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

Theoretical study on β-cyclodextrin inclusion complexes with propiconazole and protonated propiconazole

• Adrian Fifere,
• Narcisa Marangoci,
• Stelian Maier,
• Adina Coroaba,
• Dan Maftei and
• Mariana Pinteala

Beilstein J. Org. Chem. 2012, 8, 2191–2201, doi:10.3762/bjoc.8.247

• modified (by pegylation for example) in order to avoid the shielding of the cavity during the inclusion process, and, as a consequence, to improve the systemic bioavailability and pharmacokinetics of the inclusion complexes. Results and Discussions The most stable conformations of the β-CD/PP and β-CD/PPH

Hydrophobic analogues of rhodamine B and rhodamine 101: potent fluorescent probes of mitochondria in living C. elegans

• Laurie F. Mottram,
• Safiyyah Forbes,
• Brian D. Ackley and
• Blake R. Peterson

Beilstein J. Org. Chem. 2012, 8, 2156–2165, doi:10.3762/bjoc.8.243

• , that are targeted to this organelle. In general, the choice to use small-molecule probes or molecular-biology-based approaches for these types of imaging applications can be challenging because of our limited understanding of the bioavailability and bioaccumulation of small molecules in this model

• agents must be added to C. elegans at concentrations orders of magnitude higher than are used with mammalian cells in culture [35][36]. For some hydrophobic compounds, delivery systems [31][32] can improve their uptake. We hypothesized that poor bioavailability of rhodamines in C. elegans may be

Cyclodextrin-based nanosponges as drug carriers

• Francesco Trotta,
• Marco Zanetti and
• Roberta Cavalli

Beilstein J. Org. Chem. 2012, 8, 2091–2099, doi:10.3762/bjoc.8.235

• molecules is widely used in the pharmaceutical field as a strategy to increase the aqueous solubility and, consequently, bioavailability of lipophilic drugs. For hydrophilic or moderately polar drugs this approach is less effective, and consequently cyclodextrin derivatives have been investigated

• formulation and bioavailability problems can be solved by enhancing the solubility and dissolution rate of a substance, and nanosponges can greatly enhance the drug solubility. Swaminathan et al. studied a formulation of itraconazole in nanosponges [33], a drug with an aqueous solubility of about 1 ng/mL at

• available on the market. Nanosponge formulation could thus increase the bioavailability of itraconazole. The solubilisation efficiency of nanosponges with regard to tamoxifen, a nonsteroidal anti-estrogen molecule used for treating and preventing breast cancer, was observed by using a 0.5% aqueous

Total synthesis and biological evaluation of fluorinated cryptophycins

• Christine Weiß,
• Tobias Bogner,
• Benedikt Sammet and
• Norbert Sewald

Beilstein J. Org. Chem. 2012, 8, 2060–2066, doi:10.3762/bjoc.8.231

• [10][11]. Fluorinated drugs are gaining increasing importance, and currently about 20% of all pharmaceuticals on the world market contain fluorine substituents [12][13]. Fluorination is supposed to enhance bioavailability and receptor selectivity. The van der Waals-radius of a fluorine substituent

Dimerization of a cell-penetrating peptide leads to enhanced cellular uptake and drug delivery

• Jan Hoyer,
• Ulrich Schatzschneider,
• Michaela Schulz-Siegmund and
• Ines Neundorf

Beilstein J. Org. Chem. 2012, 8, 1788–1797, doi:10.3762/bjoc.8.204

• potential due to limited bioavailability and cellular uptake. In recent years, cell-penetrating peptides (CPPs) emerged as an encouraging tool to overcome this obstacle owing to their ability to autonomously cross the cellular membrane in a receptor-independent manner. This enables them to deliver a large

Regioselective synthesis of 7,8-dihydroimidazo[5,1-c][1,2,4]triazine-3,6(2H,4H)-dione derivatives: A new drug-like heterocyclic scaffold

• Nikolay T. Tzvetkov,
• Harald Euler and
• Christa E. Müller

Beilstein J. Org. Chem. 2012, 8, 1584–1593, doi:10.3762/bjoc.8.181

• -chemical space of synthetic drug-like small molecules focusing on 6,5-heterobicyclic ring systems in order to increase the diversity of our proprietary compound library [13]. Criteria for selection of the target structures include the potential for biological activity and bioavailability (peroral, and

