Formation of nanoparticles by cooperative inclusion between (S)-camptothecin-modified dextrans and β-cyclodextrin polymers

• Thorbjørn Terndrup Nielsen,
• Catherine Amiel,
• Laurent Duroux,
• Kim Lambertsen Larsen,
• Lars Wagner Städe,
• Reinhard Wimmer and
• Véronique Wintgens

Beilstein J. Org. Chem. 2015, 11, 147–154, doi:10.3762/bjoc.11.14

• trials simply due to limited aqueous solubility and thereby low bioavailability [2]. Hence, there is an urgent need for novel methods to overcome the solubility issue of these drugs and to ensure efficient transport to the desired site of action with limited adverse effects. In this respect nanoparticles

• potent anticancer activity by inhibition of topoisomerase II. Its major drawback is its extremely low aqueous solubility of 2.5 µg/mL leading to a low bioavailability and it is thus a considerable formulation challenge [4]. Furthermore, at physiological conditions its active lactone form is hydrolysed to

Synthesis of divalent ligands of β-thio- and β-N-galactopyranosides and related lactosides and their evaluation as substrates and inhibitors of Trypanosoma cruzi trans-sialidase

• María Emilia Cano,
• Rosalía Agusti,
• Alejandro J. Cagnoni,
• María Florencia Tesoriero,
• José Kovensky,
• María Laura Uhrig and
• Rosa M. de Lederkremer

Beilstein J. Org. Chem. 2014, 10, 3073–3086, doi:10.3762/bjoc.10.324

• the bioavailability in vivo [31]. Triazole-substituted β-galactopyranosides and triazole-sialyl mimetics have been synthesized by click chemistry and their inhibitory activity on the hydrolysis of 2’-(4-methylumbelliferyl)-β-D-N-acetylneuraminic acid by TcTS and trypanocidal activity were evaluated

Synthesis of uniform cyclodextrin thioethers to transport hydrophobic drugs

• Lisa F. Becker,
• Dennis H. Schwarz and
• Gerhard Wenz

Beilstein J. Org. Chem. 2014, 10, 2920–2927, doi:10.3762/bjoc.10.310

• -, β- and γ-CD, respectively [1]. CDs are well known to increase the bioavailability of active pharmaceutical ingredients (APIs) [2][3], and they are readily available in pharmaceutical purity and industrial quantities. Furthermore, they are water soluble and regarded as non-toxic in case of α- and γ

• -CD [4][5], while β-CD shows some toxic effects such as haemolysis at high concentrations [6]. CDs are generally employed to increase the bioavailability of those APIs scarcely soluble in water [7]. The observed solubilization of an API is generally based on the complexation of the hydrophobic part of

Cyclodextrin–polysaccharide-based, in situ-gelled system for ocular antifungal delivery

• Anxo Fernández-Ferreiro,
• Noelia Fernández Bargiela,
• María Santiago Varela,
• Maria Gil Martínez,
• Maria Pardo,
• Antonio Piñeiro Ces,
• José Blanco Méndez,
• Miguel González Barcia,
• Maria Jesus Lamas and
• Francisco.J. Otero-Espinar

Beilstein J. Org. Chem. 2014, 10, 2903–2911, doi:10.3762/bjoc.10.308

• most eye fungal infections; however, there are resistant species that require higher concentrations than usual [5]. Unfortunately, antifungal eye drops have low ocular bioavailability due to their poor water solubility and known effective eye clearance mechanisms [6]. Thus, after administration of

Binding mode and free energy prediction of fisetin/β-cyclodextrin inclusion complexes

• Bodee Nutho,
• Wasinee Khuntawee,
• Chompoonut Rungnim,
• Piamsook Pongsawasdi,
• Peter Wolschann,
• Alfred Karpfen,
• Nawee Kungwan and
• Thanyada Rungrotmongkol

Beilstein J. Org. Chem. 2014, 10, 2789–2799, doi:10.3762/bjoc.10.296

• applications, β-CD has been mostly used as a drug carrier, stabilizer and additive by the formation of host–guest complexes with increased solubility and consequently better bioavailability of low water soluble organic compounds (i.e., drugs) [20][21][22][23]. The inclusion complex can also improve ligand

Preparation and evaluation of cyclodextrin polypseudorotaxane with PEGylated liposome as a sustained release drug carrier

• Kayoko Hayashida,
• Taishi Higashi,
• Daichi Kono,
• Keiichi Motoyama,
• Koki Wada and
• Hidetoshi Arima

