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

• 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

• used for amide bond formation. The difference between Dox and Dau is the lack of the primary OH group in the case of the latter one. Therefore, Dau cannot be attached to peptide carriers via an ester bond. Mtx contains a glutamic acid whose carboxyl groups are suitable for the attachment to peptides

• through amide bond (this can be carried out on a solid support, prior to the cleavage of the peptide from the resin). In the conjugates used as reference compounds, Dox was coupled to the Lys in position 8 of GnRH-III through glutaric acid linked via an ester bond (O-glut) (1) (similarly to AN-152) or an

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

• , stability, release mechanism, functional groups, hydrophilicity/hydrophobicity etc. This linker can be designed to bear an enzyme-hydrolyzable unit (EHU) like a carboxylic ester or an amide bond, cleaved by esterases and amidases, respectively. The most commonly utilized linkers that bear a carboxylic ester

• bond, as the enzyme-hydrolyzable unit, are succinyl (derived from succinic acid) and glutaryl (derived from glutaric acid). Concerning the utilization of amide bond in the linker as the unit tethering the drug and the peptide, it can be tailored to be cleaved based on the targeted tissue and/or type of

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

• preclinical and clinical studies, was zoptarelin-doxorubicin also known as AEZS-108 (previously AN-152) [16]. The anthracycline doxorubicin was conjugated to the ε-amino group of GnRH-I-[6D-Lys] by insertion of a glutaric acid linker. The resulting ester bond can be cleaved by carboxylesterases, leading to

• ester or hydrazine bonds, cathepsin-B labile spacers and oxime bonds [21][22][25]. Due to its structural properties, Dau cannot be attached to the homing device by an ester bond like Dox, because of the absence of the primary hydroxy group in position C-14. However, the C-13 carbonyl group of Dox/Dau

• the ester bond resulting in a longer half-life of the conjugate during circulation. Nevertheless, the drug is released within the cancer cell by lysosomal enzymes, especially by cathepsin B, which leads to various Dau containing metabolites [26]. In case of GnRH-III–[8Lys(Dau=Aoa)] conjugates the

Preparation of trinucleotide phosphoramidites as synthons for the synthesis of gene libraries

• Ruth Suchsland,
• Bettina Appel and
• Sabine Müller

Beilstein J. Org. Chem. 2018, 14, 397–406, doi:10.3762/bjoc.14.28

• aqueous dioxane and subsequent spontaneous intramolecular cyclization leading to cleavage of the ester bond and release of the free 3'-OH group [29] (Figure 4A). Also with 3'-O-TBDMS-protected monomers as mentioned above, a full set of trimers representing codons of all 20 amino acids was synthesized

Hydrolysis, polarity, and conformational impact of C-terminal partially fluorinated ethyl esters in peptide models

• Vladimir Kubyshkin and
• Nediljko Budisa

Beilstein J. Org. Chem. 2017, 13, 2442–2457, doi:10.3762/bjoc.13.241

• undergo variable hydrolysis in biologically relevant buffers. The hydrolytic stability can be tailored over a broad pH range by varying the number of fluorine atoms in the ester moiety or by introducing adjacent charges in the peptide sequence. Keywords: conformation; ester bond; hydrolysis; peptides

• rotamer. In oligopeptides, the C-terminal 2,2-difluoroethylation increased the polyproline-II structural contribution. The effect was seen most prominently in a short oligolysine peptide. The hydrolytic stability of the ester bond in the peptide depends on the charge of the peptide, as it was impaired in

Intramolecular glycosylation

• Xiao G. Jia and
• Alexei V. Demchenko

Beilstein J. Org. Chem. 2017, 13, 2028–2048, doi:10.3762/bjoc.13.201

• wherein glycosyl acceptor was linked via an ester bond at the ortho-position of the DISAL leaving group of the donor gave best results under elevated temperatures. Thus, mannoside 98 was obtained in 58% yield with modest stereoselectivity (Scheme 22). The yields are hampered by the competing formation of

