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

• may be an interesting candidate for siderophore conjugation. Results and Discussion Typically siderophore–antibiotic conjugates consist of a linker joining the siderophore and antibiotic components. As the target is membrane-associated NDH-2 we decided to functionalise our conjugate with a non

• due course. NDH-2 is a validated target for 1 with an MIC of 1.1 µg/mL against M. tuberculosis. Synthesis of phenothiazine-PEG-amine component. Synthesis of the azotochelin siderophore component. Final conjugation and deprotection to yield a phenothiazine siderophore conjugate. Supporting Information

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

• facilitated the discovery of novel PqsD-targeting compounds through CuAAC-mediated conjugation of a fluorescent dye (Figure 9) [62]. Finally, Sangshetti et al. reported the discovery of linezolid-like Schiff bases, which showed promising anti-biofilm activity in the double-digit micromolar range [63]. Notably

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

• targeted chemotherapy favor conjugation methods resulting in a better stability of a conjugate in systemic circulation as well as GnRH derivatives with high affinity for tumor’s GnRH-R and negligible endocrine activity [13][14]. The GnRH-III (Glp-His-Trp-Ser-His-Asp-Trp-Lys-Pro-Gly-NH2), a native variant

Nucleoside macrocycles formed by intramolecular click reaction: efficient cyclization of pyrimidine nucleosides decorated with 5'-azido residues and 5-octadiynyl side chains

• Jiang Liu,
• Peter Leonard,
• Sebastian L. Müller,
• Constantin Daniliuc and
• Frank Seela

Beilstein J. Org. Chem. 2018, 14, 2404–2410, doi:10.3762/bjoc.14.217

• nucleobases are located outside of the macrocycle. The intensity of NOE’s for the CH2 groups decreased with increasing distance (Supporting Information File 1, Figures S21 and S35). As the triple bonds of the macrocycles 4 and 8 are in conjugation to the nucleobases they influence the UV spectra and affect

Applications of organocatalysed visible-light photoredox reactions for medicinal chemistry

• Michael K. Bogdos,
• Emmanuel Pinard and
• John A. Murphy

Beilstein J. Org. Chem. 2018, 14, 2035–2064, doi:10.3762/bjoc.14.179

• aromatic ring must lie in conjugation with the iminium double bond, making the orbitals of the ring orthogonal to the orbital in which the unpaired electron resides. The Xiao group have also published a method for making oxazoles using conditions that are very similar to those described above (Scheme 16

Functionalization of graphene: does the organic chemistry matter?

• Artur Kasprzak,
• Agnieszka Zuchowska and
• Magdalena Poplawska

Beilstein J. Org. Chem. 2018, 14, 2018–2026, doi:10.3762/bjoc.14.177

• carbodiimide-promoted reactions [13][14]. As presented in Figure 2, step a, the first step of a carbodiimide-type conjugation involves the generation of an O-acylisourea intermediate, which is highly electrophilic and which bears the urea-based good leaving group. Such activation of carboxyl groups onto a

• conjugation protocols do not uphold with the basic organic chemistry principles discussed above. Despite the interesting applications presented in these studies, important questions remain regarding the structure of the obtained materials. One common inaccuracy is a lack of the additives in the conjugation

• conjugation reaction, a tertiary amine (e.g., triethylamine) should be also included in the process. The tertiary amine’s role is to transform the amine hydrohalide into a free amine via the acid–base reaction. The free amine can then act as a strong nucleophile in the desired amidation process or can attack

Synthesis and characterization of π–extended “earring” subporphyrins

• Haiyan Guan,
• Mingbo Zhou,
• Bangshao Yin,
• Ling Xu and
• Jianxin Song

Beilstein J. Org. Chem. 2018, 14, 1956–1960, doi:10.3762/bjoc.14.170

• 1400 nm with several observable peaks. This remarkable absorption in the NIR region is comparable with that of the analogue “earring” porphyrins and reveals the π-conjugation between the subporphyrin and tripyrrin moiety. Conclusion In summary, we synthesized a π-extended “earring” subporphyrin from β

Artificial bioconjugates with naturally occurring linkages: the use of phosphodiester

• Takao Shoji,
• Hiroki Fukutomi,
• Yohei Okada and
• Kazuhiro Chiba

Beilstein J. Org. Chem. 2018, 14, 1946–1955, doi:10.3762/bjoc.14.169

• –Alder reaction [41][42][43][44], and hydrazone/oxime formation [45][46][47][48], have developed selective conjugation reactions under mild conditions. Although these bond-forming reactions have proven to be truly powerful approaches and will remain as first options to create novel bioconjugates

