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

• positive correlation in the heroin group and this correlation improved by week 8. Because there was no relationship between antibody affinity for 6-AM and in vivo efficacy, it is tempting to conclude that the quantity of antibody is more important for protection against a heroin challenge. However, the

Heck- and Suzuki-coupling approaches to novel hydroquinone inhibitors of calcium ATPase

• Robert J. Kempton,
• Taylor A. Kidd-Kautz,
• Soizic Laurenceau and
• Stefan Paula

Beilstein J. Org. Chem. 2019, 15, 971–975, doi:10.3762/bjoc.15.94

• -methylcyclopentyl) analogue of BHQ 3 has an IC50 value of 500 nM, which is comparable to BHQ’s value of 400 nM. Having available tethered SERCA inhibitors that are not based on the structure of TG could be beneficial for future in vivo trials because of the greater flexibility afforded by the structurally less

Photochemical generation of the 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) radical from caged nitroxides by near-infrared two-photon irradiation and its cytocidal effect on lung cancer cells

• Ayato Yamada,
• Manabu Abe,
• Yoshinobu Nishimura,
• Shoji Ishizaka,
• Masashi Namba,
• Taku Nakashima,
• Kiyofumi Shimoji and
• Noboru Hattori

Beilstein J. Org. Chem. 2019, 15, 863–873, doi:10.3762/bjoc.15.84

• 2a induced cancer cell death in vitro, although no in vivo study was performed because of the low water solubility of 2a. At this point, we cannot rule out generate of ROS by photosensitization of the chromophore in the presence of O2 for the cytotoxicity. Conclusion In the present study, novel caged

Design and synthesis of multivalent α-1,2-trimannose-linked bioerodible microparticles for applications in immune response studies of Leishmania major infection

• Chelsea L. Rintelmann,
• Tara Grinnage-Pulley,
• Kathleen Ross,
• Daniel E. K. Kabotso,
• Angela Toepp,
• Anne Cowell,
• Christine Petersen,
• Balaji Narasimhan and
• Nicola Pohl

Beilstein J. Org. Chem. 2019, 15, 623–632, doi:10.3762/bjoc.15.58

• ]. Cutaneous, the most common form, causes severe nodular and ulcerative skin lesions, while mucocutaneous destroys mucus membranes, and the most deadly form, visceral leishmaniasis, often results in organ failure [6]. L. major, the parasite used in our in vivo model, causes the cutaneous disease. In each

• investigated how truncated oligosaccharide capping structures of LPG interact with macrophage pattern recognition receptors (PRRs) to modulate an innate immune response to L. major-induced leishmaniasis in vitro and in vivo [11][40][41][42]. These studies showed that a neutral α-1,2-trimannose capping

• deprotected trimannose 16 to the dendrimeric core 25 provided the glycodendrimer 26. For the attachment of the glycodendrimer to the microparticle surface, the amino Fmoc was removed then coupled via EDCI/NHS to afford the desired bioerodible glycodendrimer microparticle 2. In vivo assessment of bioerodible

Cyclopropene derivatives of aminosugars for metabolic glycoengineering

• Jessica Hassenrück and
• Valentin Wittmann

Beilstein J. Org. Chem. 2019, 15, 584–601, doi:10.3762/bjoc.15.54

• Diels–Alder reaction; metabolic engineering; Introduction Carbohydrates are an important class of biological molecules involved in many fundamental biological processes [1]. An important tool to visualize glycoconjugates in vitro and in vivo is metabolic glycoengineering (MGE) [2][3][4]. In this

Synthesis of the polyketide section of seragamide A and related cyclodepsipeptides via Negishi cross coupling

• Jan Hendrik Lang and
• Thomas Lindel

Beilstein J. Org. Chem. 2019, 15, 577–583, doi:10.3762/bjoc.15.53

• A (1, Scheme 1) [1][2], is an ideal situation for the validation of the chemoselectivity and efficiency of photoaffinity labelling. Recently, it has been determined by cryo-electron microscopy how jasplakinolide A (1) binds to F-actin and alters the actin skeleton in vivo, resulting in pronounced

Synthesis and biological investigation of (+)-3-hydroxymethylartemisinin

• Toni Smeilus,
• Farnoush Mousavizadeh,
• Johannes Krieger,
• Xingzhao Tu,
• Marcel Kaiser and
• Athanassios Giannis