Beilstein J. Org. Chem. 2014, 10, 2756–2764, doi:10.3762/bjoc.10.292

• ][15], protein drugs [16][17], and nucleic acids [18][19][20]. We have also developed a number of PPRXs with various drugs or drug carriers and utilized them as controlled release systems. For example, γ-CD formed PPRX with coenzyme Q10, improving the solubility and bioavailability of coenzyme Q10 [21

Anomalous diffusion of Ibuprofen in cyclodextrin nanosponge hydrogels: an HRMAS NMR study

• Monica Ferro,
• Franca Castiglione,
• Carlo Punta,
• Lucio Melone,
• Walter Panzeri,
• Barbara Rossi,
• Francesco Trotta and
• Andrea Mele

Beilstein J. Org. Chem. 2014, 10, 2715–2723, doi:10.3762/bjoc.10.286

• examples of applications can be found in the recent literature, including biocatalysis [4], agriculture [5], environmental control [6] and pharmaceutical applications such as drug stabilization, enhancement of bioavailability and drug delivery [7][8][9][10][11]. A typical synthetic protocol for their

• gradual release over extended times, thus increasing the bioavailability at the target site [19]. In this scenario of growing importance of CDNS in pharmaceutical formulations as drug container and/or carrier, it is of paramount importance a clear understanding, at molecular level, of the state of the

Encapsulation of biocides by cyclodextrins: toward synergistic effects against pathogens

• Véronique Nardello-Rataj and
• Loïc Leclercq

Beilstein J. Org. Chem. 2014, 10, 2603–2622, doi:10.3762/bjoc.10.273

• biocides (e.g., increased aqueous solubility and wettability, reduced vapor pressure, etc.), ii) the controlled release and bioavailability, iii) the shelf-life, iv) the storage conditions and the environmental toxicity, and v) the biocidal property of textiles which is one of the main fields of

• . In addition, the authors have reported that the complexation of carbendazim with HP-β-CD significantly improves its bioavailability and, therefore, resulting in about a two-fold increase of the fungicidal activity against Trichioderma viride (fungus) compared to carbendazim alone. As a consequence

• must be selected to maintain an acceptable biocidal activity. Beyond these considerations, many benefits can be obtained by the use of CDs (see below). iii) Controlled release and bioavailability improvement As mentioned above, the formation of inclusion complexes can be useful to enhance the

A versatile δ-aminolevulinic acid (ΑLA)-cyclodextrin bimodal conjugate-prodrug for PDT applications with the help of intracellular chemistry

• Chrysie Aggelidou,
• Theodossis A. Theodossiou,
• Antonio Ricardo Gonçalves,
• Mariza Lampropoulou and
• Konstantina Yannakopoulou

Beilstein J. Org. Chem. 2014, 10, 2414–2420, doi:10.3762/bjoc.10.251

• hydrophobic cavity [7]. The cyclodextrins (CDs) are a notable family of semi-natural carbohydrate molecules approved as pharmaceutical excipients that improve the solubility and bioavailability of drugs through molecular encapsulation. We demonstrated [6] the conjugate’s (PpIX-CD) bimodal action of

Effect of cyclodextrin complexation on phenylpropanoids’ solubility and antioxidant activity

• Miriana Kfoury,
• David Landy,
• Lizette Auezova,
• Hélène Greige-Gerges and
• Sophie Fourmentin

Beilstein J. Org. Chem. 2014, 10, 2322–2331, doi:10.3762/bjoc.10.241

• limited water solubility, stability and poor bioavailability [8][9]. Thus, their encapsulation may enhance their apparent solubility without losing their structural integrity and bioactivity. During the past years, cyclodextrins (CDs) have been widely used as encapsulating agents to enhance the solubility

• , stability, release and bioavailability of natural compounds [10][11][12][13]. CDs are a family of cyclic oligosaccharides obtained from enzymatic degradation of starch. The most common native CDs are α-cyclodextrin (α-CD), β-cyclodextrin (β-CD) and γ-cyclodextrin (γ-CD) composed of six, seven and eight (α

Synthesis of rigid p-terphenyl-linked carbohydrate mimetics

• Maja Kandziora and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2014, 10, 1749–1758, doi:10.3762/bjoc.10.182

• -glycosides which possess structural and functional aspects of the corresponding carbohydrates, these disadvantages can be overcome, resulting in an improved bioavailability, higher affinities and improved selectivities [8][9][10][11][12][13]. Recent results indicate that divalent rigid carbohydrate

The search for new amphiphiles: synthesis of a modular, high-throughput library

• George C. Feast,
• Thomas Lepitre,
• Xavier Mulet,
• Charlotte E. Conn,
• Oliver E. Hutt,
• G. Paul Savage and
• Calum J. Drummond

