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

• well as a peptide–tubulysin A conjugate [K4(C(TubA)-βA-),F7,P34]-pNPY – representing a comparable PDC – compared to wildtype pNPY for their binding affinities at the NPY Y1 receptor subtype. While [F7,P34]-pNPY (IC50 = 1.3 nM) showed a comparable binding affinity as pNPY (IC50 = 1.8 nM), the Y1

New standards for collecting and fitting steady state kinetic data

• Kenneth A. Johnson

Beilstein J. Org. Chem. 2019, 15, 16–29, doi:10.3762/bjoc.15.2

• quantitative analysis, fulfilling the major goal of their work [1][2]. Estimating the binding affinity for the substrate as KS was an added bonus. These were profound discoveries that laid the foundation for enzymology throughout the 20th century. The Michaelis–Menten equation was originally derived assuming

• . Moreover, it shows that the Km value represents the balance point between the rate of turnover and the rate of substrate binding. The Km represents substrate binding affinity only in the special case of rapid equilibrium binding. A primary goal of fitting steady state data should be to accurately define

• binding affinity. The awkwardness is the result of historical precedent. Defining the specificity constant as kcat/Km carries with it the baggage of thinking of the specificity constant as a ratio rather than a single parameter. Logic is influenced by the words we use to describe observations. It actually

6’-Fluoro[4.3.0]bicyclo nucleic acid: synthesis, biophysical properties and molecular dynamics simulations

• Sibylle Frei,
• Andrei Istrate and
• Christian J. Leumann

Beilstein J. Org. Chem. 2018, 14, 3088–3097, doi:10.3762/bjoc.14.288

• polarizability of the modified nucleotide, and therefore influences the metabolic stability, the membrane permeability, the RNA- and protein-binding affinity of the AON [25][26][27][28][29]. Over the last almost two decades, fluorinated oligonucleotide analogs like 2’-deoxy-2’-fluoro-RNA (F-RNA) [26][30][31], 2

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

• (Figure 3) which displayed a >4-fold increase in its affinity for E. coli SC [63]. Recent evidence suggests that non-steroidal anti-inflammatory drugs (NSAIDs) have antimicrobial activity. Oakley et al. studied the E. coli β-clamp binding affinity of commercially available NSAIDs with the help of a FP

• phenylalanine benzyl ring, in which two chlorine atoms where incorporated in the benzene ring to achieve P14 (17, Figure 5) with a 15-fold increase of its binding affinity for the sliding clamp and reaching the 10−8 M range (IC50 = 0.077 μM) [65]. Recently, Løbner-Olesen and co-workers screened a library of

Pd-Catalyzed microwave-assisted synthesis of phosphonated 13α-estrones as potential OATP2B1, 17β-HSD1 and/or STS inhibitors

• Rebeka Jójárt,
• Szabolcs Pécsy,
• György Keglevich,
• Mihály Szécsi,
• Réka Rigó,
• Csilla Özvegy-Laczka,
• Gábor Kecskeméti and
• Erzsébet Mernyák

Beilstein J. Org. Chem. 2018, 14, 2838–2845, doi:10.3762/bjoc.14.262

• ]. Poirier et al. proved that 13α-derivatives of 3,17-estradiols have reduced binding affinity for estrogen receptor alpha and display no uterotropic activity [19]. The conformational change resulting from the inversion at C-13 leads to an epimer unable to bind to its nuclear receptors. We have recently

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

• of the intermediates. The various components that are assembled include the cell surface protein recognition ligand, a peptide spacer for enhanced solubility and binding affinity, a fluorescent tag for tissue staining and a chelating core to tether therapeutic cargos. This goal is smoothly achieved

• modified by removal of the L-glutamic acid residue to give the pteroic acid moiety (Figure 2). The binding affinity of the modified folate is relatively weaker than folic acid [41]. The targeting ligand, pteroic acid, is covalently coupled to 8-aminocaprylic acid to separate the active binding site of

• folate protein from the interference of fluorescent cargo attached to lysine and the chelating core as described for 13. Thus our newly designed bioconstructs 13 and 17 have the following four components, (i) a cell surface protein recognition ligand, (ii) a peptidic spacer which enhances the binding

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

• compound was tested in a whole cell ELISA, it was shown that the apparent binding affinity increases by a factor of 250 versus methyl α-D-mannoside, while the valency only increased by a factor three. It should be noted that the full length FimH adhesin consists of two domains, a lectin and a pilin domain

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

• (H-Lys(Dau=)-OH)) formed via lysosomal degradation of this type of conjugates had a lower binding affinity to DNA, than the free drug [35]. The two-fold higher intracellular fluorescence intensity of Dau was accompanied by almost two-fold higher cytotoxic activity compared to the conjugates. By

