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

• and to avoid toxicity towards normal host cells. Antimicrobial peptides (AMPs) are produced by the innate immune system of virtually every organism on Earth. These agents represent promising anticancer candidates since, in addition to their activity vs bacteria [1], viruses, parasites [2][3][4][5][6

• . Furthermore, Dec-NH2 and its analogs were hemolytic at concentrations above their MIC values for the different microorganisms studied [9][10]. MTT cytotoxicity assays MTT assays were performed to determine the toxicity of designer peptides against MCF-7 cancer cells and MCF-10A normal cells. MCF-10A cells

• analogs after 2 and 24 h of exposure to MCF-7 cancer cells. Experiments were done in triplicate. MTT assays evaluating the toxicity of Dec-NH2 and its derivatives towards MCF-10A normal cells after 2 and 24 h. Experiments were performed in triplicate. Cell death analysis using flow cytometry. Dot plot

β-Hydroxy sulfides and their syntheses

• Mokgethwa B. Marakalala,
• Edwin M. Mmutlane and
• Henok H. Kinfe

Beilstein J. Org. Chem. 2018, 14, 1668–1692, doi:10.3762/bjoc.14.143

• (-CH2X), alkoxy (-CH2O), aryloxy (PhO), aryl (Ph) and alkyl (-CH2) substituents on the epoxide. The virtues of this protocol are the low cost and ready availability of NBS, its moisture and air stability as well as low toxicity. The reaction is characterized by short reaction time, good to high product

• host–guest complexes by non-covalent bonding [64]. This mode of catalysis is similar to the way enzymes mediate biochemical reactions [64]. The use of water as a solvent and the non-toxicity of the cyclodextrin catalyst make the method attractive. This method, like the previously reported protocols, is

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

• compare the influence of sequence modification, the presence or absence of a spacer as well as the type of spacers on toxicity. Disulfide dimers were also developed based on conjugates 4, 6 and 8, resulting in compounds 9, 10 and 11. Four conjugates with two identical (Dau) or different (Dau and Mtx) drug

• concentrations (10−7 and 10−6 mol/L). In contrast, these conjugates showed significantly lower toxicity at 10−7 mol/L, but a slightly higher toxicity at the highest concentration level (10−6 mol/L) on cardiomyocytes in a long-term experiment. It is worth mentioning that none of the compounds showed toxicity on

• cardiomyocytes and HUVEC endothelial cells in the long-term study. The oxime bond-linked Dox conjugate (3) showed significantly lower toxicity on both cell types, while conjugate 2 had a similar concentration-dependent toxicity to that of the ester bond-linked conjugates on endothelial cells. The toxicity of the

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

• peptides when incubated with MCF-7 cells up to a concentration of 100 μM. Also after treating HeLa cells with the peptides up to a concentration of 50 μM, no significant toxicity could be observed for sC18*, N50, N50-sC18* and NrTP. Besides N50, all other peptide sequences did lower the amount of viable

• cells to an amount of around 80% at higher concentrations. For sC18* the results are in very good agreement to our former studies, in which we also examined the toxicity in other cell lines, like human epithelial kidney cells (HEK-293) and human colorectal adenocarcinoma cells (HCT-15) [19][20]. Notably

A survey of chiral hypervalent iodine reagents in asymmetric synthesis

• Soumen Ghosh,
• Suman Pradhan and
• Indranil Chatterjee

Beilstein J. Org. Chem. 2018, 14, 1244–1262, doi:10.3762/bjoc.14.107

• application due to their reduced toxicity, ready availability and lower costs as replacement for transition metals leading to several “metal-free” like chemical transformations. The ongoing demand of modern synthetic chemistry for the development of catalytic enantioselective C–C bond formation reactions

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

• . Hypervalent iodine reagents have drawn researchers’ considerable attentions due to their versatile reactivity, low toxicity, ready availability, environmental friendliness, and regenerability [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]. Our group has dedicated to the peptide synthesis