• the pure form, which could to be used for further reactions without column purification. With the optimized 5’-phosphitylation conditions in hand, we then investigated conjugation using the 5’-activated supported trinucleotide 2 as a model. As expected, unactivated nucleosides could be coupled to the

• activated 5’-terminus without difficulty (Scheme S2, Supporting Information File 1). Furthermore, to our delight, the conjugation was compatible with carboxylic acids that are potential nucleophiles for the activated 5’-terminus and can also induce side reactions of the phosphoramidite (Scheme 1). This

Synthesis of new tricyclic 5,6-dihydro-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]diazepine derivatives by [3⁺ + 2]-cycloaddition/rearrangement reactions

• Lin-bo Luan,
• Zi-jie Song,
• Zhi-ming Li and
• Quan-rui Wang

Beilstein J. Org. Chem. 2018, 14, 1826–1833, doi:10.3762/bjoc.14.155

• of nitriles, the strategy was also probed with aromatic nitriles 9 that were reacted with 8 under the same reaction conditions. The nucleophilicity of the N atom in aromatic nitriles should be lower than that of aliphatic ones owing to the conjugation of the triple bond with the benzene ring. To our

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

• 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

Design, synthesis and structure of novel G-2 melamine-based dendrimers incorporating 4-(n-octyloxy)aniline as a peripheral unit

• Cristina Morar,
• Pedro Lameiras,
• Attila Bende,
• Gabriel Katona,
• Emese Gál and
• Mircea Darabantu

Beilstein J. Org. Chem. 2018, 14, 1704–1722, doi:10.3762/bjoc.14.145

• the shifts of the methylene protons α-situated vs the piperazine P-1 Nsp2 nitrogen involved in p→π LP(N)→π(C=N, s-triazine; C=O, amide) conjugation (3.78–3.91 ppm). To conclude, except the well-documented deshielding promoted by the magnetic anisotropy of π-delocalised systems, such as s-triazines and

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

• ]. These side effects can limit the applicability of these chemotherapeutic drugs. The conjugation of doxorubicin and daunorubicin to a GnRH-III-based targeting peptide could lead to decreased cardiotoxic effect through the more specific drug targeting. Drug delivery systems containing doxorubicin

• drug conjugates. Dox has three potential conjugation sites; i) a primary OH group at C-14 on the aglycone part, which is suitable for ester bond formation, ii) an oxo group at C-13 is available for the generation of an oxime linkage and iii) the amino group on the daunosamine sugar moiety, which can be

• showed no significant differences in the biological activity of Mtx isomers in conjugated form [24]. Fmoc-protected Dox was reacted with glutaric anhydride in DMF. The prepared Fmoc-Dox-14-O-hemiglutarate was used for conjugation using PyBOP in the presence of NMM, followed by the removal of Fmoc group

Recent advances in phosphorescent platinum complexes for organic light-emitting diodes

• Cristina Cebrián and
• Matteo Mauro

Beilstein J. Org. Chem. 2018, 14, 1459–1481, doi:10.3762/bjoc.14.124

• chemical structure is sketched in Figure 9 [41]. Depending on the π-conjugation of the NHC-based bidentate ligand, emitting complexes with luminescence varying from blue (19 and 20) to yellow (21) were obtained. Several devices were prepared following a remote phosphor configuration, which places the

• state. Nevertheless, Che and co-workers demonstrated that extending the π-conjugation of the cyclometalated ligand led to enhanced phosphorescence quantum yields [51][52]. Indeed, the increased conjugation resulted in a modification of the frontier molecular orbitals and prevention of Jahn–Teller

• phenyl ring. As the parent complex 23a, excimer formation via metal–metal interactions was observed for both derivatives at high concentrations or in neat films. Nevertheless, the increased conjugation within the chromophoric ligand led to a lower emission energy, which fell into the NIR region. The

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

• or basic character. During the last 25–30 years, many different CPPs have been described and used for manifold applications like the delivery of nucleic acids, proteins, peptides, nanoparticles, small organic drugs, and others [10]. CPP conjugates can be generated by covalent conjugation between

• . Therefore, HeLa and MCF-7 cells were exposed to the chemotherapeutic drug doxorubicin (DOX) that is already clinically applied in cancer therapy [37]. Doxorubicin interacts with DNA by intercalation and thereby inhibits the macromolecular biosynthesis [38]. Instead of covalent conjugation of the drug, we

Novel unit B cryptophycin analogues as payloads for targeted therapy

• Eduard Figueras,
• Adina Borbély,
• Mohamed Ismail,
• Marcel Frese and
• Norbert Sewald