Beilstein J. Org. Chem. 2014, 10, 1578–1588, doi:10.3762/bjoc.10.163

• synthesise double and triple-chain amphiphiles. With tails in hand, attention was turned to the hydrophilic amphiphile head groups. Sugar head groups were selected for this library because sugars are popular drug targets; however, such compounds often suffer from poor bioavailability [39]. By loading such

Carbohydrate PEGylation, an approach to improve pharmacological potency

• M. Eugenia Giorgi,
• Rosalía Agusti and
• Rosa M. de Lederkremer

Beilstein J. Org. Chem. 2014, 10, 1433–1444, doi:10.3762/bjoc.10.147

• polyethylene glycol (PEG), known as PEGylation, has been widely used to improve the bioavailability of proteins and low molecular weight drugs. The covalent conjugation of PEG to the carbohydrate moiety of a protein has been mainly used to enhance the pharmacokinetic properties of the attached protein while

• -carbohydrates, in particular multiarm PEGylation, is presented. Keywords: bioavailability; carbohydrates; conjugates; glycoPEGylation; multivalent glycosystems; multivalent PEGylation; Introduction In recent years, the modification of biotherapeutics by covalent conjugation with polyethyleneglycol (PEG) known

• trans-sialidase (TcTS) [48], a virulence factor of Trypanosoma cruzi [49][50][51]. It was shown that lactitol prevented apoptosis caused by TcTS although it is rapidly eliminated from the circulatory system [52]. With the aim to improve bioavailability, PEGylation of lactose analogs was performed using

Syntheses of fluorooxindole and 2-fluoro-2-arylacetic acid derivatives from diethyl 2-fluoromalonate ester

• Antal Harsanyi,
• Graham Sandford,
• Dmitri S. Yufit and
• Judith A.K. Howard

Beilstein J. Org. Chem. 2014, 10, 1213–1219, doi:10.3762/bjoc.10.119

• biological activity [1], a growing number of commercially significant life science products, which owe their activity to the presence of fluorine atoms within their structures, have developed. Fluorine incorporation can lead, for example, to enhanced bioavailability, metabolic stability and lipophilicity of

Automated solid-phase peptide synthesis to obtain therapeutic peptides

• Veronika Mäde,
• Sylvia Els-Heindl and
• Annette G. Beck-Sickinger

Beilstein J. Org. Chem. 2014, 10, 1197–1212, doi:10.3762/bjoc.10.118

• derivatives [12]. Besides this success story, there are limitations restricting the use of peptides as drugs (Table 1). Notably, their low bioavailability owing to proteolytic degradation by enzymes of the intestine, blood and cell plasma leads to short circulating half-lives [13]. Depending on their size

• , possible reduced water solubility restricts their drugability. In the last years, remarkable efforts have been made to modulate the bioavailability of peptides. Basically, delivery challenges of peptide drug candidates can be overcome by chemical modification or innovative formulation techniques such as

• making them valuable for diabetes treatment. In 2011, a lipidated analog of PP (pancreatic polypeptide), a gut hormone that is known to mediate satiety, was developed. It showed an improved bioavailability demonstrated in a prolonged action in decreasing food intake in mice [99]. Apart from albumin

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

• affinity for the target/receptor and improved protease stability, bioavailability and specificity [6][7][8]. Conformational bias can be achieved via N-alkylation, α-alkylation or the introduction of alkene amide bond isosteres, but also via local or global cyclization. A prominent advantage of cyclized

Aminofluorination of 2-alkynylanilines: a Au-catalyzed entry to fluorinated indoles

• Antonio Arcadi,
• Emanuela Pietropaolo,
• Antonello Alvino and
• Véronique Michelet

Beilstein J. Org. Chem. 2014, 10, 449–458, doi:10.3762/bjoc.10.42

• are fluorinated derivatives because the inclusion of fluorine into organic compounds has been shown to improve properties such as solubility, bioavailability and metabolic stability, which are of great importance for the development of a large number of viable drug candidates [3]. Finding original

Flow microreactor synthesis in organo-fluorine chemistry

• Hideki Amii,
• Aiichiro Nagaki and
• Jun-ichi Yoshida

Beilstein J. Org. Chem. 2013, 9, 2793–2802, doi:10.3762/bjoc.9.314

• fluorine leads to the smallest steric perturbation available to us. In pharmaceuticals, fluorine is often introduced to increase lipophilicity, bioavailability, and metabolic stability; these unique properties are otherwise difficult to obtain. At present, nearly 15% of medicines and 20% of agrochemicals

Stereoselectively fluorinated N-heterocycles: a brief survey

• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2013, 9, 2696–2708, doi:10.3762/bjoc.9.306