Theoretical simulation of the infrared signature of mechanically stressed polymer solids

• Matthew S. Sammon,
• Milan Ončák and
• Martin K. Beyer

Beilstein J. Org. Chem. 2017, 13, 1710–1716, doi:10.3762/bjoc.13.165

• the ester bond decreases in intensity and almost vanishes at 4 nN. For the C–O-stretching mode in the backbone the intensity first increases similar to the C–N vibration in the amide, reaches a maximum around 2.2 nN and then decreases again. Peaks propagating from 1047 cm−1 at 0 nN to 858 cm−1 at 4 nN

• sample at 0.1, 0.3, 0.5 and 1.0 nN mean force per polymer strand. Force dependence of the modes shown in Scheme 2 in the fingerprint region from 800 to 2000 cm−1. C–O backbone stretch of the ester bond (blue); backbone stretch combined with C–H2 wagging (orange); free C-O stretch (purple). Intensities in

The chemistry and biology of mycolactones

• Matthias Gehringer and
• Karl-Heinz Altmann

Beilstein J. Org. Chem. 2017, 13, 1596–1660, doi:10.3762/bjoc.13.159

A new member of the fusaricidin family – structure elucidation and synthesis of fusaricidin E

• Marcel Reimann,
• Louis P. Sandjo,
• Luis Antelo,
• Eckhard Thines,
• Isabella Siepe and
• Till Opatz

Beilstein J. Org. Chem. 2017, 13, 1430–1438, doi:10.3762/bjoc.13.140

• °C, 2: PPh3, –78 °C → rt, 77%; i) NaClO2, NaH2PO4, amylene, t-BuOH, H2O, rt, 80%. Ester bond formation with 2,2-dimethylated pseudoproline including peptide 16. Cyclization with 2,2-dimethylated pseudoproline including peptide 16. Depsipeptide cyclization and coupling with GHPD side chain

Novel β-cyclodextrin–eosin conjugates

• Gábor Benkovics,
• Damien Afonso,
• András Darcsi,
• Szabolcs Béni,
• Sabrina Conoci,
• Éva Fenyvesi,
• Lajos Szente,
• Milo Malanga and
• Salvatore Sortino

Beilstein J. Org. Chem. 2017, 13, 543–551, doi:10.3762/bjoc.13.52

• available hydroxy groups of the CD and the carboxylic acid group of the dye [21]. These conjugates, however, cannot be used in biomedical applications because of the lability of the ester bond towards enzymatic degradation. Any cleavage of the conjugate would result in an increased free dye concentration in

New synthetic strategies for xanthene-dye-appended cyclodextrins

• Milo Malanga,
• Andras Darcsi,
• Mihaly Balint,
• Gabor Benkovics,
• Tamas Sohajda and
• Szabolcs Beni

Beilstein J. Org. Chem. 2016, 12, 537–548, doi:10.3762/bjoc.12.53

• fluorescein, resulting in a fluorescein β-CD derivative connected through an ester bond. The main idea of the synthetic step was to promote the nucleophilic substitution between 6-monotosyl-β-CD and the carboxylate of the fluorescein by adjusting the pH of the aqueous solution around pH 6 [12]. Some years

• -aminoethylamino)-β-CD was obtained by in situ conversion of the terminal amino group of the fluorophore into isothiocyanate group. To summarize, fluorescein has been connected to CDs through an ester bond by performing the reaction in water or DMF. Although the synthetic procedure is well described, the

Supramolecular structures based on regioisomers of cinnamyl-α-cyclodextrins – new media for capillary separation techniques

• Gabor Benkovics,
• Ondrej Hodek,
• Martina Havlikova,
• Zuzana Bosakova,
• Pavel Coufal,
• Milo Malanga,
• Eva Fenyvesi,
• Andras Darcsi,
• Szabolcs Beni and
• Jindrich Jindrich

