NMR Spectroscopy of supramolecular chemistry on protein surfaces

• Peter Bayer,
• Anja Matena and
• Christine Beuck

Beilstein J. Org. Chem. 2020, 16, 2505–2522, doi:10.3762/bjoc.16.203

• mostly on ligands that recognize either positively or negatively charged patches on a protein surface, discussing the molecules shown in Figure 1 in greater detail. Ligands designed to recognize positively charged regions, containing lysine (Lys) and arginine (Arg) residues, on a protein include

• phosphonate groups. While sulfonato-calix[4]arenes can bind unmodified Lys and Arg residues, their strength lies in the recognition and even tighter binding of methylated lysines [29]. Their binding affinity increases 70-fold from unmethylated over mono- and di- to trimethylated lysine, as every methyl group

• adds more hydrophobic interactions with the aromatic side walls of the bowl-shaped calixarene core. A similar, but even more pronounced trend, is observed for the pumpkin-shaped macrocycle cucurbit[7]uril, favoring the trimethylated over unmethylated lysine by a factor of 3500 [49]. Methylated lysines

Naphthalene diimide–amino acid conjugates as novel fluorimetric and CD probes for differentiation between ds-DNA and ds-RNA

• Annike Weißenstein,
• Myroslav O. Vysotsky,
• Ivo Piantanida and
• Frank Würthner

Beilstein J. Org. Chem. 2020, 16, 2032–2045, doi:10.3762/bjoc.16.170

• [nm] = 581; Φfl = 0.21. Synthesis of (S)-N,N'-bis((3-(trimethylammonium)propyl)amino)-2- (5-amino-5-carboxypentyl)amino-6-chloro-1,4,5,8-naphthalenetetracarboxylic acid diimide dichloride (3b): Diimide (1, 100 mg, 190 µmol) and Nα-(tert-butoxycarbonyl)-ʟ-lysine (95.0 mg, 390 µmol) were placed under

Automated high-content imaging for cellular uptake, from the Schmuck cation to the latest cyclic oligochalcogenides

• Rémi Martinent,
• Javier López-Andarias,
• Dimitri Moreau,
• Yangyang Cheng,
• Naomi Sakai and
• Stefan Matile

Beilstein J. Org. Chem. 2020, 16, 2007–2016, doi:10.3762/bjoc.16.167

• far exceeds the related tetrapeptide analogues with arginine or lysine residues. As a result, the gene transfection efficiency of 13 is better than that of polyethylenimine (PEI) with a large number of charges, which is one of the current standards in gene transfection. The uptake takes place through

• offsetting a charge repulsion of the extra lysine residues, and thus allowing the formation of stable cationic nanofibers. These nanoaggregates, assembled from the monomer 16, are efficient gene transfection vectors. However, the control peptide 17, which cannot self-assemble into nanotubes, shows negative

Synthesis, docking study and biological evaluation of ᴅ-fructofuranosyl and ᴅ-tagatofuranosyl sulfones as potential inhibitors of the mycobacterial galactan synthesis targeting the galactofuranosyltransferase GlfT2

• Marek Baráth,
• Jana Jakubčinová,
• Zuzana Konyariková,
• Stanislav Kozmon,
• Katarína Mikušová and
• Maroš Bella

Beilstein J. Org. Chem. 2020, 16, 1853–1862, doi:10.3762/bjoc.16.152

• C5 hydroxy group very often interacts with the catalytic base aspartate D372 side chain. Moreover, in the poses where this interaction has been found, the C5 hydroxy group creates a hydrogen bond with the ammonium group of the lysine K369 residue. In many docking poses the interaction of the C3

Heterogeneous photocatalysis in flow chemical reactors

• Christopher G. Thomson,
• Ai-Lan Lee and
• Filipe Vilela

Beilstein J. Org. Chem. 2020, 16, 1495–1549, doi:10.3762/bjoc.16.125

A systematic review on silica-, carbon-, and magnetic materials-supported copper species as efficient heterogeneous nanocatalysts in “click” reactions

