Ring-closing-metathesis-based synthesis of annellated coumarins from 8-allylcoumarins

• Christiane Schultze and
• Bernd Schmidt

Beilstein J. Org. Chem. 2018, 14, 2991–2998, doi:10.3762/bjoc.14.278

• these established methods necessary. Examples from the past 15 years include transition metal-catalyzed transformations [21][22][23], solid-phase synthesis directed at combinatorial library design [24] and organocatalytic annellation reactions [25][26]. Sparked by our interest in the development and

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

• successfully designed and demonstrated a novel continuous process for assembling targeting ligands, peptidic spacers, fluorescent tags and a chelating core for the attachment of cytotoxic molecules, radiotracers, nanomaterials in a standard Fmoc solid-phase peptide synthesis in high yield and purity. The

• differentially protected Fmoc-Lys-(Tfa)-OH plays a vital role in attaching fluorescent tags while growing the peptide chain in an uninterrupted manner. The methodology is versatile for solid-phase resins that are sensitive to mild and strong acidic conditions when acid-sensitive side chain amino protecting

• tag; Fmoc-Lys-(Tfa)-OH; prostate cancer and ovarian cancer; solid-phase peptide synthesis; Introduction The understanding of cell processes is indispensable to devise new strategies for diagnosis and treatment of cancer and inflammatory diseases through targeted drug delivery techniques [1]. The

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

• antiproliferative/cytotoxic activities, the cell adhesion and migration modulator effects of conjugates and their ability to induce apoptosis or cell cycle arrest in A2058 melanoma cell line. Results and Discussion Synthesis of Dau–GnRH-III conjugates The modified GnRH-III derivatives were prepared by solid phase

Defining the hydrophobic interactions that drive competence stimulating peptide (CSP)-ComD binding in Streptococcus pneumoniae

• Bimal Koirala,
• Robert A. Hillman,
• Erin K. Tiwold,
• Michael A. Bertucci and
• Yftah Tal-Gan

Beilstein J. Org. Chem. 2018, 14, 1769–1777, doi:10.3762/bjoc.14.151

• ), homophenylalanine (hPhe), or Tyr; Figure 3). The CSP1 analogs were constructed using standard solid-phase peptide synthesis (SPPS) protocols (see Materials and Methods for SPPS procedures), followed by purification to homogeneity by semipreparative RP-HPLC (see the Supporting Information File 1 for full

• reagents and instrumentation. All chemical reagents and solvents were purchased from Sigma-Aldrich and used without further purification. Water (18 MΩ) was purified using a Millipore Analyzer Feed System. Solid-phase resins were purchased from Chem-Impex or P3 Biosystems. Reversed-phase high-performance

• . All the CSP1 analogs were synthesized on a 4-benzyloxybenzyl alcohol (Wang) resin (0.65 mmol/g) pre-loaded with Fmoc-L-Lys(Boc). With the exception of the phenylglycine and norvaline derivatives, the CSP1 analogs were synthesized using standard Fmoc-based solid-phase peptide synthesis (SPPS

An amine protecting group deprotectable under nearly neutral oxidative conditions

• Shahien Shahsavari,
• Chase McNamara,
• Mark Sylvester,
• Emily Bromley,
• Savannah Joslin,
• Bao-Yuan Lu and
• Shiyue Fang

Beilstein J. Org. Chem. 2018, 14, 1750–1757, doi:10.3762/bjoc.14.149

• Dmoc group for amine protection in automated solid-phase oligodeoxynucleotide (ODN) synthesis [18]. For deprotection, we found that sodium periodate could effectively oxidize multiple Dmoc functions in the ODNs to achieve complete deprotection. Under these oxidative conditions, oxidation of the ODN was

Natural and redesigned wasp venom peptides with selective antitumoral activity

• Marcelo D. T. Torres,
• Gislaine P. Andrade,
• Roseli H. Sato,
• Cibele N. Pedron,
• Tania M. Manieri,
• Giselle Cerchiaro,
• Anderson O. Ribeiro,
• Cesar de la Fuente-Nunez and
• Vani X. Oliveira Jr.