• than via intracellular mechanisms induced after the internalization of conjugates. Although the conjugates showed an opposite activity on melanoma adhesion (increasing effects) and chemotaxis (decreasing or neutral effects), based on our previous studies about the receptor binding affinity of

Rational design of boron-dipyrromethene (BODIPY) reporter dyes for cucurbit[7]uril

• Mohammad A. Alnajjar,
• Jürgen Bartelmeß,
• Robert Hein,
• Pichandi Ashokkumar,
• Mohamed Nilam,
• Werner M. Nau,
• Knut Rurack and
• Andreas Hennig

Beilstein J. Org. Chem. 2018, 14, 1961–1971, doi:10.3762/bjoc.14.171

• cyclohexylmethylammonium (cyH) cations by displacement titrations (see below) in our mixture of 30% (v/v) ACN/H2O, which gave Ka(Bnz) = 1.4 × 105 M−1 and Ka(cyH) = 1.5 × 107 M−1. This indicated that the binding affinity is lowered 100 to 1000-fold by reducing the hydrophobic effect in presence of 30% acetonitrile as also

Diazirine-functionalized mannosides for photoaffinity labeling: trouble with FimH

• Femke Beiroth,
• Tomas Koudelka,
• Thorsten Overath,
• Stefan D. Knight,
• Andreas Tholey and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2018, 14, 1890–1900, doi:10.3762/bjoc.14.163

• the following amino acid sequence: FACKTANGTAIPIGGGSANVYVNLAPVVNVGQNL-VVDLSTQIFCHNDYPETITDYVTLQRGSAYGGVLSNFSG-TVKYSGSSYPFPTTSETPRVVYNSRTDKPWPVALYLT-PVSSAGGVAIKAGSLIAVLILRQTNNYNSDDFQF-VWNIYANNDVVVPTGGHHHHHH. Docking studies Computer-aided docking studies were performed to evaluate the binding affinity

Synthesis of 9-arylalkynyl- and 9-aryl-substituted benzo[b]quinolizinium derivatives by Palladium-mediated cross-coupling reactions

• Siva Sankar Murthy Bandaru,
• Darinka Dzubiel,
• Heiko Ihmels,
• Mohebodin Karbasiyoun,
• Mohamed M. A. Mahmoud and
• Carola Schulzke

Beilstein J. Org. Chem. 2018, 14, 1871–1884, doi:10.3762/bjoc.14.161

• pH-sensitive light-up probe. Photometric and fluorimetric titrations of duplex and quadruplex DNA to 9-(arylethynyl)benzo[b]quinolizinium derivatives revealed a significant binding affinity of these compounds towards both DNA forms with binding constants of Kb = 0.2–2.2 × 105 M−1. Keywords: DNA

Synthesis of trifluoromethylated 2H-azirines through Togni reagent-mediated trifluoromethylation followed by PhIO-mediated azirination

• Jiyun Sun,
• Xiaohua Zhen,
• Huaibin Ge,
• Guangtao Zhang,
• Xuechan An and
• Yunfei Du

Beilstein J. Org. Chem. 2018, 14, 1452–1458, doi:10.3762/bjoc.14.123

• sciences. The introduction of this functional group in drug molecules can enhance their chemical and metabolic stability, improve their lipophilicity and bioavailability, and increase protein-binding affinity [1][2][3][4][5][6]. In this regard, the CF3 group has been introduced into many pharmaceutical

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

• the vinca domain (Lys176, Val177 and Tyr210). Other than previously reported [52], the methoxy group of subunit B forms a hydrogen bond with Lys176 (Figure 2). Another binding mode of 2 with high binding affinity and hydrogen bond formation did not involve any interaction of subunit B, yet it was

• the other derivatives 23 and 24 (Figure 4). Besides hydrogen bond formation and binding affinity of inhibitors 2, 23 and 24, π-interactions and hydrophobic contacts with the binding pocket of the vinca domain were detected that would in turn increase the affinity of the inhibitor and its effect on the

Recyclable hypervalent-iodine-mediated solid-phase peptide synthesis and cyclic peptide synthesis

• Dan Liu,
• Ya-Li Guo,
• Jin Qu and
• Chi Zhang

Beilstein J. Org. Chem. 2018, 14, 1112–1119, doi:10.3762/bjoc.14.97

• . Compound 6 was subsequently oxidized with NaOCl/HCl to obtain FPID in 90% yield. Cyclic peptides, an important kind of peptides, possess several favorable properties such as target selectivity, good binding affinity and low toxicity, which make them attractive candidates in the development of therapeutics