• . 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

• high binding affinity to B-DNA duplexes, several groups have designed various structural analogs of Hoechst 33258 in order to achieve a better sequence-specific DNA binder with reduced toxicity [114]. Yang et al. reported a series of novel symmetrical bisbenzimidazoles as DNA minor groove binders. A

• promyelocytic leukemia cells) tumor cell line and 0.58 μM for U937 (Human leukemic monocyte lymphoma cells) tumor cell line with reduced toxicity in comparison to paclitaxel and 5-FU [116]. Ivanov et al. reported two different sets of strong minor groove binders, derived from well-known DNA minor groove binder

• charged phosphates, thereby stabilizing the complex through the formation of cross-links between neighboring duplexes [83]. However, due to intrinsic toxicity, various structural analogs of pentamidine were designed over the years by replacing the ether linkage with bis-amide 61 [125], introducing

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

• toxicity present in healthy tissues. It is estimated that about 30% of the clinical trials on ClinicalTrials.gov are related to cancer, while only 10% of them eventually gain market approval [3], rendering the drug development, especially in this therapeutic direction, costly and inefficient. Specifically

• intervention, radiation and chemotherapy. Drugs used for this purpose are inevitably cytotoxic in order to eliminate cancer cells, but they lack selectivity that could be developed through targeting malignant cells (Figure 1). Due to the uncontrolled peripheral toxicity, anticancer drugs usually kill healthy

• tissues, resulting in severe effects on the patient’s health. One representative example is gemcitabine, which demonstrates higher toxicity for healthy cells, after long-term administration, with respect to cancer cells. This happens since cancer cells evolve more rapidly and develop drug resistance by

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

• conjugates revealed substantial in vitro cytostatic/cytotoxic effects. Our results indicated that the conjugates had an antitumor effect against both CD13+ HT-1080 cells and CD13− (but integrin receptor positive) HT-29 human colon cancer cells. Moreover, we showed that the toxicity and the selectivity of the

• positive [17]. The effect of the new drug conjugates was compared with the toxicity of free Dau and our lead compound Dau=Aoa-GFLGK(c[KNGRE]-GG)-NH2 (K). The bioconjugates enter cancer cells most likely by receptor-mediated endocytosis (at least at lower micromolar concentration) followed by the release of

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

• reduced toxicity. In food industry β-CD has been used in many applications such as flavor protection and flavor delivery, controlled release of desired constituents and removal and masking of undesirable components [16]. But the most prevalent use of CD in this field is the removal of cholesterol from

Recent advances in synthetic approaches for medicinal chemistry of C-nucleosides

• Kartik Temburnikar and
• Katherine L. Seley-Radtke

Beilstein J. Org. Chem. 2018, 14, 772–785, doi:10.3762/bjoc.14.65

• ]. However, 7-TP serves as a substrate for mitochondrial RNA polymerase, thereby causing toxicity in rats [63]. The 2'-F and 2'-β-Me compounds 8 and 9 are active against the HCV, but lack activity against EBOV and RSV in cell-based assays [65]. The pharmacokinetic properties of 4 were improved by converting

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

• diseases worldwide and malignant tumors and metastases often lead to high mortality. Chemotherapy is a widely used method to treat cancerous diseases, but the lack of selectivity, drug-specific side-effects and toxicity to healthy tissues result in various complications, which restrict the application of

Electrochemical Corey–Winter reaction. Reduction of thiocarbonates in aqueous methanol media and application to the synthesis of a naturally occurring α-pyrone

• Ernesto Emmanuel López-López,
• José Alvano Pérez-Bautista,
• Fernando Sartillo-Piscil and
• Bernardo A. Frontana-Uribe

