Fluorine-containing substituents: metabolism of the α,α-difluoroethyl thioether motif

• Andrea Rodil,
• Alexandra M. Z. Slawin,
• Nawaf Al-Maharik,
• Ren Tomita and
• David O’Hagan

Beilstein J. Org. Chem. 2019, 15, 1441–1447, doi:10.3762/bjoc.15.144

• literature [3], substituents which are typically introduced to stop metabolism of aryl rings [4]. Other fluorinated motifs are gaining in importance too, such as aryl–OCF3 and aryl–SCF3 ethers, although these substituents can significantly raise lipophilicity (log P) [5][6]. There are relatively few

• ) that is marketed as the active component [11][12]. The increase in lipophilicity associated with these substituents is not always desirable. In this regard, partially fluorinated alkyl substituents become an interesting alternative, as the fluorines polarise the adjacent hydrogens and lipophilicity

Tuning the stability of alkoxyisopropyl protection groups

• Zehong Liang,
• Henna Koivikko,
• Mikko Oivanen and
• Petri Heinonen

Beilstein J. Org. Chem. 2019, 15, 746–751, doi:10.3762/bjoc.15.70

• of these acetone-based acetal groups are faster removed than a dimethoxytrityl group, and they are easier to cleave completely in solution. The structural variation allows steering of the stability and lipophilicity of the compounds in some range. Keywords: acetal; hydrolysis; protecting groups

• [7]. We realized that the lability of the acetal group can be easily steered by varying the alkoxy group, while preserving other beneficial properties of the protecting groups. On the other hand, structural modifications can also affect the lipophilicity of the protected compounds. The present study

N-Acylated amino acid methyl esters from marine Roseobacter group bacteria

• Hilke Bruns,
• Lisa Ziesche,
• Nargis Khakin Taniwal,
• Laura Wolter,
• Thorsten Brinkhoff,
• Jennifer Herrmann,
• Rolf Müller and
• Stefan Schulz

Beilstein J. Org. Chem. 2018, 14, 2964–2973, doi:10.3762/bjoc.14.276

• and ESI mass spectra revealed fragmentation patterns helpful for the detection of similar compounds derived from other amino acids. Some of these compounds showed antimicrobial activity. The structural similarity of N-acylated amino acid methyl esters and similar lipophilicity to AHLs might indicate a

Nucleoside macrocycles formed by intramolecular click reaction: efficient cyclization of pyrimidine nucleosides decorated with 5'-azido residues and 5-octadiynyl side chains

• Jiang Liu,
• Peter Leonard,
• Sebastian L. Müller,
• Constantin Daniliuc and
• Frank Seela

Beilstein J. Org. Chem. 2018, 14, 2404–2410, doi:10.3762/bjoc.14.217

• display increased lipophilicity they have the potential to be utilized for the transmembrane delivery of nucleotides and oligonucleotides. More important, all of the macrocyle moieties and the size of the macrocycle can be altered. The system can be regarded as a new lead for further structural and

Synthesis of new p-tert-butylcalix[4]arene-based polyammonium triazolyl amphiphiles and their binding with nucleoside phosphates

• Vladimir A. Burilov,
• Guzaliya A. Fatikhova,
• Mariya N. Dokuchaeva,
• Ramil I. Nugmanov,
• Diana A. Mironova,
• Pavel V. Dorovatovskii,
• Victor N. Khrustalev,
• Svetlana E. Solovieva and
• Igor S. Antipin

Beilstein J. Org. Chem. 2018, 14, 1980–1993, doi:10.3762/bjoc.14.173

• packaging density of aggregates and their general lipophilicity. To reveal this, absorbance spectra of the 10b–EY system in the presence of ADP and ATP were recorded (Figure 5a and b). The addition of small amounts of nucleotides leads to a bathochromic shift of the EY adsorption due to a deeper penetration

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

Two new 2-alkylquinolones, inhibitory to the fish skin ulcer pathogen Tenacibaculum maritimum, produced by a rhizobacterium of the genus Burkholderia sp.