Beilstein J. Org. Chem. 2016, 12, 97–109, doi:10.3762/bjoc.12.11

• . Because this application requires chemically stable conjugates, we decided to prepare conjugates where the guest molecule is bound to the CD by a stable ether bond instead of the labile ester bond. This led us to the family of Cin-α-CD. The complete set of peracetylated regioisomers of Cin-α-CD was

The marine sponge Agelas citrina as a source of the new pyrrole–imidazole alkaloids citrinamines A–D and N-methylagelongine

• Christine Cychon,
• Ellen Lichte and
• Matthias Köck

Beilstein J. Org. Chem. 2015, 11, 2029–2037, doi:10.3762/bjoc.11.220

• carboxylic acid in position C-5. The 1H,1H-COSY spectrum showed the connectivity of the methylene groups H-8 (4.65 ppm) and H-9 (5.07 ppm) and the 1H,13C-HMBC correlation H-8 to C-6 linked the ethylene group with the N-methyl-3-bromopyrrole carboxylic acid via an ester bond. The 1D 1H NMR spectrum of 5

Polythiophene and oligothiophene systems modified by TTF electroactive units for organic electronics

• Alexander L. Kanibolotsky,
• Neil J. Findlay and
• Peter J. Skabara

Beilstein J. Org. Chem. 2015, 11, 1749–1766, doi:10.3762/bjoc.11.191

• potentiodynamic and potentiostatic electrodeposition. Nevertheless, the labile ester bond and its potential cleavage remain an issue due to formation of acid upon electropolymerisation. Roncali and co-workers used more reliable ether bonds to anchor a TTF moiety to a thiophene monomer via a long aliphatic spacer

Natural phenolic metabolites with anti-angiogenic properties – a review from the chemical point of view

• Qiu Sun,
• Jörg Heilmann and
• Burkhard König

Beilstein J. Org. Chem. 2015, 11, 249–264, doi:10.3762/bjoc.11.28

• stability and the inability of the compound to cross cellular membranes [66]. To prevent oxidation and improve its bioavailability, modifications of EGCG focus on synthesizing more stable analogs (Figure 7). Anderson et al. [67] replaced the hydrolytically labile ester bond with a more stable amine and

(2R,1'S,2'R)- and (2S,1'S,2'R)-3-[2-Mono(di,tri)fluoromethylcyclopropyl]alanines and their incorporation into hormaomycin analogues

• Armin de Meijere,
• Sergei I. Kozhushkov,
• Dmitrii S. Yufit,
• Christian Grosse,
• Marcel Kaiser and
• Vitaly A. Raev

Beilstein J. Org. Chem. 2014, 10, 2844–2857, doi:10.3762/bjoc.10.302

• '-nitrocyclopropyl)alanine and the 3-(2'-fluoromethylcyclopropyl)alanines, HATU as well as the combination of EDC and 7-aza-1-hydroxybenzotriazole (HOAt) [61] were used for each condensation step to ensure high yields. The most unusual fragment in hormaomycin (1) and its analogues is the ester bond between the

Glycosystems in nanotechnology: Gold glyconanoparticles as carrier for anti-HIV prodrugs

• Fabrizio Chiodo,
• Marco Marradi,
• Javier Calvo,
• Eloisa Yuste and
• Soledad Penadés

Beilstein J. Org. Chem. 2014, 10, 1339–1346, doi:10.3762/bjoc.10.136

• corresponding ester prodrug candidates with a free thiol-ending group fundamental for their gold chemo-adsorption (Figure 1 and Supporting Information File 1). Abacavir (ABC) and lamivudine (3TC) were functionalized at the primary hydroxy groups through an ester bond that will be cleaved by cellular esterase

A novel family of (1-aminoalkyl)(trifluoromethyl)- and -(difluoromethyl)phosphinic acids – analogues of α-amino acids