Beilstein J. Org. Chem. 2018, 14, 547–552, doi:10.3762/bjoc.14.41

• formed by β-fragmentation of radical anion F, is maximum when is locked in an antiperiplanar conformation (Scheme 4). Therefore, this electrochemical reaction represents a promising way to produce trans-olefins from their respective thiocarbonates, overcoming thus the toxicity and safety issues of the

Functionalization of N-arylglycine esters: electrocatalytic access to C–C bonds mediated by n-Bu₄NI

• Mi-Hai Luo,
• Yang-Ye Jiang,
• Kun Xu,
• Yong-Guo Liu,
• Bao-Guo Sun and
• Cheng-Chu Zeng

Beilstein J. Org. Chem. 2018, 14, 499–505, doi:10.3762/bjoc.14.35

• the presence of excess amounts of oxidant. On the other hand, the toxicity of residual traces of transition metal (photo)catalyst in products is also highly concerned. Consequently, metal-free and environmentally friendly oxidative C–C bond formation is highly desired. Electrochemistry has proved to

Latest development in the synthesis of ursodeoxycholic acid (UDCA): a critical review

• Fabio Tonin and
• Isabel W. C. E. Arends

Beilstein J. Org. Chem. 2018, 14, 470–483, doi:10.3762/bjoc.14.33

• aspects. Conclusion The organic synthesis of CDCA and UDCA starting from taurinated and glycinated cholic acid is a long process, complicated and risky due to the nature and toxicity of the reagents used, the costs of disposal of large amounts of sodium hydroxide, chromium salts and organic solvents, and

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

• cells or tissues, off-target effects and toxicity hamper the path to success of ON-based therapeutics and need to be solved. Fortunately, various chemical modifications of ONs have been designed to address these issues [9]. The most common modification in AONs and siRNAs is the phosphorothioate (PS

• ) backbone in the replacement of the phosphate ester internucleotide linkages. This modification provides nuclease stability and favorable pharmacokinetic properties but can lead to some toxicity. In addition, the most extensively used sugar modifications are represented by the 2’-modifications: 2’-O-methyl

• . However, in hypoxic cells after removal of the 4-nitrobenzyl groups, the resulting native ONs should form stable active duplexes with their targets. These hypoxia-labile modifications seem promising for the development of ON therapeutics with specific activity in hypoxic tumor cells and low toxicity in

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

• hepatocytes, where the transporting protein OATP1B3 internalizes amatoxins resulting in high liver toxicity [2][3]. This strong toxicity in the presence of endocytosis mediators allowing cell permeation, aroused interest towards the use of α-amanitin as a payload for targeted cancer therapy. In 1981, Davis

• a slight enhancement in toxicity over α-amanitin was observed. The transmembrane receptor αVβ3 integrin is widely expressed on the blood vessels of several human cancers (for example, breast cancer, glioblastoma, pancreatic tumor, prostate carcinoma) but not on the vasculature of healthy tissues [9

Synthesis of fluoro-functionalized diaryl-λ³-iodonium salts and their cytotoxicity against human lymphoma U937 cells

• Prajwalita Das,
• Etsuko Tokunaga,
• Hidehiko Akiyama,
• Hiroki Doi,
• Norimichi Saito and
• Norio Shibata

Beilstein J. Org. Chem. 2018, 14, 364–372, doi:10.3762/bjoc.14.24

• suggested that antitumor drug candidates could be designed by further structural modification of these compounds 3. Moreover, with 3p exhibiting the greatest potency against U937 cells with comparably lower toxicity against AGLCL cells, further biological studies using 3p including in vivo evaluation should

Recent advances on organic blue thermally activated delayed fluorescence (TADF) emitters for organic light-emitting diodes (OLEDs)

• Thanh-Tuân Bui,
• Fabrice Goubard,
• Malika Ibrahim-Ouali,
• Didier Gigmes and
• Frédéric Dumur