• Pezhman Shiri and
• Jasem Aboonajmi

Beilstein J. Org. Chem. 2020, 16, 551–586, doi:10.3762/bjoc.16.52

Light-controllable dithienylethene-modified cyclic peptides: photoswitching the in vivo toxicity in zebrafish embryos

• Sergii Afonin,
• Oleg Babii,
• Aline Reuter,
• Volker Middel,
• Masanari Takamiya,
• Uwe Strähle,
• Igor V. Komarov and
• Anne S. Ulrich

Beilstein J. Org. Chem. 2020, 16, 39–49, doi:10.3762/bjoc.16.6

• (open)24h vs LD50(opened)24h. An exception was noted for the elongated analogues 16–18, where the light-generated ring-opened forms did not restore the activity levels observed in the direct application experiment. This behavior could be explained by a decreased proteolytic stability of these lysine

α,ß-Didehydrosuberoylanilide hydroxamic acid (DDSAHA) as precursor and possible analogue of the anticancer drug SAHA

• Shital K. Chattopadhyay,
• Subhankar Ghosh,
• Sarita Sarkar and
• Kakali Bhadra

Beilstein J. Org. Chem. 2019, 15, 2524–2533, doi:10.3762/bjoc.15.245

• , originally recognized as a pan-inhibitor, recent studies have established that it is unable to inhibit Class IIA lysine deacetylases (HDAC/4/5/79), thus showing some selectivity profile [6][7]. Moreover, pan-inhibition is also a cause of increased concern due to adverse side effects [8]. The closely related

Azologization and repurposing of a hetero-stilbene-based kinase inhibitor: towards the design of photoswitchable sirtuin inhibitors

• Christoph W. Grathwol,
• Nathalie Wössner,
• Sören Swyter,
• Adam C. Smith,
• Enrico Tapavicza,
• Robert K. Hofstetter,
• Anja Bodtke,
• Manfred Jung and
• Andreas Link

Beilstein J. Org. Chem. 2019, 15, 2170–2183, doi:10.3762/bjoc.15.214

• . This class of lysine deacetylases (KDACs) is distinguished from others by their dependence on the cosubstrate NAD+. In mammals, seven sirtuin isoforms have been identified to date [1]. These can be grouped into five classes (I, II, III, IV and V) according to their phylogenetic relationship [2]. The

Complexation of chiral amines by resorcin[4]arene sulfonic acids in polar media – circular dichroism and diffusion studies of chirality transfer and solvent dependence

• Bartosz Setner and
• Agnieszka Szumna

Beilstein J. Org. Chem. 2019, 15, 1913–1924, doi:10.3762/bjoc.15.187

• configurations and ee values were simultaneously determined by circular dichroism spectroscopy [20]. Recently, dyn[4]arene, first described by the Leclaire and co-authors [21], was demonstrated to bind various lysine derivatives which leads to distinct ICD outputs in buffered aqueous solution [22]. Even a larger

• ), H-Val-OMe (∙HCl). After a few minutes, complexes of 1 with lysine, arginine and histidine methyl esters precipitated. The obtained solids were isolated and dried in vacuum. 1(LysOMe)2, yield 71% (10 mg). 1H NMR (600 MHz, methanol-d4, δ) 7.28 (s, 4H), 4.58 (t, J = 7.9 Hz, 4H), 4.26 (dd, J = 14.0 Hz

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

• core allowed for various potential linkage options in addition to providing the amine handle for microparticle surface functionalization. Unfortunately, the sterically encumbered tertiary amine of the dendrimer prevented simple coupling of commercially available Nα-TAMRA-Nε-Teoc-L-lysine to the