Beilstein J. Org. Chem. 2018, 14, 1281–1286, doi:10.3762/bjoc.14.109

• potential for chemotherapy. Since targeted therapy provides new perspectives for treatment of cancer, new potent analogues of cytotoxic agents containing functional groups for conjugation to homing devices are required. We describe the design, synthesis and biological evaluation of three new unit B

• analogues containing functional groups that would allow the conjugation of a homing device were developed [41][42][43][44][45][46]. Some of these functionalized analogues have been recently used for the preparation of antibody–drug conjugates (ADCs) and peptide–drug conjugates (PDCs) [46][47][48][49][50][51

• ]. Nevertheless, there is still a strong need of novel cryptophycin analogues with maintained activity containing a suitable functional group that would allow the conjugation to the homing device. Cryptophycin-1 contains a methoxy group in the aromatic ring of the unit B, which is a chlorinated derivative of D

London dispersion as important factor for the stabilization of (Z)-azobenzenes in the presence of hydrogen bonding

• Andreas H. Heindl,
• Raffael C. Wende and
• Hermann A. Wegner

Beilstein J. Org. Chem. 2018, 14, 1238–1243, doi:10.3762/bjoc.14.106

• other azobenzenes 5–7 in tert-butyl methyl ether (TBME) as solvent. This observation is surprising, since azobenzenes 4–7 are electronically very similar as the methylene linker prevents conjugation of the N-aryl and the azobenzene moieties. At first thought, the large spatial separation of the N

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

• prodrug with enhanced plasma stability and/or cell permeability [27] and in the same time diminished toxicity for normal cells; c) covalent attachment of a drug on a tumor-targeting element (small molecule, peptide or antibody) able to selectively target and permeate cancer cells. The conjugation is being

• conjugation with the therapeutic payload. The overall experimental procedure to synthesize a PDC is usually rapid and facile. Notably, the overall cost to produce a PDC, where an already approved drug can be selected and re-used from a pool of available cytotoxic agents, is much lower compared to the cost of

• in sufficient levels to pump inside the cell efficacious doses of the drug. The peptide-carrier should be constructed in such way that the conjugation with a drug or/and a fluorophore is feasible. Conjugation usually occurs on lysine, cysteine and glutamic acid [34] via orthogonal coupling or on the

Development of novel cyclic NGR peptide–daunomycin conjugates with dual targeting property

• Andrea Angelo Pierluigi Tripodi,
• Szilárd Tóth,
• Kata Nóra Enyedi,
• Gitta Schlosser,
• Gergely Szakács and
• Gábor Mező

Beilstein J. Org. Chem. 2018, 14, 911–918, doi:10.3762/bjoc.14.78

• ) prior to the Dau conjugation. The final cyclic NGR peptide–Dau conjugates were characterized by analytical HPLC and mass spectrometry (Table 1, Supporting Information File 1), whereby the purity was over 95% in all cases. In comparison with the control conjugate (K) significantly higher overall yield

• ); h) daunomycin conjugation (rt, 24 h) in 0.2 M NH4OAc solution (pH 5.0); i) Fmoc-cleavage 4% hydrazine/DMF (rt, 2 h). (A) HT1080 and (B) HT-29 cells. Uptake of conjugate 1 (light green); 2 (red); 3 (light blue); 4 (pink); 5 (green); K (yellow). Empty control with purple color. List of the peptide

Two novel blue phosphorescent host materials containing phenothiazine-5,5-dioxide structure derivatives

• Feng-Ming Xie,
• Qingdong Ou,
• Qiang Zhang,
• Jiang-Kun Zhang,
• Guo-Liang Dai,
• Xin Zhao and
• Huai-Xin Wei

Beilstein J. Org. Chem. 2018, 14, 869–874, doi:10.3762/bjoc.14.73

• phosphorescence (77 K) spectra of CEPDO (a) and CBPDO (b) in solution, respectively. Obviously, the strong absorption peak at 236 nm can be ascribed to the π→π* transition of carbazole moiety of the molecules, and the weaker absorptions around 295 nm assign to the n→π* transition of the conjugation of the whole

Recent advances in synthetic approaches for medicinal chemistry of C-nucleosides

• Kartik Temburnikar and
• Katherine L. Seley-Radtke

Beilstein J. Org. Chem. 2018, 14, 772–785, doi:10.3762/bjoc.14.65

• ' pseudoaxial methoxy groups further stabilize the intermediate in E3 conformer, thereby favoring the E3 confomer over the 3E. In the case of an anomeric phenyl group (Ph, Figure 6C), stabilization of the positive charge (C=O+) through conjugation, via parallel alignment, helps to overcome the unfavorable

Synthesis and in vitro biochemical evaluation of oxime bond-linked daunorubicin–GnRH-III conjugates developed for targeted drug delivery