• Dandan Li,
• Naoya Oku,
• Atsumi Hasada,
• Masafumi Shimizu and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2018, 14, 1446–1451, doi:10.3762/bjoc.14.122

• and 8. Among 1–6, the 2-heptenyl-3-methyl congener 4 was the most active. Compounds 3–6 also inhibited the growth of the fungi R. oryzae and T. rubrum, while 1 and 2 did not. This may to some extent attributable to the global lipophilicity of molecules, as 1and 2 are among the fastest eluting

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

• lipophilicity [53]. These structural analogs comprise of branched N-alkyl- and N-cycloalkylpyrroles to test the conformational flexibility towards DNA binding. Hydrophobic N-terminal amides and substituted thiazole replacing pyrrole were installed in order to impart more lipophilicity. All these compounds were

• alkylation. In addition, longer linker imparts more lipophilicity, which in turn, favors better transportation of these compounds into the cells. Anthony et al. reported a series of short MGBs based on the lead compounds distamycin and thiazotropsins with the installation of hydrophobic aromatic head groups

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

• ) [22]. The fundamental advantage of using enzyme-cleavable modifications of the phosphodiester backbone in ONs is to transitorily mask the negative charges of the phosphate by neutral phosphotriesters. Consequently, the backbone is less prone to nuclease degradation, and the lipophilicity of the pro-ON

• phosphotriester ONs is rather poor [29], the design of ONs combining phosphodiester and phosphotriester linkages is required to ensure aqueous solubility and sufficient lipophilicity for cell uptake. Several attempts to obtain such chimeras were made in Imbach’s laboratory in the early 2000s. In particular, the

• targeting the nuclease resistance of the ON prodrug. On the other hand, the thermosensitive groups are more suitable for the protection of the thiophosphates flanking the CpG motif of DNA prodrugs to provide both lipophilicity (better cellular uptake) and hydrophilicity (better solubility once groups are

Progress in copper-catalyzed trifluoromethylation

• Guan-bao Li,
• Chao Zhang,
• Chun Song and
• Yu-dao Ma

Beilstein J. Org. Chem. 2018, 14, 155–181, doi:10.3762/bjoc.14.11

• such as metabolic stability, lipophilicity and permeability [1][2][3][4]. Therefore, organic molecules bearing trifluoromethyl groups are widely used in pharmaceuticals and agrochemicals, such as the antidepressant fluoxetine, the anti-ulcer drug lansoprazole and so on (Figure 1). The specific roles of

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation. Part 1: Use of CF₃SO₂Na

• Hélène Guyon,
• Hélène Chachignon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2764–2799, doi:10.3762/bjoc.13.272

• , judicious installation of CF3 group(s) in catalysts or ligands is an effective tool to tune their reactivity and selectivity in synthesis. As a pharmacophore, CF3 substantially improves the catabolic stability, lipophilicity, and transport rate. In association with chalcogens (OCF3, SCF3, SeCF3), the CF3

• group imparts enhanced lipophilicity of aromatic compounds in comparison with aryl–CF3 analogues (Hansch’s hydrophobic parameter π(SCF3) = 1.44; π(OCF3) = 1.04 versus π(CF3) = 0.88). Trifluoromethyl sources are manifold displaying nucleophilic, electrophilic or radical reactivities [11]. The most

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

• showed higher lipophilicity, which can improve its pharmacokinetic properties. Altman and co-workers also studied a fluorinated mutant of the Leu-enkephaline [41]. The isostere Boc-Tyr-ψ[(Z)-CF=CH]-Gly (see Scheme 12) was coupled to a tripeptide to afford Boc-Tyr-ψ[(Z)-CF=CH]-Gly-Gly-Phe-Leu. Then, the

Electrophilic trifluoromethylselenolation of terminal alkynes with Se-(trifluoromethyl) 4-methylbenzenesulfonoselenoate

• Clément Ghiazza,
• Anis Tlili and
• Thierry Billard

Beilstein J. Org. Chem. 2017, 13, 2626–2630, doi:10.3762/bjoc.13.260

• ][8][9][10][11][12][13][14][15]. In the objective to design new molecules with specific properties, novel fluorinated substituents have been developed, such as diverse trifluoromethylchalcogeno groups, due to their particular electronic properties [16] and, more especially, to their high lipophilicity

• [25][26][27][28][29][30][31][32][33] and drug design [34][35][36][37]. Furthermore, very recently, the Hansch lipophilicity parameter of CF3Se has been determined (πR = 1.29) – a high value lying between that of CF3O and CF3S [38]. Consequently, trifluoromethylselenolated molecules could represent