Beilstein J. Org. Chem. 2018, 14, 1693–1703, doi:10.3762/bjoc.14.144

• , purification and analysis Peptides were synthesized by solid-phase peptide synthesis on Rink Amide resin, with a substitution degree of 0.52 mmol g−1 on a 0.1 mmol scale, using the Fmoc strategy on a peptide synthesizer (PS3 – Protein Technologies) as described by Torres et al. [9][10]. Dry-protected peptidyl

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

• here are shown in Figure 1 and Figure 2. The GnRH derivatives were prepared by solid phase peptide synthesis (SPPS) according to Fmoc/t-Bu strategy (Supporting Information File 1). Three drug molecules, doxorubicin (Dox), daunorubicin (Dau) and methotrexate (Mtx), were employed in the preparation of

• acid followed by its attachment to the ε-amino group of 8Lys in GnRH-III. The conjugation was carried out in the presence of PyBOP/HOBt coupling agents resulting in conjugate 2. For the preparation of the oxime linkage, a Boc protected aminooxyacetic acid was attached to the Lys side chain on solid

• phase prior to the cleavage of the peptide derivatives from the resin. The oxime bond formation was carried out in 0.2 M NaOAc solution at pH 5 for 12 hours. In contrast to the synthesis of the conjugates with ester or amide bond, the oxime bond formation was almost quantitatively. In the case of the

Phosphoramidite building blocks with protected nitroxides for the synthesis of spin-labeled DNA and RNA

• Timo Weinrich,
• Eva A. Jaumann,
• Ute M. Scheffer,
• Thomas F. Prisner and
• Michael W. Göbel

Beilstein J. Org. Chem. 2018, 14, 1563–1569, doi:10.3762/bjoc.14.133

• therefore developed a third strategy based on photolabile protective groups [41][42][43] finally leading to phosphoramidite 6. This building block behaves in solid-phase RNA synthesis as any normal TOM protected amidite. It is completely stable against the conditions used for strand assembly, RNA

• are seen with DNA analogs 22c and 24c, in full accord with NUPACK predictions and the experimentally observed levels of modulation depth. Conclusion All three phosphoramidite building blocks 5, 7, and 8 are applicable for automated solid-phase synthesis using standard reaction cycles. As in the case

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

• sequences, as well as sC18* alone. All peptides were readily synthesized via Fmoc/t-Bu solid-phase peptide synthesis, purified, and analyzed by LC–MS methods as previously described [19][20]. Moreover, 5(6)-carboxyfluorescein (CF)-labeled versions were generated (Table 1). As shown in Table 1 and Figures S1

• synthesized using a combination of standard Fmoc/t-Bu solid-phase peptide synthesis (SPPS) on a Syro I peptide synthesizer (MultiSynTech, Bochum, Germany) and manual coupling protocols according to previous works [17][19][20]. Peptides were generated on a Rink amide resin (loading 0.48 mmol/g) yielding C

Oligonucleotide analogues with cationic backbone linkages

• Melissa Meng and
• Christian Ducho

Beilstein J. Org. Chem. 2018, 14, 1293–1308, doi:10.3762/bjoc.14.111

• oligonucleotide analogues was performed on solid support using H-phosphonate chemistry (Scheme 1). Thus, solid phase-linked thymidine 12 was coupled with 5'-dimethoxytrityl-(DMTr)-protected thymidine 3'-H-phosphonate 13 to give dimeric H-phosphonate 14, which was then acidically DMTr-deprotected to furnish 15

• , Bruice and co-workers used an iterative solution-phase protocol (reactions not shown) [51]. This method was associated with some limitations, such as its moderate yields and the need for purification after each synthetic step. Subsequently, two different approaches for the solid phase-supported synthesis

• was then converted into a reactive carbodiimide 24 and coupled to a terminal amino group of the solid phase 25 (Scheme 2). This coupling furnished solid phase-attached intermediate 26, which was Fmoc-deprotected to the amine 27. Iterative repetition of this coupling-deprotection cycle gave oligomer 28

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

• ) reagent FPID and (4-MeOC6H4)3P was successfully applied to solid-phase peptide synthesis and cyclic peptide synthesis. Four peptides with biological activities were synthesized through SPPS and the bioactive cyclic heptapeptide pseudostellarin D was obtained via solution-phase peptide synthesis. It is

• worth noting that FPID can be readily regenerated after the peptide coupling reaction. Keywords: cyclic peptide; FPID; hypervalent iodine(III) reagent; recyclable; solid-phase peptide synthesis (SPPS); Introduction The amide bond is one of the most fundamental functional groups in organic chemistry