Beilstein J. Org. Chem. 2019, 15, 567–570, doi:10.3762/bjoc.15.51

• [8][9][10]. Recently, it was shown that artemisinin interacts with the mammalian protein gephyrin and by stabilizing it, it enhances GABAA receptor signaling resulting in in vivo conversion of pancreatic α-cells into functional β-like cells [11]. Therefore, this sesquiterpene lactone may also find an

Back to the future: Why we need enzymology to build a synthetic metabolism of the future

• Tobias J. Erb

Beilstein J. Org. Chem. 2019, 15, 551–557, doi:10.3762/bjoc.15.49

• , multiple level 3 and level 4 routes for the transformation of the one-carbon compound formate into cellular building blocks were designed that should theoretically outcompete natural formate assimilation pathways [18][19]. Some of the level 3 pathways were recently reconstructed in vivo [20][21][22][23

Aqueous olefin metathesis: recent developments and applications

• Valerio Sabatino and
• Thomas R. Ward

Beilstein J. Org. Chem. 2019, 15, 445–468, doi:10.3762/bjoc.15.39

• , yielding 85% of product 22 (Table 5). A substitution of lysine with histidine at position 198 (Table 5, entries 8 and 9) did not improve the catalytic efficiency of ArM 2 at pH 7.0. Jeschek et al. subsequently evolved ArM 1 in vivo by directed evolution of an artificial metathase [68]. Tethering an OmpA

• and co-workers led to several biological applications [79][80]. Kiessling and co-workers were the first to use ROMP for the synthesis of biologically active polymers and for the synthesis of multivalent antigens to probe signaling pathways in vivo [81][82]. In 2008, Davis and co-workers performed site

• tags. c) PEG-tethered catalysts. Chemical structure and components of amphiphilic molecule PTS and derivatives. In vivo metathesis with an artificial metalloenzyme based on the biotin–streptavidin technology. Most common metathesis reactions. Ring-opening metathesis polymerization (ROMP), acyclic diene

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

• the nanoparticles were formed by a ABCBA pentablock copolymer. In this polymer A stands for hydrophilic oligo(ethylene glycol) (OEG)-grafted polynorbornene possessing stealth-like and antifouling properties that are useful for in vivo applications. The B block is formed by polynorbornene

• 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

Systematic synthetic study of four diastereomerically distinct limonene-1,2-diols and their corresponding cyclic carbonates

• Hiroshi Morikawa,
• Jun-ichi Yamaguchi,
• Shun-ichi Sugimura,
• Masato Minamoto,
• Yuuta Gorou,
• Hisatoyo Morinaga and
• Suguru Motokucho

Beilstein J. Org. Chem. 2019, 15, 130–136, doi:10.3762/bjoc.15.13

• is detected as metabolite in vivo in biochemistry [15], and is known to react in the atmosphere to afford the secondary organic aerosol as air pollutants [16]. Among the four diastereomers of LMdiols (Figure 2), 2b and 2c have already been reported [14][17][18][19][20]. Conversely, the distinct

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

• treatment of, for instance, cancer cells: (1) a sufficient in vivo half-life, ideally hours to days, to reach the diseased cells with a high portion of intact PDC; (2) a selective conjugate binding to a specific target molecule, e.g., a cell-surface receptor, that is characteristic for the diseased cells

• been published, whereby the peptide moiety always is based on [F7,P34]-pNPY [32][39][40]. However, so far none of these [F7,P34]-pNPY-based conjugates proved a convincing in vivo efficacy. To further improve the general setting of peptide–drug conjugates, major efforts have been made to enhance target

• occur in vivo in case of untargeted applications. For that reason, feasible therapeutic windows of this class of toxins are only realistic if the toxins are applied as ‘detoxified’ prodrugs, e.g., in the form of peptide–toxin conjugates, whereby the effect of tubulysin or tubugi, respectively, is

Lectins of Mycobacterium tuberculosis – rarely studied proteins

• Katharina Kolbe,
• Sri Kumar Veleti,
• Norbert Reiling and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2019, 15, 1–15, doi:10.3762/bjoc.15.1

• indeed shown that alveolar type II pneumocytes can also become infected with Mtb bacteria in vitro and in vivo [13][14][15][16][17]. Furthermore, dendritic cells and neutrophils internalize Mtb bacteria and are important key players in the immune response against this pathogen [18][19][20]. Bacterial

• following successful antituberculosis therapy [80]. The results underline that mycobacterial lectins are expressed in vivo and might be important for Mtb infections. Furthermore, anti-sMTL-13 antibodies could serve as a biomarker of disease treatment progression. The exact function of sMTL-13 and its ligand