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

• natural compounds is a widely used approach in medicinal chemistry [1]. The increased lipophilicity of adamantane-containing compounds compared with non-adamantylated derivatives [2] leads to considerably higher solubility of these compounds in blood plasma and their easier penetration through cell

Synthesis and supramolecular properties of regioisomers of mononaphthylallyl derivatives of γ-cyclodextrin

• Markéta Bláhová,
• Sergey K. Filippov,
• Lubomír Kováčik,
• Jiří Horský,
• Simona Hybelbauerová,
• Zdenka Syrová,
• Tomáš Křížek and
• Jindřich Jindřich

Beilstein J. Org. Chem. 2017, 13, 2509–2520, doi:10.3762/bjoc.13.248

• CDs are attractive building blocks for various types of supramolecular structures [6][7]. Necessary non-covalent interactions depend on the type and derivatization of CD, on lipophilicity, shape, and size of the guest molecule, and on conditions such as temperature, pH, or solvent used [8]. In

One-pot three-component route for the synthesis of S-trifluoromethyl dithiocarbamates using Togni’s reagent

• Azim Ziyaei Halimehjani,
• Martin Dračínský and
• Petr Beier

Beilstein J. Org. Chem. 2017, 13, 2502–2508, doi:10.3762/bjoc.13.247

• fields of pharmaceuticals, agrochemicals, and materials sciences. The key properties such as metabolic and chemical stability, polarity, bioavailability, viscosity and lipophilicity can be altered in molecules containing the CF3 group in comparison with the nonfluorinated analogues. Numerous methods have

Hydrolysis, polarity, and conformational impact of C-terminal partially fluorinated ethyl esters in peptide models

• Vladimir Kubyshkin and
• Nediljko Budisa

Beilstein J. Org. Chem. 2017, 13, 2442–2457, doi:10.3762/bjoc.13.241

• used to model the effects of fluorination on the lipophilicity, hydrolytic stability and on conformational properties. The conformational impact of the 2,2-difluoromethyl ester on several neutral and charged oligopeptides was also investigated. Our results demonstrate that partially fluorinated esters

• -mimicking models [39] did not support this suggestion. Though, this was reported later in a context of a hydrophobic core of model protein structures [40]. Furthermore, the influence of the fluorinated groups on lipophilicity remains uncertain, especially in biochemical literature. The impact of partially

• fluorinated alkyl groups on the polarity of small molecules was recently investigated in a series of model studies by Huchet and others [41][42][43][44]. These investigations demonstrated the checkmark-shape of the lipophilicity (logP) changes upon increasing the number of fluorine atoms in the terminal

Solvent-free copper-catalyzed click chemistry for the synthesis of N-heterocyclic hybrids based on quinoline and 1,2,3-triazole

• Martina Tireli,
• Silvija Maračić,
• Stipe Lukin,
• Marina Juribašić Kulcsár,
• Dijana Žilić,
• Mario Cetina,
• Ivan Halasz,
• Silvana Raić-Malić and
• Krunoslav Užarević

Beilstein J. Org. Chem. 2017, 13, 2352–2363, doi:10.3762/bjoc.13.232

• found that halogenated compounds have an important role in therapeutic application increasing their lipophilicity, metabolic stability and improving interactions of protein–ligand complexes [36]. Taking into consideration the aforementioned, we have designed and synthesized 6-phenylquinoline derivatives

Synthesis and application of trifluoroethoxy-substituted phthalocyanines and subphthalocyanines

• Satoru Mori and
• Norio Shibata

Beilstein J. Org. Chem. 2017, 13, 2273–2296, doi:10.3762/bjoc.13.224

• phthalocyanines and subphthalocyanines are easy to handle, it is possible to obtain diverse derivatives and to fully demonstrate their functions. They are also expected to be developed into new material fields due to their high stability, high solubility and high lipophilicity. By combining the characteristics of

Preparation of imidazo[1,2-a]-N-heterocyclic derivatives with gem-difluorinated side chains

• Layal Hariss,
• Kamal Bou Hadir,
• Mirvat El-Masri,
• Thierry Roisnel,
• René Grée and
• Ali Hachem

Beilstein J. Org. Chem. 2017, 13, 2115–2121, doi:10.3762/bjoc.13.208

• widely recognized as a general strategy toward drug development in pharmaceutical research. This is connected to fluorine's electronegativity, size, and lipophilicity [15][16], which can strongly improve the biological properties of molecules through, for instance, increase of metabolic stability and