• mechanism for this FPID-mediated amide bond formation reaction was proposed with the acyloxyphosphonium intermediate B being the key intermediate (Scheme 1). Herein, as part of our continuing exploration of the application of FPID in peptide synthesis, we disclose its successful application in solid-phase

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

• phase synthetic approach for the syntheses of cyclic Py/Im polyamides [84]. This group previously optimized and reported a machine-assisted Fmoc solid phase synthesis of simpler polyamides to afford high step-wise coupling yield [85]. A seven-member library of cyclic polyamides targeting androgen

• challenging tandem hairpin Py/Im polyamides which could recognize >10 base pairs with flexible linker conjugated with a fluorescent dye (either Texas Red (TR) or Cyanine 3 (Cy3)) using a Fmoc-based solid phase synthetic approach; two of the representative conjugates 23 and 24 are shown in the Figure 8 [86][87

• sequence-specific DNA binding, the lack of viable strategies for facile synthesis of library of structural variants of these classes of conjugates remains a huge challenge for the researchers. In order to resolve this issue, Dervan et al. recently published a modular microwave-assisted Fmoc-based solid

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

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

• analytical grade or highest available purity. Synthesis of oxime bond-linked GnRH-III–[4Ser/4Lys(Bu), 6Aaa, 8Lys(Dau=Aoa)] bioconjugates The Dau–GnRH-III derivatives were synthesized by solid phase peptide synthesis according to Fmoc/t-Bu chemistry on a Rink-Amide MBHA resin (0.73 mmol/g coupling capacity

Volatiles from the xylarialean fungus Hypoxylon invadens

• Jeroen S. Dickschat,
• Tao Wang and
• Marc Stadler

Beilstein J. Org. Chem. 2018, 14, 734–746, doi:10.3762/bjoc.14.62

• and ecologists in volatile secondary metabolites. Volatile natural products can efficiently be captured on charcoal filter traps by using a closed-loop stripping apparatus (CLSA) [6] or on polydimethylsiloxane fibres by application of the solid phase micro-extraction method (SPME) [7], followed by GC

Nanoreactors for green catalysis

• M. Teresa De Martino,
• Loai K. E. A. Abdelmohsen,
• Floris P. J. T. Rutjes and
• Jan C. M. van Hest

Beilstein J. Org. Chem. 2018, 14, 716–733, doi:10.3762/bjoc.14.61

• sites are dispersed [49][50]. Homogeneous catalysis is generally performed under milder operative conditions than heterogeneous catalysis [51]. In fact, heterogeneous catalysts generally possess very high decomposition temperatures (above 100 °C) [52]. The presence of a solid phase often results in the

Enzyme-free genetic copying of DNA and RNA sequences

• Marilyne Sosson and
• Clemens Richert

Beilstein J. Org. Chem. 2018, 14, 603–617, doi:10.3762/bjoc.14.47

• (Figure 2), and assay buffers containing high concentrations of Mg2+ ions [15]. When advances in automated solid-phase synthesis made oligonucleotides of any given sequence readily available [16], copying reactions involving the extension of a primer bound to a specific sequence of hairpins mimicking this

Stimuli-responsive oligonucleotides in prodrug-based approaches for gene silencing

• Françoise Debart,
• Christelle Dupouy and
• Jean-Jacques Vasseur

Beilstein J. Org. Chem. 2018, 14, 436–469, doi:10.3762/bjoc.14.32

• partially 2’-O-masked with PivOM groups were synthesized via a solid-phase method involving silyl-based protections on amino functions of the nucleobases combined to CNE on phosphates and Q-linker between pro-RNA and the solid support [48]. One of them with five PivOM groups at the 5’-end was active in a

• available unmodified ONs, while the second approach first requires the synthesis of a modified unit followed by its incorporation into ON during solid-phase synthesis. However, the first approach is far less efficient than the second one because the labeling of phosphodiester linkages with diazo compounds

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

• of potentially successful candidates. This purpose is best achieved by the usage of trinucleotide synthons for codon-based gene synthesis. We here review the strategies for the preparation of fully protected trinucleotides, emphasizing more recent developments for their synthesis on solid phase and