Beilstein J. Org. Chem. 2018, 14, 282–308, doi:10.3762/bjoc.14.18

• % for phosphorescent OLEDs [5]. As drawback, triplet emitters are transition-metal complexes mostly based on iridium, platinum and osmium and the scarcity of these metals on Earth, their toxicity and high cost make these materials unsuitable candidates for a mass-production of OLEDs [6]. However

Aminosugar-based immunomodulator lipid A: synthetic approaches

• Alla Zamyatina

Beilstein J. Org. Chem. 2018, 14, 25–53, doi:10.3762/bjoc.14.3

• adjuvant monophosphoryl lipid A, MPLA – leads to the induction of a different cytokine profile that weakens toxicity but preserves the beneficial adjuvant effects of endotoxin. Other Gram-negative bacteria can produce lipid A variants which are either less endotoxic or inactive (e.g., cannot be recognised

• oligosaccharide, hydrolysis of the 1-phosphate from the reducing end glucosamine, and removal of the acyl chain from position 3 of the disaccharide backbone [59]. Lower toxicity of the TLR4 ligand MPLA compared to its parent LPS/lipid A was linked to the absence of the phosphate group in position 1 of the

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

• principal targets in the last decades [1], larger biomolecules, such as peptides, are now widely studied [2][3]. The interest of these biopolymers originates, in part, from their high potency and selectivity towards the target, which results in a decrease of the toxicity and/or side effects. However

A semisynthesis of 3'-O-ethyl-5,6-dihydrospinosyn J based on the spinosyn A aglycone

• Kai Zhang,
• Shenglan Liu,
• Anjun Liu,
• Hongxin Chai,
• Jiarong Li and
• Lamusi A

Beilstein J. Org. Chem. 2017, 13, 2603–2609, doi:10.3762/bjoc.13.257

• persistence and low mammalian and avian toxicity [12]. Therefore, spinosad was awarded the Presidential Green Chemistry Challenge Award in 1999. However, spinosad was not effective in killing certain key pests of fruit trees and nut trees. To solve this problem, Dow AgroSciences used an "artificial neural

¹⁵N-Labelling and structure determination of adamantylated azolo-azines in solution

• Sergey L. Deev,
• Alexander S. Paramonov,
• Tatyana S. Shestakova,
• Igor A. Khalymbadzha,
• Oleg N. Chupakhin,
• Julia O. Subbotina,
• Oleg S. Eltsov,
• Pavel A. Slepukhin,
• Vladimir L. Rusinov,
• Alexander S. Arseniev and
• Zakhar O. Shenkarev

Beilstein J. Org. Chem. 2017, 13, 2535–2548, doi:10.3762/bjoc.13.250

• membranes. The conjugation of adamantane with heterocyclic compounds also provides a method to modify the pharmacological profile and frequently leads to a new type of bioactivity. For example, N-adamantyl tetrazoles 1 and 2 (Figure 1A) demonstrate lower toxicity and, simultaneously, more potent activity

Exploring mechanochemistry to turn organic bio-relevant molecules into metal-organic frameworks: a short review

• Vânia André,
• Sílvia Quaresma,
• João Luís Ferreira da Silva and
• M. Teresa Duarte

Beilstein J. Org. Chem. 2017, 13, 2416–2427, doi:10.3762/bjoc.13.239

• be studied for their potential medicinal applications. Here, the main focus was their use as drug-delivery systems [71][72][89], with particular attention to the toxicity of the metal centers [84]. Toxicity is a concern not only for the safe use of these compounds for humans but also for

• display a specific bioactive function in appropriate dosages, allowing to take benefits of possible synergetic effects between the metal and the APIs. Nevertheless, toxicity is also dependent on many other factors such as speciation, chemical nature, administration route, exposition time and accumulation

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

• of being able to generate amino acids of different backbone lengths (e.g., 5, 6, Figure 1) via a unified strategy; (ii) an ability to access any stereoisomer of the target molecules (provided that the stereoselectivity in each fluorination step was catalyst-controlled); (iii) the lower toxicity of