• bioavailability of a drug molecule; this concept is explored in the next section. 5. Fluorination alters the basicity of N-heterocycles The 3-piperidinylindole derivative 38 (Table 1) binds to the human 5-HT2A serotonin receptor, and was identified as a promising antipsychotic drug lead [48]. However, the

• bioavailability of 38 was poor, and this was attributed to the basicity of the secondary amine group which made the molecule positively charged at physiological pH and hence unable to traverse biological membranes. This problem was overcome by introducing a fluorine atom onto the piperidine ring (39): the

• basicity of the secondary amine was thereby reduced by nearly two orders of magnitude, and this led to a marked improvement in bioavailability. Incidentally, it is also worthy of note that the bioavailability (and 5-HT2A binding affinity) could be further improved by the introduction of a second fluorine

Recent advances in transition metal-catalyzed Csp²-monofluoro-, difluoro-, perfluoromethylation and trifluoromethylthiolation

• Grégory Landelle,
• Armen Panossian,
• Sergiy Pazenok,
• Jean-Pierre Vors and
• Frédéric R. Leroux

Beilstein J. Org. Chem. 2013, 9, 2476–2536, doi:10.3762/bjoc.9.287

• . Perfluoroalkyl substituents are particularly interesting as they often lead to a significant increase in lipophilicity and thus bioavailability albeit with a modified stability. Therefore, it is of continual interest to develop new, environmentally benign methods for the introduction of these groups into target

Cu-catalyzed trifluoromethylation of aryl iodides with trifluoromethylzinc reagent prepared in situ from trifluoromethyl iodide

• Yuzo Nakamura,
• Motohiro Fujiu,
• Tatsuya Murase,
• Yoshimitsu Itoh,
• Hiroki Serizawa,
• Kohsuke Aikawa and
• Koichi Mikami

Beilstein J. Org. Chem. 2013, 9, 2404–2409, doi:10.3762/bjoc.9.277

• , biological, and physical properties [1][2][3][4][5][6]. Particularly, trifluoromethylated compounds can be widely employed as one of the most effective analogues of bioactive compounds, because the trifluoromethyl group enhances the metabolic stability, lipophilicity, and bioavailability of these compounds

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

• alkyl chain to moderate their bioavailability resulting in the ultimate discovery of tiagabine (2.36) which has an embedded (R)-nipecotate unit as the class indicative pharmacophore. The synthesis of tiagabine (2.36) is readily accomplished by the union of ethyl nipecotate with the bis-thiophene

Recent progress in the discovery of small molecules for the treatment of amyotrophic lateral sclerosis (ALS)

• Allison S. Limpert,
• Margrith E. Mattmann and
• Nicholas D. P. Cosford

Beilstein J. Org. Chem. 2013, 9, 717–732, doi:10.3762/bjoc.9.82

• stability and oral bioavailability, as well as high brain accumulation [33]. Due to its advantageous pharmacological properties, 14 was tested in SOD1 G93A transgenic mice to determine whether it was able to extend lifespan and alleviate symptoms in a mouse model of ALS. However, this compound demonstrated

• 16 was found to be highly active in both of these assays and additionally demonstrated high potency and low toxicity, as well as excellent solubility and plasma stability [35]. Further studies indicated that compound 16 was able to cross the BBB and exhibited good oral bioavailability [35]. An

Quantification of N-acetylcysteamine activated methylmalonate incorporation into polyketide biosynthesis

• Stephan Klopries,
• Uschi Sundermann and
• Frank Schulz

Beilstein J. Org. Chem. 2013, 9, 664–674, doi:10.3762/bjoc.9.75

• . Especially the bioavailability and the coupled acceptance efficiency to the corresponding CoA-esters remain to be clarified. This has recently become highly relevant, as the first example for an acyltransferase domain with artificially broadened substrate specificity has been constructed and introduced in

Asymmetric synthesis of host-directed inhibitors of myxoviruses

• Terry W. Moore,
• Kasinath Sana,
• Dan Yan,
• Pahk Thepchatri,
• John M. Ndungu,
• Manohar T. Saindane,
• Mark A. Lockwood,
• Michael G. Natchus,
• Dennis C. Liotta,
• Richard K. Plemper,
• James P. Snyder and
• Aiming Sun

Beilstein J. Org. Chem. 2013, 9, 197–203, doi:10.3762/bjoc.9.23

• bioavailability [15]. Additionally, it was shown that the methyl group at the stereogenic center alpha to the carbonyl is important for biological activity [8][12][14]. Compound 1 was previously prepared as the racemate, but subsequently separated into enantiomers by chiral HPLC. To enable large-scale preparation