• Sabine Schuster,
• Beáta Biri-Kovács,
• Bálint Szeder,
• Viktor Farkas,
• László Buday,
• Zsuzsanna Szabó,
• Gábor Halmos and
• Gábor Mező

Beilstein J. Org. Chem. 2018, 14, 756–771, doi:10.3762/bjoc.14.64

• antiproliferative activity. Furthermore, the absence of the free ε-amino group additionally reduced the endocrine effect [23][24]. Thus, the 8Lys can be utilized as conjugation site for cytotoxic agents like anthracyclines. In the past decade, a variety of different linkage systems has been carried out including

• provides a suitable conjugation site and can be used for the formation of oximes. We have recently reported that Dau was efficiently linked to the 8Lys side-chain by incorporation of an aminooxyacetic acid (Aoa) moiety [21][25]. The formed oxime linkage is more stable under physiological conditions than

• peptide without the daunorubicin (Dau) part. This indicates that the main conformational preferences are not changed by the conjugation. The shapes of the ECD curves show a highly dynamic peptide structure in water. This is in agreement with the NMR study made by Pappa et al. that presented an extended

An uracil-linked hydroxyflavone probe for the recognition of ATP

• Márton Bojtár,
• Péter Zoltán Janzsó-Berend,
• Dávid Mester,
• Dóra Hessz,
• Mihály Kállay,
• Miklós Kubinyi and
• István Bitter

Beilstein J. Org. Chem. 2018, 14, 747–755, doi:10.3762/bjoc.14.63

• made to selectively recognize and detect these analytes, especially ATP using small-molecule fluorescent chemosensors. Despite the various solutions, the selective detection of ATP is still challenging due to the structural similarity of various nucleotides. In this paper, we report the conjugation of

D–A–D-type orange-light emitting thermally activated delayed fluorescence (TADF) materials based on a fluorenone unit: simulation, photoluminescence and electroluminescence studies

• Lin Gan,
• Xianglong Li,
• Xinyi Cai,
• Kunkun Liu,
• Wei Li and
• Shi-Jian Su

Beilstein J. Org. Chem. 2018, 14, 672–681, doi:10.3762/bjoc.14.55

• around 345 and 456 nm. The peaks at around 456 nm result from their ICT states from the donor to the acceptor, while the absorption below 380 nm is caused by their short π-conjugation. It is obvious that 2 has not only a higher oscillator strength (f) than 1 from its transition of charge-transfer states

• in a dilute solution of toluene, which could be attributed to the strong electron-withdrawing ability and excess conjugation length of fluorenone plane compared with conventional benzophenone acceptor [18]. In addition, low temperature photoluminescence (LTPL) spectra of the materials in toluene at

• is a promising acceptor for orange TADF materials, which aids in the design of the TADF behavior and luminescence color of 1 and 2. Owing to the strong electron-withdrawing ability and extended conjugation length of fluorenone unit, the emission peaks of both materials show obvious red-shifts from

Stimuli-responsive oligonucleotides in prodrug-based approaches for gene silencing

• Françoise Debart,
• Christelle Dupouy and
• Jean-Jacques Vasseur

Beilstein J. Org. Chem. 2018, 14, 436–469, doi:10.3762/bjoc.14.32

• enzymolabile phosphotriester groups, namely, t-Bu-SATE, OH-SATE and a conjugable aldehyde A-SATE for conjugation to delivery and targeting domains, have been selected for complete evaluation (Scheme 9A, 9B, and 9C, respectively). The optimum phosphotriester placement and number of phosphotriester groups were

Synthesis and biological evaluation of RGD and isoDGR peptidomimetic-α-amanitin conjugates for tumor-targeting

• Lizeth Bodero,
• Paula López Rivas,
• Barbara Korsak,
• Torsten Hechler,
• Andreas Pahl,
• Christoph Müller,
• Daniela Arosio,
• Luca Pignataro,
• Cesare Gennari and
• Umberto Piarulli

Beilstein J. Org. Chem. 2018, 14, 407–415, doi:10.3762/bjoc.14.29

• , unfavorable pharmacokinetics (low tissue diffusion and low accumulation rate) and possible elicitation of immune response [6]. By conjugation to a specific cell-membrane-receptor ligand, the toxin can be delivered at the tumor site and internalized through receptor-mediated endocytosis. In 2013, Reshetnyak

• group (-CH2NH2) as a handle for conjugation to cytotoxic drugs (Figure 2, ligands 2 and 4) [28][29][30]. Conjugates of the functionalized ligands 2 and 4 with paclitaxel (PTX) via a 2’-carbamate with a self-immolative spacer and the lysosomally cleavable Val-Ala linker [31] were synthesized (Figure 2