Chemical approaches to discover the full potential of peptide nucleic acids in biomedical applications

• Nikita Brodyagin,
• Martins Katkevics,
• Venubabu Kotikam,
• Christopher A. Ryan and
• Eriks Rozners

Beilstein J. Org. Chem. 2021, 17, 1641–1688, doi:10.3762/bjoc.17.116

• , especially, red-shifted dyes with stronger fluorescence enhancement. Future design of novel PNA nucleobases that enhance the fluorescence signal while selectively hybridizing to natural nucleobases will be highly beneficial for in vitro and in vivo probes and diagnostics. Covalent PNA conjugates for delivery

• ][159][160]. Looking forward, conjugation of PNA with various delivery enhancing compounds, most notably cell-penetrating peptides (CPP) that deliver the conjugates mainly through endocytosis (Figure 11) has become one of the most promising approaches to improving cellular uptake of PNA [161][162

• ]. However, the uptake of most PNA–CPP conjugates is limited by endosomal entrapment. While the uptake can be improved either by increasing the concentration of PNA–CPP conjugates or by using endosomolytic compounds (for example, chloroquine or calcium ions) this leads to toxicity that is not viable for in

Total synthesis of ent-pavettamine

• Memory Zimuwandeyi,
• Manuel A. Fernandes,
• Amanda L. Rousseau and
• Moira L. Bode

Beilstein J. Org. Chem. 2021, 17, 1440–1446, doi:10.3762/bjoc.17.99

• metabolic regulators [5]. In addition to this, some PAs are currently being used as therapeutic drugs, being incorporated as drug conjugates, or are under investigation for other applications [6][7][8][9][10][11][12]. The elucidation of the structure of pavettamine revealed a new class of polyamines with a

Enhanced target cell specificity and uptake of lipid nanoparticles using RNA aptamers and peptides

• Roslyn M. Ray,
• Anders Højgaard Hansen,
• Maria Taskova,
• Bernhard Jandl,
• Jonas Hansen,
• Citra Soemardy,
• Kevin V. Morris and
• Kira Astakhova

Beilstein J. Org. Chem. 2021, 17, 891–907, doi:10.3762/bjoc.17.75

• -HAIYPRH-NH2 Tat: H-YGRKKRRQRRR-NH2 Modified Tat: dipalmitoyl-Dap-YGRKKRRQRRR-NH2 Peptide conjugation with a lipid reagent The peptides were N-terminally modified on solid support by coupling of Fmoc-Dap(Fmoc)-OH, followed by the coupling of palmitic acid to afford the complete peptide–lipid conjugates

• . Coupling of Fmoc-Dap(Fmoc)-OH and Fmoc deprotection were carried out as described above. To ensure the complete lipidation of the two free amines of Dap, 8 equiv of palmitic acid, 8 equiv of HATU, and 12 equiv of DIPEA in DMF were used. Cleavage of the peptide–lipid conjugates from the solid support and

[2 + 1] Cycloaddition reactions of fullerene C₆₀ based on diazo compounds

• Yuliya N. Biglova

Beilstein J. Org. Chem. 2021, 17, 630–670, doi:10.3762/bjoc.17.55

• biologically active molecules that already find practical use. It has been found that complexation improves the transportation of a drug and prolongs its effect, and a synergistic effect is observed in some cases [36]. The situation with covalent binding in fullerene–drug conjugates is different. C60 is an

• ideal partner for drug lipophilization by conjugation [37]. Highly efficient fullerene conjugates with chemotherapeutic agents have been synthesized and patented; moreover, the biological activity profile is often preserved, but in some cases it can also change since a molecular structure with a

• given in Scheme 9 [87]. On this pathway for the synthesis of conjugates 19 and 20, acid 18 is cross-linked with a peptide component using a milder carbodiimide method via the starting methanofullerene 17. Similar to Scheme 8, fullerene adducts 21 and 22 with glycine and phenylalanine, respectively, were

Synthesis and physicochemical evaluation of fluorinated lipopeptide precursors of ligands for microbubble targeting

• Masayori Hagimori,
• Estefanía E. Mendoza-Ortega and
• Marie Pierre Krafft

Beilstein J. Org. Chem. 2021, 17, 511–518, doi:10.3762/bjoc.17.45

• Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan 10.3762/bjoc.17.45 Abstract Ligand-targeted microbubbles are focusing interest for molecular imaging and delivery of chemotherapeutics. Lipid–peptide conjugates (lipopeptides) that feature alternating