• dendrimer. Therefore, we settled on first coupling Nα-Fmoc-Nε-(4-methyltrityl)-L-lysine (17) to the dendrimeric amine 18 by standard HATU amide coupling conditions (Scheme 3). The protecting groups were chosen specifically for selective deprotection and compatibility with the TAMRA fluorophore, which is

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

• approach similar to that used in previously described experiments [24], HEK 293T cells (18000 cells cm−1) were seeded in a 4-well ibiTreat µ-Slides (ibidi) Ph+ coated with poly-L-lysine (0.0025

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

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

• biophysical and biochemical methods the domain structure of HBHA has been determined, and includes a canonical lysine-rich C-terminal heparin binding domain (see Figure 5) [83][102][103][104][105], which has been shown to bind sulfated glycoconjugates like heparin, facilitating the adhesion of mycobacteria to

• binding domain. Amino acids involved in heparin bind are colored in blue (lysine) and green (alanine). Recently, pili were detected on the cell surface of Mtb, which were classified as curli and type IV pili (T4P). While the expression of curli pili is associated with biofilm formation and adhesion to

Unnatural α-amino ethyl esters from diethyl malonate or ethyl β-bromo-α-hydroxyiminocarboxylate

• Eloi P. Coutant,
• Vincent Hervin,
• Glwadys Gagnot,
• Candice Ford,
• Racha Baatallah and
• Yves L. Janin

Beilstein J. Org. Chem. 2018, 14, 2853–2860, doi:10.3762/bjoc.14.264

• was used for the historic preparation of racemic lysine from diethyl malonate and γ-chlorobutyronitrile [4] and appears to be of a very large scope. The key α-hydroxyimino esters 2 precursors to the α-amino esters 1 are usually prepared by oximation of substituted malonates 3, themselves made, for

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

• in high chemical yield and purity by strategically introducing differentially protected dibasic amino acids such as lysine whose α- and ε-amino groups are protected as base labile Fmoc and trifluoroacetyl (Tfa) protecting groups, respectively. The whole concept is successfully illustrated using

• position of the fluorescent tag and chelating core would lie outside the surface of the protein tunnel. Moreover, differentially protected α- and ε-amino groups of the amino acid lysine (Lys), Fmoc-Lys-(Tfa)-OH, is also introduced in the peptide chain. The main purpose of this exercise is to connect the

• chelating core through carboxylic acid of lysine and attachment of fluorescent probe via ε-amino group present in the lysine amino acid. Increased hydrophobicity due to the introduction of long chain amino acids, aromatic amino acids in the targeted ligand peptide conjugate 13 would decrease the solubility

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

• literature procedure in two steps (Scheme 2) [16]. Building block 7 was coupled to commercially available L-lysine methyl ester dihydrochloride to yield 8 in moderate yield. The majority of the dicyclohexylurea byproduct could be removed by cooling a solution of the residue dissolved in acetonitrile; however

Investigation of the electrophilic reactivity of the biologically active marine sesquiterpenoid onchidal and model compounds

• Melissa M. Cadelis and
• Brent R. Copp

Beilstein J. Org. Chem. 2018, 14, 2229–2235, doi:10.3762/bjoc.14.197

• , Figure 4), while enol esters 13 and 17 gave 29 and 31 (7% and 5% yields), respectively, upon reaction with the amine nucleophile. We next investigated the reactivity of onchidal (6) and analogues 11–13 and 15–17 towards the lysine-rich model protein lysozyme. Previous studies have reported hen egg white

• ), three new peaks representing mass additions of +198 mu, +216 mu, and +230 mu were detected (Figure 5 and Table 1). These adducts are likely the result of the reaction of lysine residues present in the enzyme [17]. The latter two adducts are proposed to be pyrrole adducts with incorporation of solvolytic

• apparent with the lysine-rich enzyme hen egg white lysozyme, with onchidal (6) and model compounds 11–13 and 15–17 affording pyrrole adducts of the enzyme that were detected by (+)-ESIMS. The more reactive dialdehydes were also found to lead to protein crosslinking with formation of lysozyme dimers and

