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

Polarization spectroscopy methods in the determination of interactions of small molecules with nucleic acids – tutorial

• Tamara Šmidlehner,
• Ivo Piantanida and
• Gennaro Pescitelli

Beilstein J. Org. Chem. 2018, 14, 84–105, doi:10.3762/bjoc.14.5

• general protocol for the use of ECD for the simultaneous determination of the binding mode and binding affinity of ligand/DNA complexes. In the light of the limitations listed above, here we would present an alternative approach, whereby an unknown DNA (or RNA)/ligand system is characterized primarily by

Recent applications of click chemistry for the functionalization of gold nanoparticles and their conversion to glyco-gold nanoparticles

• Vivek Poonthiyil,
• Thisbe K. Lindhorst,
• Vladimir B. Golovko and
• Antony J. Fairbanks

Beilstein J. Org. Chem. 2018, 14, 11–24, doi:10.3762/bjoc.14.2

• (Figure 1b). The most frequently employed approach here is to first synthesize citrate-stabilized AuNPs (Cit-AuNPs) [28], and then to replace the citrate ligands with the desired thiol-linked carbohydrate derivatives [29][30]. Ligand exchange on the AuNP surface is driven by the higher binding affinity of

Microfluidic radiosynthesis of [¹⁸F]FEMPT, a high affinity PET radiotracer for imaging serotonin receptors

• Thomas Lee Collier,
• Steven H. Liang,
• J. John Mann,
• Neil Vasdev and
• J. S. Dileep Kumar

Beilstein J. Org. Chem. 2017, 13, 2922–2927, doi:10.3762/bjoc.13.285

• [18F]FEMPT as an agonist PET ligand for 5-HT1AR. Results and Discussion Synthesis and binding affinity of FEMPT Desmethyl-MPT, the radiolabeling precursor, was synthesized as described previously [15]. The reference standard FEMPT (7) was synthesized in 70% by reacting desmethyl-MPT (6) with 1-bromo-2

• Psychoactive Drug Screening Program (NIMH-PDSP). FEMPT shows 0.2 nM binding affinity (Ki) to 5-HT1AR. The next closest bindings for MPT are Sigma2 PC12, H1, 5-HT7, and 5-HT1B (Table 1) and are >50 times higher than 5-HT1AR. The Ki values for several other brain receptors and transporters were low (0.1 to 10 μM

Synthetic mRNA capping

• Fabian Muttach,
• Nils Muthmann and
• Andrea Rentmeister

Beilstein J. Org. Chem. 2017, 13, 2819–2832, doi:10.3762/bjoc.13.274

• structure and the exact positioning of the triazole linkage, modified cap analogues varied largely with regard to their functionality in in vitro translational assays, binding affinity to eIF4E and resistance to the decapping enzyme DcpS. Best translational efficiencies similar to the standard cap were

Recent progress in the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isosteres

• Myriam Drouin and
• Jean-François Paquin

Beilstein J. Org. Chem. 2017, 13, 2637–2658, doi:10.3762/bjoc.13.262

• obtain Tyr-Gly-Gly-ψ[(Z)-CF=CH]-Phe-Leu. The fluorinated Leu-enkephaline presented a 6-fold decreased binding affinity towards the DOPr receptor that the non-fluorinated analogue, showing that a hydrogen bond acceptor is necessary at this position of the peptide (Figure 6). The fluorinated peptide also

What contributes to an effective mannose recognition domain?

• Christoph P. Sager,
• Deniz Eriş,
• Martin Smieško,
• Rachel Hevey and
• Beat Ernst

Beilstein J. Org. Chem. 2017, 13, 2584–2595, doi:10.3762/bjoc.13.255

• is the highly mannosylated glycoprotein uroplakin 1a (UPIa) [35][36]. The binding pocket of FimH accommodates a single α-D-mannose (1) with an extended hydrogen-bond network [37][38]. Accordingly, any modifications on the hydroxy groups of the mannose virtually abolish binding affinity [37][38][39

• structure based on a homologous MBP lectin domain from Rattus norvegicus and accordingly compared the measured binding affinity of rat MBP (Figure 1, F). Finally, a special case is the bacterial adhesin FimH, which can adopt three different affinity states (see below). For our discussion we focus

• ) forms a complex network of eight hydrogen bonds with ligand 2, one of them mediated by a conserved water [37]. Various approaches to realize binding affinity The immense variability of binding affinities among mannose-binding receptors is remarkable, albeit not surprising. While CRDs involved in the

Homologated amino acids with three vicinal fluorines positioned along the backbone: development of a stereoselective synthesis

• Raju Cheerlavancha,
• Ahmed Ahmed,
• Yun Cheuk Leung,
• Aggie Lawer,
• Qing-Quan Liu,
• Marina Cagnes,
• Hee-Chan Jang,
• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2017, 13, 2316–2325, doi:10.3762/bjoc.13.228

• ; Introduction The incorporation of unnatural amino acids into a peptide structure can potentially reduce conformational disorder and hence improve the binding affinity of the peptide for its biological target. For example, conformationally rigid amino acids such as 1 (Figure 1) have been shown to dramatically

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 novel approach to oxoisoaporphine alkaloids via regioselective metalation of alkoxy isoquinolines

• Benedikt C. Melzer and
• Franz Bracher

Beilstein J. Org. Chem. 2017, 13, 1564–1571, doi:10.3762/bjoc.13.156

• synthetic, oxoisoaporphine-like analogues were found to have strong DNA binding affinity and therefore high cytotoxicity [5] as well as antiplasmodial activity [6]. Besides menisporphine (2), the related oxoisoaporphine alkaloids dauriporphine (3), 6-O-demethylmenisporphine (4), dauriporphinoline (5) and

Synthesis and metal binding properties of N-alkylcarboxyspiropyrans

• Alexis Perry and
• Christina J. Kousseff

Beilstein J. Org. Chem. 2017, 13, 1542–1550, doi:10.3762/bjoc.13.154

• for binding divalent metal cations and a modest increase in M2+ binding affinity correlated with increased alkycarboxylate tether length. Keywords: carboxylate ligand; merocyanine; metal binding; photochromism; spiropyran; Introduction Spiropyrans are a class of spiro-fused indolochromene (e.g

• ). The extension of this basic bidentate ligand with further substituents has been employed to generate structures with bespoke binding characteristics (e.g., metal ion specificity, control of complex stoichiometry, greater binding affinity) [17]. Typifying this approach, Natali et al. synthesised

• divalent over monovalent metal cations and a modest increase in M2+ binding affinity correlated with increasing alkycarboxylate tether length. This paper details a clear, effective protocol for the synthesis of N-alkylcarboxyspiropyrans and a thorough analysis of the effect of metal cations upon their

Synthesis of novel 13α-estrone derivatives by Sonogashira coupling as potential 17β-HSD1 inhibitors

• Ildikó Bacsa,
• Rebeka Jójárt,
• János Wölfling,
• Gyula Schneider,
• Bianka Edina Herman,
• Mihály Szécsi and
• Erzsébet Mernyák

Beilstein J. Org. Chem. 2017, 13, 1303–1309, doi:10.3762/bjoc.13.126

• activity was shown by Poirier et al. [5]. They demonstrated that 13 epimers exhibit no substantial binding affinity for the estrogen receptor alpha and no uterotropic activity. Accordingly, the 13α-estrane core may serve as fundamental moiety for the design of hormonally inactive estrone derivatives