An overview of recent advances in duplex DNA recognition by small molecules

• Sayantan Bhaduri,
• Nihar Ranjan and
• Dev P. Arya

Beilstein J. Org. Chem. 2018, 14, 1051–1086, doi:10.3762/bjoc.14.93

• as inhibitors of Werner and Bloom syndrome helicases and dual topoisomerase I/II inhibitors [37][38]. In order to improve DNA binding affinity and sequence specificity with reduced side effects, a series of synthetic hybrid molecules derived from distamycin and netropsin was synthesized and their

• affinity, sequence specificity, more cytotoxicity and minimizing the unwanted physiological side effects [43]. It has been observed that drugs with high degree of sequence specific binding affinity and selective alkylation of DNA could inhibit the binding of the regulatory proteins to DNA. Several

• fashion, they further reported a series of novel hybrids by tethering distamycin A with the antineoplastic agent uramustine via a flexible polymethylene chain of variable length (n = 1 to 6) in order to test their DNA binding affinity and cytotoxicity [57]. It has been observed that hybrid conjugates 8, 9

The first Pd-catalyzed Buchwald–Hartwig aminations at C-2 or C-4 in the estrone series

• Ildikó Bacsa,
• Dávid Szemerédi,
• János Wölfling,
• Gyula Schneider,
• Lilla Fekete and
• Erzsébet Mernyák

Beilstein J. Org. Chem. 2018, 14, 998–1003, doi:10.3762/bjoc.14.85

• -estradiol derivatives of 13α-estrone [23]. The 13-epimers were shown to exhibit no significant binding affinity for estrogen receptor alpha and display no uterotropic activity. Nevertheless, certain 13α-estrone derivatives possess important biological activities including antitumoral effect [24][25][26][27

• ]. Thus 13α-estrone is a suitable compound for the development of biologically active steroids lacking estrogenicity. Literature reveals that besides the inversion of C-13, the introduction of an amino group onto C-2 or C-4 of estrone also leads to significant decreases in its binding affinity for nuclear

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

• free N-terminus of the peptide during solid phase peptide synthesis. Though, the conjugation site should be carefully selected, since perturbations induced in the peptide structural microenvironment may result in the abolishment of its binding affinity/selectivity to the targeted receptor. The linker

• should be carefully selected to succeed the optimal performance of the PDC. An injudicious selection may cause diminished binding affinity of the peptide to the receptor or/and reduction of the therapeutic window of the drug. Additionally, it should be enzymatically stable during the blood circulation in

• ], while the most frequently used GnRH analog is D-Lys6-GnRH-I, which is known to bind selectively to GnRH-R. The substitution of Gly6 of the native hormone with D-Lys6 provided an analog with higher binding affinity, stabilized β-bend and resistance to proteolytic cleavage. Moreover, the side chain of

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

• in vitro antitumor activity of the conjugates. We believe that the measurement of binding affinity on isolated receptors, that was not task of this experiment, could not explain properly the efficacies and selectivity. The receptor profile of both cell types are very complex. HT-1080 contain

• the peptide [2]. In addition the binding affinity of the different integrins is not consequent to the peptides. Furthermore, there are only a few binding affinity studies for CD13 suggesting several hundred nM IC50 values for NGR peptide derivatives [22]. The biological activity of NGR and isoDGR

• explained by the binding affinity of isoDGR peptides to integrin receptors. However, to confirm this findings further binding studies of cyclic NGR peptide–drug conjugates to different integrin receptors are needed. Taken together, the synthetic and biological results suggest that the Dau=Aoa-GFLGK(c

Crystal structure of the inclusion complex of cholesterol in β-cyclodextrin and molecular dynamics studies

• Elias Christoforides,
• Andreas Papaioannou and
• Kostas Bethanis

Beilstein J. Org. Chem. 2018, 14, 838–848, doi:10.3762/bjoc.14.69

• characterization of the cholesterol/β-CD inclusion complex [22], its binding affinity [23][24][25], the inclusion mode of the complex [26] and its dynamic behavior through MD simulations [27][28][29] but its crystal structure is absent. In this work, the structure of CHL/β-CD is determined by X-ray crystallography

• coordinates was based on the asymmetric unit of the determined structure and the dynamic behavior of the inclusion complex was monitored at two different temperatures (300 and 340 K) to gain some insight on the evolution of the host–guest interactions and to estimate the host–guest binding affinity in aqueous

• simulation time frame and calculate the host–guest binding affinity in each case. By monitoring the frames during the time interval of the simulations, we observed that the sterol group of the guest cholesterol molecule remains encapsulated inside the hydrophobic β-CD dimeric cavity while its aliphatic tail

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

• receptor binding affinity and an enhanced antiproliferative activity without substantial effect on the endocrine activity [31][32][33], we developed six novel GnRH-III–Dau conjugates in which the 6Asp was replaced by D-Aaa. Here we report on the synthesis of GnRH-III bioconjugates containing D-Asp, D-Glu