• hydrophobic chains (CnF2n+1, n = 6, 7, 8, 1–3) grafted through a lysine moiety on a hydrophilic chain composed of a lysine–serine–serine (KSS) sequence followed by 5 SG sequences. These F-lipopeptides are precursors of targeting lipopeptide conjugates. A hydrocarbon counterpart with a C10H21 chain (4) was

• particular cell surface receptor [7][9][10][11][12][13][14]. To this aim, ligand–lipid conjugates have been developed in research and preclinical development for liposome targeting for decades. In particular, peptide ligands offer significant advantages, including efficient synthesis routes, versatility, and

1,2,3-Triazoles as leaving groups: S_NAr reactions of 2,6-bistriazolylpurines with O- and C-nucleophiles

• Dace Cīrule,
• Irina Novosjolova,
• Ērika Bizdēna and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 410–419, doi:10.3762/bjoc.17.37

• temperatures to be completed. Among the widely studied 1,2,3-triazolyl nucleoside conjugates [57][58], the synthesis of 2-triazolylpurine derivatives containing a designed substituent at C6 has been little discussed. 6-N-Substituted purines have been the most studied [11][59][60][61][62], but 6-S- [14][63] or

Regioselective chemoenzymatic syntheses of ferulate conjugates as chromogenic substrates for feruloyl esterases

• Olga Gherbovet,
• Fernando Ferreira,
• Apolline Clément,
• Mélanie Ragon,
• Julien Durand,
• Sophie Bozonnet,
• Michael J. O'Donohue and
• Régis Fauré

Beilstein J. Org. Chem. 2021, 17, 325–333, doi:10.3762/bjoc.17.30

• regioselective functionalization of 4-nitrocatechol and enzymatic transferuloylation. The use of this strategy to characterize type A feruloyl esterase from Aspergillus niger reveals the advantages of this substrate for the characterizations of feruloyl esterases. Keywords: esterase; feruloylated conjugates

¹⁹F NMR as a tool in chemical biology

• Diana Gimenez,
• Aoife Phelan,
• Cormac D. Murphy and
• Steven L. Cobb

Beilstein J. Org. Chem. 2021, 17, 293–318, doi:10.3762/bjoc.17.28

• cell lines [44]. Here, the incorporation of CF3 and CF3O groups as NMR reporters into the tumour-targeting drug conjugates enabled the direct investigation of the mechanism of the pro-drug metabolic cleavage and the pharmacophore release by real-time 19F NMR analysis. 19F NMR was also employed as a

Supramolecular polymerization of sulfated dendritic peptide amphiphiles into multivalent L-selectin binders

• David Straßburger,
• Svenja Herziger,
• Katharina Huth,
• Moritz Urschbach,
• Rainer Haag and
• Pol Besenius

Beilstein J. Org. Chem. 2021, 17, 97–104, doi:10.3762/bjoc.17.10

• to its functionalization with negatively charged sulfate groups. The binding behavior of dPGS to L-selectin has been thoroughly probed as dendrimer [26][27], conjugated to a polymer [28] or as amphiphilic adamantyl conjugates that are able to self-assemble on cyclodextrin vesicles [29]. Our group

Changed reactivity of secondary hydroxy groups in C8-modified adenosine – lessons learned from silylation

• Jennifer Frommer and
• Sabine Müller

Beilstein J. Org. Chem. 2020, 16, 2854–2861, doi:10.3762/bjoc.16.234

• , functionalized phosphoramidite building blocks of all four nucleosides are highly desired. The number of commercially available RNA phosphoramidites that carry a suitable functionality for post-synthetic attachment of dyes, reporter groups or other conjugates is still rather limited. In particular, monomer

Synthesis and investigation of quadruplex-DNA-binding, 9-O-substituted berberine derivatives

• Jonas Becher,
• Daria V. Berdnikova,
• Heiko Ihmels and
• Christopher Stremmel

Beilstein J. Org. Chem. 2020, 16, 2795–2806, doi:10.3762/bjoc.16.230

• berberine derivatives was synthesized by the Cu-catalyzed click reaction of 9-propargyladenine with 9-O-(azidoalkyl)berberine derivatives. The association of the resulting berberine–adenine conjugates with representative quadruplex-forming oligonucleotides 22AG dA(G3TTA)3G3 and a2 d(ACAG4TGTG4)2 was

• with one representative ligand from the series that such berberine–adenine conjugates exhibit a selective binding, specifically a selectivity to quadruplex DNA in competition with duplex DNA, and a preferential thermal stabilization of the G4-DNA forms 22AG and KRAS. Notably, the experimental data do