• showed reduced dissemination to other regions of the body relative to wild type, suggesting that HBHA plays an important role in extrapulmonary spread [84]. It has also been shown that antibodies directed against HBHA can limit adhesion of mycobacteria to epithelial cells in vitro and in vivo [80][83

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

• the secretion of exotoxins. Furthermore, cisplatin was also demonstrated to eradicate in vitro biofilms and in vivo biofilms in a murine keratitis model. This showed that cisplatin could be effectively used to eradicate biofilm infections which were otherwise difficult to be treated by conventional

• were shown for in vivo biofilms. Student’s t-test was performed for testing differences between groups. *P < 0.01. Supporting Information Supporting Information File 500: Additional information. Disclosure of Financial and Competing Interests This research is supported by the National Research

• useful strategy for eradicating persistent biofilm-associated infections. Cisplatin treatment attenuates P. aeruginosa infection As cisplatin could reduce the synthesis of T3SS-mediated virulent products and kill biofilms of P. aeruginosa, we further tested if cisplatin treatment was able to eradicate in

Olefin metathesis catalysts embedded in β-barrel proteins: creating artificial metalloproteins for olefin metathesis

• Daniel F. Sauer,
• Johannes Schiffels,
• Takashi Hayashi,
• Ulrich Schwaneberg and
• Jun Okuda

Beilstein J. Org. Chem. 2018, 14, 2861–2871, doi:10.3762/bjoc.14.265

• and challenges and opportunities in this emerging field are shown from simple small-molecule transformations over ring-opening metathesis polymerizations to in vivo olefin metathesis. Keywords: artificial metalloprotein; β-barrel protein; metathease; olefin metathesis; ruthenium; Introduction Olefin

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

• ), an inhibitor of the RAP/TRAP (RNAIII-activating protein/target of RAP) quorum sensing system in S. aureus (Figure 1) [12][13][14]. Furthermore, hamamelitannin has been shown to inhibit biofilm formation and to potentiate the activity of antibiotics against staphylococcal biofilms in vitro and in vivo

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

• , the potency of such phenothiazines, including 1, needs to be significantly increased to have more activity in vivo and direct clinical application [11]. A validated target of 1 has been identified as type II NADH dehydrogenase (NDH-2), a respiratory enzyme essential for growth in M. tuberculosis and

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

• with G302 could be observed. Various halogenated derivatives of AA could also reduce HHQ and PQS levels. Especially 4- and 6-CABA (3, 4) showed promising results in the suppression of signal molecules as well as in an in vivo mouse survival model at a concentration of 1.5 mM [47]. Anthraniloyl-AMP

• mutation experiments [79]. Moreover an in vivo cross-linking assay of full-length PqsR and a corresponding I68F mutant was carried out leading to the suggestion that upon binding of M64 the protein stability might be increased. Based on these results it was proposed that M64 induces a change in

• using PA14, target engagement was demonstrated in vivo measuring PQS and HHQ levels from the corresponding tissues after treatment. Compound 45 was able to reduce PQS and HHQ levels to 50% and 40%, respectively, 12 hours post-infection. Up to now no further optimization or development of these compounds

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

• adhesion in mice [18][19]. These compounds have been extensively optimized in many works published by both groups, culminating in the identification of mannophosphates as prodrugs to increase oral bioavailability [20] and mannose C-glycosides, such as compound 6 , demonstrating enhanced in vivo metabolic

• ] which are also important for mediating bacterial virulence in vivo [33]. Therefore, both LecA and LecB have served as targets for pathoblocker development [22][23][30][34][35]. As a result of the comparatively low affinity of both lectins towards their natural carbohydrate ligands (α-galactosides for

• inhalative administration [46]. Despite its LecB-mediated in vivo activity, this compound had no effect on biofilms in vitro at concentrations up to 2000-fold above the Kd; a biofilm reduction by 80% could be achieved at concentrations as high as 100000-fold above Kd (5 mM). For a future systemic application

Learning from B₁₂ enzymes: biomimetic and bioinspired catalysts for eco-friendly organic synthesis