• suitable range for perorally active drugs. A pKa value of 10.0, and a logP value of 3 was determined. Thus, the molecule will be uncharged under physiological conditions and the logP value is in a range which allows us to predict oral bioavailability [29]. Conclusion In conclusion, we have designed and

Similarity analysis, synthesis, and bioassay of antibacterial cyclic peptidomimetics

• Workalemahu M. Berhanu,
• Mohamed A. Ibrahim,
• Girinath G. Pillai,
• Alexander A. Oliferenko,
• Levan Khelashvili,
• Farukh Jabeen,
• Bushra Mirza,
• Farzana Latif Ansari,
• Ihsan ul-Haq,
• Said A. El-Feky and
• Alan R. Katritzky

Beilstein J. Org. Chem. 2012, 8, 1146–1160, doi:10.3762/bjoc.8.128

• free carboxylic groups. It is reasonable to assume that such a zwitter-ionic structure alters the charge distribution and also eliminates hydrogen bonding in which the pyridine nitrogen atom acts as a H-bond acceptor. These factors increase hydrophobicity and thus deteriorate bioavailability, as

Algicidal lactones from the marine Roseobacter clade bacterium Ruegeria pomeroyi

• Ramona Riclea,
• Julia Gleitzmann,
• Hilke Bruns,
• Corina Junker,
• Barbara Schulz and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2012, 8, 941–950, doi:10.3762/bjoc.8.106

• bioavailability of metal ions by the formation of metal–MeSH complexes [7] and can be used for the biosynthesis of various sulfur-containing secondary metabolites [20]. A sulfur-containing metabolite, for which the direct sulfur precursor has not been determined yet, is the antibiotic tropodithietic acid (TDA, 2

Synthesis and antifungal properties of papulacandin derivatives

• Marjolein van der Kaaden,
• Eefjan Breukink and
• Roland J. Pieters

Beilstein J. Org. Chem. 2012, 8, 732–737, doi:10.3762/bjoc.8.82

• fungal infections in immunocompromised patients has been observed [1]. Treatment failure is frequent and mortality is unacceptably high in high-risk patients [2]. Reasons for this include delayed diagnosis, toxicity and low bioavailability of current drugs, and the development of antifungal drug

Investigation of the network of preferred interactions in an artificial coiled-coil association using the peptide array technique

• Raheleh Rezaei Araghi,
• Carsten C. Mahrenholz,
• Rudolf Volkmer and
• Beate Koksch

Beilstein J. Org. Chem. 2012, 8, 640–649, doi:10.3762/bjoc.8.71

• the concept of rational drug design based on coiled-coil proteins [6]. In this context, the use of unnatural amino acids in peptidomimetics is advisable, to enhance enzymatic stability, limit conformational flexibility, and improve pharmacodynamics and bioavailability [7]. In order to manipulate helix

Advances in synthetic approach to and antifungal activity of triazoles

• Kumari Shalini,
• Nitin Kumar,
• Sushma Drabu and
• Pramod Kumar Sharma

Beilstein J. Org. Chem. 2011, 7, 668–677, doi:10.3762/bjoc.7.79

• metabolism. Fluconazole (9) has nearly complete oral bioavailability, circulates in plasma as the free form, shows negligible hepatic metabolism, and is excreted unchanged through the kidneys. Itraconazole (10) is well absorbed by the gastrointestinal tract, high protein binding extensive hepatic metabolism

• , and is excreted in an inactive form via liver and kidneys. Fluconazole is 94% absorbed and its oral bioavailability is not affected by food or gastric pH. It is excreted unchanged in urine with t1/2 = 25–30 h. Itraconazole is largely metabolized in liver by cytochrome P450 3A4, an active metabolite is

• in the abdomen, kidney, bladder wall and wounds, and infections caused by Scedosporium apiospermum and Fusarium spp [51]. Voriconazole is available for both oral as well as intravenous (i.v.) administration and has excellent bioavailability (90%). It is metabolized in the liver and, in case of renal

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

• Marcus Baumann,
• Ian R. Baxendale,
• Steven V. Ley and
• Nikzad Nikbin

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

• II receptor were of a peptidic nature, suffered from poor bioavailability and also showed some agonistic activities. The first non-peptide antagonists were developed in the early 80’s. Although these compounds were selective for the AT2 receptor, they bound only weakly to their target protein. On

• suffer from poor absorption and low bioavailability. At this stage a classical bioisostere exchange, i.e., replacing a carboxylic acid group with a tetrazole ring, was performed which resulted in increased lipophilicity [48] and the development of the orally active losartan. In the absence of a crystal