• . With this background, we proposed that the functionalization of the berberine scaffold with adenine-appended alkyl substituents may provide a useful platform to further explore this important aspect. Specifically, we wished to examine whether adenine–berberine conjugates with a varying linker length

3-Acetoxy-fatty acid isoprenyl esters from androconia of the ithomiine butterfly Ithomia salapia

• Florian Mann,
• Daiane Szczerbowski,
• Lisa de Silva,
• Melanie McClure,
• Marianne Elias and
• Stefan Schulz

Beilstein J. Org. Chem. 2020, 16, 2776–2787, doi:10.3762/bjoc.16.228

• -6-nonenoic acid and derivatives including dimers and fatty acid conjugates as major constituents of the androconia of Oleria onega [18]. Here we report on the chemical composition of the androconia of Ithomia salapia aquinia and I. s. derasa. A new type of butterfly scent gland constituents

The B & B approach: Ball-milling conjugation of dextran with phenylboronic acid (PBA)-functionalized BODIPY

• Patrizia Andreozzi,
• Lorenza Tamberi,
• Elisamaria Tasca,
• Gina Elena Giacomazzo,
• Marta Martinez,
• Mirko Severi,
• Marco Marradi,
• Stefano Cicchi,
• Sergio Moya,
• Giacomo Biagiotti and
• Barbara Richichi

Beilstein J. Org. Chem. 2020, 16, 2272–2281, doi:10.3762/bjoc.16.188

• range of biomolecules: amino acids [8], peptides [9], glycosides [10], nucleosides/nucleotides [11], and lipids [12]. Also, protein-based nano-bio-conjugates [13] have been prepared by ball milling, retaining the native properties of the proteins after mechanochemical synthesis. Boronic acids and their

• ) in the conventional approach was higher compared to the ball billing approach (Figure 2A). The yield of both, solution-based and ball mill conjugations was monitored by measuring the absorption of the conjugates (λmax = 508–511 nm) and the relative amount of conjugated PBA-BODIPY (1) was calculated

• conjugate (milled reaction) compared to a 0.61% w/w of 1 in the Dex-1a conjugate (conventional solution reaction) was obtained. The loading of 1 in both conjugates was also confirmed by inductively coupled plasma atomic emission spectroscopy (ICP-AES) analysis which showed in Dex-1b a boron content roughly

Synthetic approaches to bowl-shaped π-conjugated sumanene and its congeners

• Shakeel Alvi and
• Rashid Ali

Beilstein J. Org. Chem. 2020, 16, 2212–2259, doi:10.3762/bjoc.16.186

• ferrocene–sumanene conjugates by employing reductive amination reaction for the formation of compounds 110 and 116. Whereas compounds 111, 113, and 117 were prepared by means of condensation reaction as depicted in Scheme 27. On the other hand, Lentz’s group has reported the synthesis of sumanenylferrocene

Naphthalene diimide bis-guanidinio-carbonyl-pyrrole as a pH-switchable threading DNA intercalator

• Poulami Jana,
• Filip Šupljika,
• Carsten Schmuck and
• Ivo Piantanida

Beilstein J. Org. Chem. 2020, 16, 2201–2211, doi:10.3762/bjoc.16.185

• recognition of various DNA/RNA sequences could be reversibly changed by adjusting the pH of the solution. The fine structural tuning of such aryl-GCP conjugates allowed us to prepare a wide variety of small molecules with different DNA or RNA sequence selectivity, many of them acting as multipurpose probes

• most likely bind within one of the DNA/RNA grooves, as in previously described aryl-GCP conjugates [16][17][18][19][20][21][22]. Further, the designed novel naphthalene diimide (NDI) analogue 4 (Scheme 1) is characterized by four pH-dependent positive charges, two of them present at neutral conditions

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

• interacted with ds-DNA/RNA by threading intercalation. Different from a reference NDI dye with identical visible range absorbance (520–540 nm) and Stokes shifts in emission (+60 nm, quantum yield > 0.2), only these amino acid–NDI conjugates showed selective fluorimetric response for GC-DNA in respect to AT(U

• developed several series of fluorophore–amino acid conjugates, thereby making use of the availability of C- and N-terminal amino acid residues for peptide-bond formation. Also, several short multichromophoric peptide constructs were prepared and studied with regard to their interactions with DNA/RNA [11][12

• ][13][14][15][16]. These inspiring results encouraged us to broaden the palette of available amino acid (AA)–chromophore conjugates. Therefore, in this work we have chosen a naphthalene diimide (NDI) chromophore [17][18][19][20], a well-known DNA/RNA binding moiety, which differs from previously used

Cation-induced ring-opening and oxidation reaction of photoreluctant spirooxazine–quinolizinium conjugates

