have reported the synthesis of the epoxyheptose derivative 11 targeting a cysteine residue

Comparative cell biological study of in vitro antitumor and antimetastatic activity on melanoma cells of GnRH-III-containing conjugates modified with short-chain fatty acids

• Eszter Lajkó,
• Sarah Spring,
• Rózsa Hegedüs,
• Beáta Biri-Kovács,
• Sven Ingebrandt,
• Gábor Mező and
• László Kőhidai

Beilstein J. Org. Chem. 2018, 14, 2495–2509, doi:10.3762/bjoc.14.226

• -targeting by application of a GnRH analog as a carrier to deliver a covalently linked chemotherapeutic drug directly to the tumor cells. In this study our aim was (i) to analyze the effects of GnRH-drug conjugates on melanoma cell proliferation, adhesion and migration, (ii) to study the mechanisms of tumor

• cancer cell behavior and effects of targeted chemotherapeutics with small structural differences (e.g., length of the side chain in 4Lys) was also clearly suggested. Keywords: drug-targeting conjugates; gonadotropin-releasing hormone-III; holographic microscopy; impedimetry; short-chain fatty acids

• approaches to diminish this kind of cytotoxic effects on healthy tissues is the employment of drug delivery systems directed specifically to cancer cells. The chemotherapeutic drug targeting is often based on the receptors for certain peptide hormones that are preferentially expressed by cancer cells. The

Synthesis and photophysical studies of a multivalent photoreactive Ru^II-calix[4]arene complex bearing RGD-containing cyclopentapeptides

• Sofia Kajouj,
• Lionel Marcelis,
• Alice Mattiuzzi,
• Adrien Grassin,
• Damien Dufour,
• Pierre Van Antwerpen,
• Didier Boturyn,
• Eric Defrancq,
• Mathieu Surin,
• Julien De Winter,
• Pascal Gerbaux,
• Ivan Jabin and
• Cécile Moucheron

Beilstein J. Org. Chem. 2018, 14, 1758–1768, doi:10.3762/bjoc.14.150

• is also faced by complexes anchored on cell-penetrating peptides. In order to provide a selective cell targeting, we developed a multivalent system composed of a photoreactive ruthenium(II) complex tethered to a calix[4]arene platform bearing multiple RGD-containing cyclopentapeptides. Extensive

• , once incorporated into targeted cancer cells thanks to the multivalent platform. Keywords: anticancer drug; calixarene; cell targeting; RGD peptide; ruthenium complex; Introduction Long-living luminescent polyazaaromatic ruthenium(II) complexes are intensively studied in a biological context, in

• of the complex [38]. It should be noted that modifications of ligands to make the resulting complexes more lipophilic or the conjugation of a complex to a CPP do not provide any control on the way these complexes will be internalized by cells and prevent thus any targeting of malignant cells over

Natural and redesigned wasp venom peptides with selective antitumoral activity

• Marcelo D. T. Torres,
• Gislaine P. Andrade,
• Roseli H. Sato,
• Cibele N. Pedron,
• Tania M. Manieri,
• Giselle Cerchiaro,
• Anderson O. Ribeiro,
• Cesar de la Fuente-Nunez and
• Vani X. Oliveira Jr.

Beilstein J. Org. Chem. 2018, 14, 1693–1703, doi:10.3762/bjoc.14.144

• low as 12.5 μmol L−1 for the selective targeting of MCF-7 breast cancer cells. Flow cytometry assays further revealed that treatment with wild-type (WT) peptide Dec-NH2 led to necrosis of MCF-7 cells. Additional atomic force microscopy (AFM) measurements indicated that the roughness of cancer cell

• therapies because of their potential for selectively targeting cancer cells without harm to normal counterparts [37][38][39]. Membrane phospholipids confer permeability to the cell and regulate the flux of metabolites between the extracellular environment and the intracellular content [40]. The membrane of

• cancer cells is typically negatively charged due to a higher expression of anionic molecules such as phosphatidylserines, and negatively charged glycoproteins and glycosaminoglycans [22][23]. Here, we devised a strategy to exploit the negatively charged environment of cancer cells by targeting it with

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

• Chemistry, Pázmány P. stny 1/A, Hungarian Academy of Science, Budapest, 1117, Hungary 10.3762/bjoc.14.136 Abstract Background: Cardiomyopathy induced by the chemotherapeutic agents doxorubicin and daunorubicin is a major limiting factor for their application in cancer therapy. Chemotactic drug targeting

• : cardiotoxicity; drug targeting; GnRH-conjugates; HCM; HUVEC; impedimetry; Introduction Gonadotropin-releasing hormone (GnRH) is a peptide hormone secreted by the hypothalamus, which stimulates the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary. Thus, it represents

• . Small peptides that recognize target receptors on tumor cells might be suitable targeting moieties for this purpose. Hormone peptides, in particular, GnRH and somatostatin derivatives that possess antiproliferative effect on their own, are among the best candidates as homing peptides [10]. A.V. Schally

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

• ) with selective suborganelle-targeting properties. The nuclear localization sequence N50, as well as the nucleoli-targeting sequence NrTP, respectively, were fused to a shortened version of the cell-penetrating peptide sC18. We examined cellular uptake, subcellular fate and cytotoxicity of these novel

• excluded. However, initial drug delivery studies demonstrated the high versatility of these new peptides as efficient transport vectors targeting specifically nuclei and nucleoli. In future, they could be further explored as parts of newly created peptide–drug conjugates. Keywords: anticancer drugs; cell

• nuclei; cell-penetrating peptides; nucleoli; subcellular targeting; Introduction Various drugs act on targets that are located within the nucleus, the control center of the eukaryotic cell. A lipid bilayer membrane, which is perforated with nuclear pore complex structures through which the transfer of

Acyl-group specificity of AHL synthases involved in quorum-sensing in Roseobacter group bacteria

• Lisa Ziesche,
• Jan Rinkel,
• Jeroen S. Dickschat and
• Stefan Schulz

Beilstein J. Org. Chem. 2018, 14, 1309–1316, doi:10.3762/bjoc.14.112

• enzyme PgaI2 from P. inhibens, competition experiments were performed. Targeting the optimal chain length of the fully saturated substrates first, a mixture with equal molar concentrations of the substrates 10a–h was offered to the recombinant protein. GC/MS analysis of the resulting extract (Figure 2A