• Natalia V. Pavlenko,
• Tatiana I. Oos,
• Yurii L. Yagupolskii,
• Igor I. Gerus,
• Uwe Doeller and
• Lothar Willms

Beilstein J. Org. Chem. 2014, 10, 722–731, doi:10.3762/bjoc.10.66

• storage in a ratio of ~ 3:2 with acid 1 as an impurity. The low stability of all three esters 2–4 can be attributed to the lability of the O–C ester bond, resulting from the electron-withdrawing effect of the CF3 group attached to phosphorus, therefore esters 2, 3 and 4 were used in the syntheses only

The conjugation of nonsteroidal anti-inflammatory drugs (NSAID) to small peptides for generating multifunctional supramolecular nanofibers/hydrogels

• Jiayang Li,
• Yi Kuang,
• Junfeng Shi,
• Yuan Gao,
• Jie Zhou and
• Bing Xu

Beilstein J. Org. Chem. 2013, 9, 908–917, doi:10.3762/bjoc.9.104

• acetylsalicylic acid (aspirin) to connect with dipeptides results in a compound hydrolyzing easily at the ester bond of aspirin, we use salicylic acid (Sal) instead to conjugate with diphenylalanine and dialanine (AA) to make compounds 5a and 5g, respectively. Self-assembly and hydrogelation After the synthesis

Glycosylation efficiencies on different solid supports using a hydrogenolysis-labile linker

• Mayeul Collot,
• Steffen Eller,
• Markus Weishaupt and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2013, 9, 97–105, doi:10.3762/bjoc.9.13

• glycosylation efficiencies on different types of resin. Therefore, Zemplén conditions were employed as an alternative cleavage method. Sodium methoxide-mediated cleavage of the ester bond between linker 1 and the solid support in the case of polystyrene resins, as well as the ester bond between linker 1 and

A macrolactonization approach to the total synthesis of the antimicrobial cyclic depsipeptide LI-F04a and diastereoisomeric analogues

• James R. Cochrane,
• Dong Hee Yoon,
• Christopher S. P. McErlean and
• Katrina A. Jolliffe

Beilstein J. Org. Chem. 2012, 8, 1344–1351, doi:10.3762/bjoc.8.154

• unreacted cyclic peptide (retention time = 34.0 min) and ● is a peak attributed to hydrolysis of both the cyclic peptide ester bond and Cbz protecting group (LCMS m/z = 902 [M + H]+). Structures and lowest-energy conformers of 24 (left) and 25 (right) obtained using Macromodel. Hydrogen bonding is

Synthesis of szentiamide, a depsipeptide from entomopathogenic Xenorhabdus szentirmaii with activity against Plasmodium falciparum

• Friederike I. Nollmann,
• Andrea Dowling,
• Marcel Kaiser,
• Klaus Deckmann,
• Sabine Grösch,
• Richard ffrench-Constant and
• Helge B. Bode

Beilstein J. Org. Chem. 2012, 8, 528–533, doi:10.3762/bjoc.8.60

• -methylmorpholine (NMM) at 4 °C, affording the synthetic intermediate 4. The attempts to form the ester bond by using catalytic amounts of 4-dimethylaminopyridine (DMAP) with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), DMAP together with N,N′-diisopropylcarbodiimide (DIC), or a mixture of the DMAP

• hydrochloride and DMAP together with DIC all turned out to be unsuccessful. However, we were then able to establish the ester bond in 5 using modified Yamaguchi conditions [17]. Subsequently, the Fmoc-protecting group was removed at room temperature, and the peptide was cleaved from the resin with 3

• -methylmorpholine (NMM; Sigma Aldrich, Germany) in DMF (c = 12.5 mmol/L) at 4 °C over night. Ester bond formation. The depsipeptide bond was formed by using 20 equiv Fmoc-protected amino acid, 20 equiv benzoyl chloride (BzCl, Sigma Aldrich, Germany) and 40 equiv (Et3N, Sigma Aldrich, Germany) in DCM (c = 62.5 mmol