• allows the preparation of the trinucleotide, its conversion into a coupling competent building block, and its subsequent use in chemical DNA synthesis. Trinucleotides have been prepared in solution [19], on solid phase [20], and more recently on soluble polymers [21][22][23] (Figure 1), followed by

• . Preparation of trinucleotides on solid phase Given the fact that trinucleotide synthesis in solution requires tedious purification and isolation of the products after each step of the synthesis, the assembly of trimers on a solid phase appears to be an attractive alternative. However, it has to be taken into

Fluorogenic PNA probes

• Tirayut Vilaivan

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

• unbound probes, which is most commonly achieved by solid phase hybridization followed by washing to eliminate the unbound probes before performing the fluorescence readout. These assays require multiple steps, and so are time-consuming making them unsuitable for real-time monitoring, such as nucleic acid

Fluorescent nucleobase analogues for base–base FRET in nucleic acids: synthesis, photophysics and applications

• Mattias Bood,
• Sangamesh Sarangamath,
• Moa S. Wranne,
• Morten Grøtli and
• L. Marcus Wilhelmsson

Beilstein J. Org. Chem. 2018, 14, 114–129, doi:10.3762/bjoc.14.7

• sodium methoxide in MeOH, which yielded the free nucleoside 15 in 71%. Standard DMTr protection furnished compound 16 which was then activated for oligonucleotide solid-phase synthesis (SPS) by phosphitylation using CEP-Cl. The total yield of tCnitro deoxyribose phosphoramidite was 0.8% over 6 steps

• protection and phosphitylation using CEP-Cl generated the fully protected monomer ready for solid-phase synthesis [50]. The complete synthesis of the RNA building block of tCO was in this way achieved over five steps with a total yield of 28%, improved from the four step DNA building block synthesis of tCO

• glycosylation using Hoffer’s α-chloro sugar and compounds 52 and 53 provided the desired β-anomer after purification in 69% and 55% yield, respectively. Global deprotection using sodium methoxide followed by standard DMTr-protection and phosphitylation provides the activated monomers for solid-phase synthesis

Synthetic mRNA capping

• Fabian Muttach,
• Nils Muthmann and
• Andrea Rentmeister

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

• solid-phase synthesis is limited in its maximum length, RNAs with a length of several thousand nucleotides can easily be prepared through IVT. On the other hand, enzymatically produced RNA is often inhomogeneous in length and for short RNAs the yields obtained after purification may be low. This impedes

• adenosyltransferase variant (MAT-Var.). The AdoMet analogue was directly converted by the methyltransferases, resulting in double alkyne modified cap analogues [95]. Chemical synthesis of capped mRNA Solid-phase synthesis of capped RNA Chemical synthesis of capped RNA is based on the solid-phase synthesis of RNA

• followed by chemical or enzymatic installation of the 5′-cap. The general principle of solid-phase RNA synthesis is beyond the scope of this review and has been described in excellent review articles [101][102][103][104]. The longest RNA synthesized via solid-phase chemistry to date has a length of 170

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

• alkene analogues (Table 4). Comparison between Phe-ψ[(Z)-CF=CH]-Gly and Phe-ψ[(E)-CF=CH]-Gly isosteres and their alkene analogues was also performed in an antagonist activity study towards GPR54. The fluorinated isosteres were incorporated into pentapeptides using Fmoc solid phase peptide synthesis (SPPS

Dialkyl dicyanofumarates and dicyanomaleates as versatile building blocks for synthetic organic chemistry and mechanistic studies

• Grzegorz Mlostoń and
• Heinz Heimgartner

Beilstein J. Org. Chem. 2017, 13, 2235–2251, doi:10.3762/bjoc.13.221

• observed by 1H NMR spectroscopy [8]. Similar systems were prepared on solid phase and used as a new molecular recognition system [44]. The [4 + 2]-cycloaddition reactions of E- and Z-1b with electron-rich 1,3-dienes have been studied extensively by Sustmann and collaborators. Thus, 1-methoxybuta-1,3-diene

Phosphonic acid: preparation and applications

• Charlotte M. Sevrain,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2017, 13, 2186–2213, doi:10.3762/bjoc.13.219

• ][58]. This supramolecular behavior was also involved in the development of organic materials exhibiting proton conduction [59], or organo-gel properties [60]. In the field of analytical chemistry, molecules functionalized with phosphonic acid groups were used to prepare the solid phase for immobilized