• Phil M. Pithan,
• Sören Steup and
• Heiko Ihmels

Beilstein J. Org. Chem. 2020, 16, 904–916, doi:10.3762/bjoc.16.82

• the quinolizinium ion to develop photoswitchable functional quinolizinium derivatives. With this goal in mind, we synthesized and investigated the spirooxazine–quinolizinium conjugates 3a and 3b. But much to our surprise, our studies revealed that these derivatives are among the rare examples of

• photoreluctant spirooxazine derivatives with regard to the electrocyclic ring opening, and they could not be employed as molecular photoswitches. At the same time, however, we discovered that the addition of Cu2+ or Fe3+ to the conjugates 3a and 3b, respectively, led to the fast and quantitative formation of

• indolinonaphthoxazoles. Herein, we present the synthesis of, and investigation on the conjugates 3a and 3b, as well as mechanistic studies on the metal ion-induced formation of the derivatives 4a and 4b, along with the pertinent spectroscopic data of the products. Results and Discussion Synthesis The spirooxazine

p-Pyridinyl oxime carbamates: synthesis, DNA binding, DNA photocleaving activity and theoretical photodegradation studies

• Panagiotis S. Gritzapis,
• Panayiotis C. Varras,
• Nikolaos-Panagiotis Andreou,
• Katerina R. Katsani,
• Konstantinos Dafnopoulos,
• George Psomas,
• Zisis V. Peitsinis,
• Alexandros E. Koumbis and
• Konstantina C. Fylaktakidou

Beilstein J. Org. Chem. 2020, 16, 337–350, doi:10.3762/bjoc.16.33

• amidoxime, ethanone oxime and aldoxime (VI, VII, VIII, R1 = p-pyridyl, Figure 1) as DNA photosensitizers. Based on our previous experimental results with o-, m- and p-pyridine oximes as carriers of the carboxylic [9] and sulfonic [11] ester conjugates, we proclaimed p-substituted pyridine ring as the most

• appropriate oxime supporting scaffold for experimenting with our novel carbamate esters, because this ring exhibited a better profile compared to the other pyridine analogues [9][11]. In order to provide a structure–activity relationship study, a series of O-carbamoyl conjugates consisted of benzyl as well as

Chemical tuning of photoswitchable azobenzenes: a photopharmacological case study using nicotinic transmission

• Lorenzo Sansalone,
• Jun Zhao,
• Matthew T. Richers and
• Graham C. R. Ellis-Davies

Beilstein J. Org. Chem. 2019, 15, 2812–2821, doi:10.3762/bjoc.15.274

• the electron donor effect of the methylene substituent decreases the thermodynamic stability of the cis form compared to that report by Hecht [13], protein conjugates of 1 would be highly stable in vivo over the course of a typical daily mouse behavioral experiment [15]. cis-MAHoCh has a significantly

• retention time on UPLC (Figure 3). LC–MS analysis revealed a molecular ion confirming the addition product 12. Under the conditions we used for this chemical reaction it was complete within a few minutes. It has been reported that maleimide–peptide conjugates undergo hydrolysis of the succinimide to give a

• physiological conditions. The broad success [22] of this strategy since 2004 [19] suggests that even though careful in silico modeling is a standard step in photoprobe development [22], this is always performed with unhydrolyzed conjugates. Perhaps for long-term use in vivo an additional modeling step involving

Photoreversible stretching of a BAPTA chelator marshalling Ca²⁺-binding in aqueous media

• Aurélien Ducrot,
• Arnaud Tron,
• Robin Bofinger,
• Ingrid Sanz Beguer,
• Jean-Luc Pozzo and
• Nathan D. McClenaghan

Beilstein J. Org. Chem. 2019, 15, 2801–2811, doi:10.3762/bjoc.15.273

• chelating groups would also have a significant effect. Some groups reported BAPTA-diarylethene and EDTA-spiropyran conjugates, while noting limitations for implementation in terms of fatigue, solubility and relatively small affinity changes [25][26]. We further highlight a structurally elegant design

Fluorinated maleimide-substituted porphyrins and chlorins: synthesis and characterization

• Valentina A. Ol’shevskaya,
• Elena G. Kononova and
• Andrei V. Zaitsev

Beilstein J. Org. Chem. 2019, 15, 2704–2709, doi:10.3762/bjoc.15.263

• ) or Ni(II) with N-propargylmaleimide via the CuAAC click reaction to afford fluorinated porphyrin–triazole–maleimide conjugates. New maleimide derivatives were isolated in reasonable yields and identified by UV–vis, 1H NMR, 19F NMR spectroscopy and mass-spectrometry. Keywords: chlorin; maleimide