Selective enzymatic esterification of lignin model compounds in the ball mill

• Ulla Weißbach,
• Saumya Dabral,
• Laure Konnert,
• Carsten Bolm and
• José G. Hernández

Beilstein J. Org. Chem. 2017, 13, 1788–1795, doi:10.3762/bjoc.13.173

• lipophilicity, for instance through sulfation [18], silylation or esterification [19] of the aliphatic hydroxy and phenolic groups found in lignin. Chemical esterification of lignin [19][20][21] or its model compounds [22], using acetic anhydride in organic solvents such as DCM or pyridine have previously been

Synthesis of acylhydrazino-peptomers, a new class of peptidomimetics, by consecutive Ugi and hydrazino-Ugi reactions

• Angélica de Fátima S. Barreto,
• Veronica Alves dos Santos and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2016, 12, 2865–2872, doi:10.3762/bjoc.12.285

• peptoids the side chain of the Cα is bound to the nitrogen atom. Due to the consequent lack of the polar N–H bonds, their lipophilicity is increased, which may result in improved membrane permeability [16][17]. Furthermore, peptoids have also found utility in supra- and macromolecular engineering [18] and

Biomimetic synthesis and HPLC–ECD analysis of the isomers of dracocephins A and B

• Viktor Ilkei,
• András Spaits,
• Anita Prechl,
• Áron Szigetvári,
• Zoltán Béni,
• Miklós Dékány,
• Csaba Szántay Jr,
• Judit Müller,
• Árpád Könczöl,
• Ádám Szappanos,
• Attila Mándi,
• Sándor Antus,
• Ana Martins,
• Attila Hunyadi,
• György Tibor Balogh,
• György Kalaus (†),
• Hedvig Bölcskei,
• László Hazai and
• Tibor Kurtán

Beilstein J. Org. Chem. 2016, 12, 2523–2534, doi:10.3762/bjoc.12.247

• calculated (total polar surface area; TPSA) and measured (pKa, log P/D and Pe) parameters are shown in Table 1. The lipophilicity of neutral species of naringenin and dracocephins A and B are 3.39, 2.52 and 2.39, respectively. Similarly to this lipophilicity trend, the TPSA value of (±)-naringenin is lower

• -permeable compounds, respectively. These results are in good correlation with a lower lipophilicity (log P/D7.4) and higher TPSA of dracocephins A and B compared to that of naringenin. Pharmacological studies In connection with the BBB penetration studies, 2a–d and 3a–d were tested for their potential

Synthesis, dynamic NMR characterization and XRD studies of novel N,N’-substituted piperazines for bioorthogonal labeling

• Constantin Mamat,
• Marc Pretze,
• Matthew Gott and
• Martin Köckerling

Beilstein J. Org. Chem. 2016, 12, 2478–2489, doi:10.3762/bjoc.12.242

• Novel, functionalized piperazine derivatives were successfully synthesized and fully characterized by 1H/13C/19F NMR, MS, elemental analysis and lipophilicity. All piperazine compounds occur as conformers resulting from the partial amide double bond. Furthermore, a second conformational shape was

• development of new building blocks for specific and bioorthogonal labeling of biologically active compounds is of high importance. Depending on their size and composition, building blocks can influence (bio-)chemical parameters such as the lipophilicity (log P) affecting the solubility and the biological

• ], FBAM (log P = 2.7) [41], 4-fluorobenzaldehyde (log P = 1.9) [42] or the click labeling building block p-[18F]F-SA (log P = 1.7) [43], the lipophilicity of our 18F-building blocks is reduced. The hydrophilic character of the building blocks enables a radiolabeling in aqueous solutions and the influence

Efficient mechanochemical synthesis of regioselective persubstituted cyclodextrins

• Laszlo Jicsinszky,
• Marina Caporaso,
• Katia Martina,
• Emanuela Calcio Gaudino and
• Giancarlo Cravotto

Beilstein J. Org. Chem. 2016, 12, 2364–2371, doi:10.3762/bjoc.12.230

• solution phase synthesis of heptakis(6-deoxy-6-S-alkyl)-β-CDs is typical for the syntheses of intermediates of such compounds, however, their high lipophilicity means that isolation is not a technically trivial task. Scale up of the 1-dodecanethiol mechanochemical reaction (synthesis of compound 6, entry