• or D-Trp in position 6 and Ser or Lys(Bu) in position 4. Moreover, the novel GnRH-III–Dau conjugates were compared systematically with our lead compound K2 in terms of in vitro cytostatic effect, receptor binding affinity, cellular uptake and lysosomal digestion in the presence of rat liver lysosomal

• compounds whereby the degradation profile of 2 and 4 displayed an enhanced release of the smallest Dau-containing metabolite indicating that the GnRH-III bioconjugates vary in their affinity for the GnRH-RI and/or their cellular uptake. Radioligand binding studies To investigate the binding affinity of the

Heterogeneous Pd catalysts as emulsifiers in Pickering emulsions for integrated multistep synthesis in flow chemistry

• Katharina Hiebler,
• Georg J. Lichtenegger,
• Manuel C. Maier,
• Eun Sung Park,
• Renie Gonzales-Groom,
• Bernard P. Binks and
• Heidrun Gruber-Woelfler

Beilstein J. Org. Chem. 2018, 14, 648–658, doi:10.3762/bjoc.14.52

• with phenylboronic acids yielding the corresponding biphenyls as product [7]. The biphenyl unit is a common structural motif in various pharmaceutically active agents and plays a crucial role in the binding affinity and the oral bioavailability of diverse APIs [8], including antihypertensive [9] and

Carbohydrate inhibitors of cholera toxin

• Vajinder Kumar and
• W. Bruce Turnbull

Beilstein J. Org. Chem. 2018, 14, 484–498, doi:10.3762/bjoc.14.34

• the second galactosyl moiety could bind to another CT molecule. They found that non-spanning bivalent inhibitors 9–12 as shown in Figure 5, show more binding affinity than the monovalent ones, which could also be derived from a statistical effect of a higher rebinding rate. Bernardi, Casnati and co

• exhibit binding affinity one order higher than m-nitrophenyl galactopyranoside (4) [48]. In another recent report, low molecular weight poly(N-acryloylmorpholine) was used to link galactose residues to form a bivalent inhibitor, but the biological assay demonstrated only moderate inhibitory activity [49

• synthesising bivalent and tetravalent multivalent inhibitors and showed substantial gains in binding affinity in comparison to the corresponding monovalent ligands. Pieters and co-workers attached a lactose-derived monomeric ligand to the dendrimer 18, and found that there was an affinity and potency gain from

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

• synthesized by joining integrin ligands to α-amanitin via various linkers and spacers. The conjugates were evaluated for their ability to inhibit biotinylated vitronectin binding to the purified αVβ3 receptor, retaining good binding affinity, in the same nanomolar range as the free ligands. The

• Gennari and Piarulli groups in the last decade [24][25][26][27]. Among them, the cyclo[DKP-RGD] 1 [25] and cyclo[DKP-isoDGR] 3 [26] (Figure 2) showed a binding affinity for the purified receptor αVβ3 in the low nanomolar range and a good selectivity for this integrin in comparison with integrin αVβ5 (33

• , 10 and 11 retain good binding affinity for αVβ3 integrin, in the same range as the free ligands (cf. Table 2 with Table 1). These results encouraged us to proceed with cell viability assays in αVβ3 positive and αVβ3 negative cell lines, to study the ability of the conjugates to selectively target

Fluorogenic PNA probes

• Tirayut Vilaivan

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

• have been realized by constraining the conformational flexibility by incorporating a suitable substituent at a suitable position (such as in γPNA) [30], or by incorporating cyclic structures into the PNA backbones (such as in acpcPNA, Figure 2) [31][32]. The high binding affinity and excellent

• pyrrolocytosine (PhpC) recognizes dG in DNA and G in RNA with a slightly increased and decreased affinity, respectively, relative to C [190]. Addition of a positively charged pendant group at the ortho-position of the phenyl substituent, such as in boPhpC, substantially increased the binding affinity as well as

• the specificity due to the additional hydrogen-bonding interactions with the pairing G residue analogous to G-clamp phenoxazine. Moving the substituent to the meta-position, as in mmGuaPhpC, increased the binding affinity towards RNA while still maintaining good DNA binding [191]. When incorporated

5-Aminopyrazole as precursor in design and synthesis of fused pyrazoloazines

• Ranjana Aggarwal and
• Suresh Kumar

Beilstein J. Org. Chem. 2018, 14, 203–242, doi:10.3762/bjoc.14.15

• were evaluated as neuropeptide NPY Y1R antagonists with high binding affinity and selectivity. Using a similar approach Dwyer et al. [97] reported the synthesis of various pyrazolo[1,5-a]pyrimidinyl derivatives 142, 143, 145 and 146 following a sequence of reactions as depicted in Scheme 40 and Scheme