• the maleimide group with its rich biological activity to the tetrapyrrole macrocycles with their unique photophysical properties may result in new conjugates with improved chemical, biological and anticancer characteristics [28]. Moreover, maleimide is a stable functionality that rapidly and

• covalently conjugates thiol groups of cysteine residues in proteins or peptides by the thio-Michael addition to the double bond of the maleimide to form a corresponding succinimidyl thioether. Conjugation of the cysteine sulfhydryl group with maleimide moieties allows us to prepare the bioconjugates

In search of visible-light photoresponsive peptide nucleic acids (PNAs) for reversible control of DNA hybridization

• Lei Zhang,
• Greta Linden and
• Olalla Vázquez

Beilstein J. Org. Chem. 2019, 15, 2500–2508, doi:10.3762/bjoc.15.243

• tetra-ortho-fluoroazobenzene–PNA conjugates have promising properties (fast reversible isomerization, exceptional thermal stability, high isomer conversions and sensitivity to visible-light irradiation) as reversible modulators to control oligonucleotide hybridization in biological contexts. Furthermore

• compatible with the standard TFA/m-cresol/H2O (90:5:5) acidolysis yielding the photoswitchable PNA conjugates. These and all further studied PNAs in this work (Table 2) were purified by reversed-phase (RP) HPLC and fully characterized. Analogous compounds lacking the photoswitch were used as controls. First

• synthesized longer PNA conjugates (6–11, 18 and 19) with flanking lysines, which improved the solubility of the probes. In addition, we compared our probes with the ones that contained the classical unmodified azobenzene moiety (Azo) (PNA 12–17). The lower stability of the unmodified cis-Azo forced us to

Archangelolide: A sesquiterpene lactone with immunobiological potential from Laserpitium archangelica

• Silvie Rimpelová,
• Michal Jurášek,
• Lucie Peterková,
• Jiří Bejček,
• Vojtěch Spiwok,
• Miloš Majdl,
• Michal Jirásko,
• Miloš Buděšínský,
• Juraj Harmatha,
• Eva Kmoníčková,
• Pavel Drašar and
• Tomáš Ruml

Beilstein J. Org. Chem. 2019, 15, 1933–1944, doi:10.3762/bjoc.15.189

• ] and was also found to be cytotoxic with localization to the endoplasmic reticulum [8]. The cytotoxicity of compound 2 prompted the preparation and evaluation of compound 2 conjugates with porphyrins [9] and steroids [10] for targeted uptake of compound 2 into cancer cells, and the conjugates showed

• these compounds for further work including synthetic modifications using azide–alkyne Huisgen cycloaddition. We previously showed the preparation of fluorescent trilobolide conjugates [8] that retained the activity of the parental compounds and proved to be useful for live-cell imaging. In this article

Design, synthesis and biological evaluation of immunostimulating mannosylated desmuramyl peptides

• Rosana Ribić,
• Ranko Stojković,
• Lidija Milković,
• Mariastefania Antica,
• Marko Cigler and
• Srđanka Tomić

Beilstein J. Org. Chem. 2019, 15, 1805–1814, doi:10.3762/bjoc.15.174

• the adjuvant activity in experiments in vivo [20][21]. Two series of manno-conjugates were prepared: (i) derivatives with glycolyl linker and (ii) the ones with (R)-hydroxyisobutyryl linker which is present in the parent ManAdTP. The glycolic linker was introduced due to the fact that N-glycolyl

Steroid diversification by multicomponent reactions

• Leslie Reguera,
• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Daniel G. Rivera

Beilstein J. Org. Chem. 2019, 15, 1236–1256, doi:10.3762/bjoc.15.121

• paraformaldehyde and benzyl isocyanide to form hybrid 11 in good yield. Similarly, the spirostanic lactone 12 was transformed into spirostanic acid 13 and amine 14, which were next ligated to alanine methyl ester and Boc-histidine leading to the amino acid–steroid conjugates 15 and 16, respectively. This approach

• Conjugation of steroids to carbohydrates and peptides The conjugation of steroids to other biomolecules such as carbohydrates and peptides represents a valuable strategy for providing new properties to the hydrophobic steroid skeleton. Naturally occurring steroid–sugar conjugates such as saponins have shown

• to possess physicochemical and biological features different from those of the two separate molecular entities [57][58]. Despite nature does not provide examples of steroid–peptide conjugates, chemists have produced such conjugates to be employed as protease-like artificial enzymes [59] as mimics of