• Keishiro Tahara,
• Ling Pan,
• Toshikazu Ono and
• Yoshio Hisaeda

Beilstein J. Org. Chem. 2018, 14, 2553–2567, doi:10.3762/bjoc.14.232

• 10.3762/bjoc.14.232 Abstract Cobalamins (B12) play various important roles in vivo. Most B12-dependent enzymes are divided into three main subfamilies: adenosylcobalamin-dependent isomerases, methylcobalamin-dependent methyltransferases, and dehalogenases. Mimicking these B12 enzyme functions under non

• Cobalamins (B12) are naturally occurring cobalt complexes with unique structures that play various important roles in vivo [1][2][3][4][5]. In B12, the cobalt center is coordinated by four equatorial pyrroles of the corrin ring and 2,3-dimethylbenzimidazole as a lower axial ligand (Figure 1a) [6][7][8]. The

• shown in Figure 2a. The remarkable in vivo and in vitro characters of B12 are summarized as follows: B12 shows good accessibility to Co(I) species with a redox potential (the Co(II)/Co(I) couple in the base-off form) of −500 mV vs the standard hydrogen electrode [21], because of the monoanionic corrin

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

• ), or acetyl-Lys (Lys(Ac)) could improve the proteolytic stability of conjugates [17]. The results of in vitro and in vivo assays demonstrated that the conjugate containing Lys(Ac) in position 4 and Dau in position 8 ([4Lys(Ac)]-GnRH-III(Dau=Aoa)) had higher tumor growth inhibition activity than the

• 4Lys could negatively affect the fitting of the conjugates to the N-terminal part of the GnRH-R. On the basis of these findings [4Lys(Bu)]-GnRH-III(Dau=Aoa), was chosen for the further studies (e.g., in vivo experiments [22]) to evaluate the suitability of this conjugate for targeted chemotherapy

• demonstrated in melanoma cell lines [25][26]. There are also evidences that the short-chain fatty acids, including sodium butyrate and valproic acid, could inhibit the proliferation of melanoma cells both in in vitro (e.g., A2058 [27], B16 cell lines [28]) and in vivo experiments [28][29] or could abrogate the

The enzymes of microbial nicotine metabolism

• Paul F. Fitzpatrick

Beilstein J. Org. Chem. 2018, 14, 2295–2307, doi:10.3762/bjoc.14.204

• succinate semialdehyde and methylamine, mao. The expression of both proteins is regulated by nicotine [38][39], suggesting that both contribute in vivo. Mabo (γ-N-methylaminobutyrate demethylating oxidase) is similar in sequence to sarcosine dehydrogenase, and characterization of purified Mabo showed that

• , suggesting that Mao operates in vivo. Finally, pAO1 also contains the sad gene that codes for an NADP+-dependent succinate semialdehyde dehydrogenase forming succinate as product [39]. 2,3-Dihydroxypyridine 3-hydroxylase (2,6-DHPH), the enzyme converting 2,6-dihydroxypyridine to 2,3,6-trihydroxypyridine, has

Synthesis of a water-soluble 2,2′-biphen[4]arene and its efficient complexation and sensitive fluorescence enhancement towards palmatine and berberine

• Xiayang Huang,
• Xinghua Zhang,
• Tianxin Qian,
• Junwei Ma,
• Lei Cui and
• Chunju Li

Beilstein J. Org. Chem. 2018, 14, 2236–2241, doi:10.3762/bjoc.14.198

• the blood stream, but also be effectively dis-assembled in the acidic tumor environment, and thus improve the anticancer activity of oxaliplatin in vivo. In 2015, we introduced a new class of macrocyclic arenes, 4,4’-biphen[n]arenes (n = 3,4) with 4,4’-biphenol or 4,4’-biphenol ether monomers linked

Defining the hydrophobic interactions that drive competence stimulating peptide (CSP)-ComD binding in Streptococcus pneumoniae

• Bimal Koirala,
• Robert A. Hillman,
• Erin K. Tiwold,
• Michael A. Bertucci and
• Yftah Tal-Gan

Beilstein J. Org. Chem. 2018, 14, 1769–1777, doi:10.3762/bjoc.14.151

• could be applied to study QS in vivo. Results and Discussion Design and synthesis of CSP1 analogs In this work, we aimed to define the binding pockets in ComD1 that accommodate the hydrophobic side-chain residues in CSP1 and determine their degree of occupancy as a means to optimize CSP1–ComD1

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

• approach of co-administration is often favored owing to the ease of preparation and a higher capacity of drug that can be administered. Such a combination therapy of DOX and a tumor-penetrating peptide has been recently investigated in vivo using clinically relevant tumor models [41]. Doxorubicin is known