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

• was already determined [28]. In this case, the uptake turned out to be very low, what is in agreement with our results. The observed enhanced cellular uptake of the novel chimeric peptides might be due to an increased amount of positive charges caused by the presence of more lysine and arginine

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

• -DNA by fluorescence microscopy with preference for A·T-rich sequences [106]. Two positively charged lysine residues are expected to interact with ds-DNA electrostatically. Upon binding to the minor groove of ds-DNA, the conformation of conjugate 43 was changed from an extended to a folded form

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

• 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

• lysine contains a free amine group (εNH2) allowing orthogonal coupling with a cytotoxic warhead [19]. A considerable number of PDCs based on GnRH [59][60][61][62][63] exist and our group has exploited this peptide to construct two PDCs [18][19]. Somatostatin (SST): Somatostatin is a neuropeptide produced

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

• spacer to the lysine side chain connected to the chatepsin B labile GFLG spacer that allows lysosomal drug release. Dau was conjugated to the GFLG spacer via oxime linkage through an incorporated aminooxyacetyl (Aoa) moiety. The preparation of the conjugate required a sophisticated synthetic route and

• different amino acids (Ala, Leu, Nle, Pro and Ser). The main goal of the present study was to investigate whether the exchange of the lysine in the cycle has any influence on the chemostability, selectivity and antitumor activity of the conjugates. Here we report on the synthesis and characterization of the

Phosphodiester models for cleavage of nucleic acids

• Satu Mikkola,
• Tuomas Lönnberg and
• Harri Lönnberg

Beilstein J. Org. Chem. 2018, 14, 803–837, doi:10.3762/bjoc.14.68

• transfer from the attacking 2´-OH to non-bridging phosphoryl oxygen. Primary amines are, in turn, used to mimic the action of the ε-amino group of lysine. Both guanidine and primary amino groups are basic functions that at physiological pH are present as guanidinium and ammonium ions. These ions tend to

• the lysine ε-amino group in the catalytic center of RNase A has been elucidated by incorporating an amino group covalently in the vicinity of the scissile phosphodiester linkage of the model compound. For this purpose, compound 12a bearing two aminomethyl groups at C4´ was prepared and its reactions

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

• ) and human colon cancer cells (HT-29), is GnRH-III–[4Lys(Bu), 8Lys(Dau=Aoa)] (K2). Recent studies demonstrated that the butyrilation of the lysine in position 4 not only leads to an increased in vitro but also to an enhanced in vivo antitumor activity [29][30]. In order to achieve a better

• homogenate. Results and Discussion Synthesis of oxime bond-linked GnRH-III–[4Ser/Lys(Bu), 6Aaa, 8Lys(Dau=Aoa)] bioconjugates The GnRH-III bioconjugates were prepared as shown in Scheme 1. All peptides were synthesized by standard Fmoc-SPPS using orthogonal lysine protecting groups. Fmoc-Lys(Dde)-OH was

• . Furthermore, the incorporation of an acetylated lysine instead of the native serine in position 4 decelerated the degradation by α-chymotrypsin which catalyzed the hydrolysis of the peptide bond exclusively between 3Trp and 4Aaa. A similar effect was observed for GnRH-III conjugates in which the ε-amino group

Mannich base-connected syntheses mediated by ortho-quinone methides

• Petra Barta,
• Ferenc Fülöp and
• István Szatmári

Beilstein J. Org. Chem. 2018, 14, 560–575, doi:10.3762/bjoc.14.43

• such intermediates. By selecting the appropriate reaction conditions (various pH and temperatures), they were able to alkylate free amino acids, e.g., glycine (Gly), L-serine (Ser), L-cysteine (Cys), L-lysine (Lys), L-tyrosine (Tyr) and glutathione (Glu) in aqueous solution to isolate 55 (Scheme 8