A straightforward approach to antibodies recognising cancer specific glycopeptidic neoepitopes

Aberrantly truncated immature O-glycosylation in proteins occurs in essentially all types of epithelial cancer cells, which was demonstrated to be a common feature of most adenocarcinomas and strongly associated with cancer proliferation and metastasis. Although extensive efforts have been made toward the development of anticancer antibodies targeting MUC1, one of the most studied mucins having cancer-relevant immature O-glycans, no anti-MUC1 antibody recognises carbohydrates and the proximal MUC1 peptide region, concurrently. Here we present a general strategy that allows for the creation of antibodies interacting specifically with glycopeptidic neoepitopes by using homogeneous synthetic MUC1 glycopeptides designed for the streamlined process of immunization, antibody screening, three-dimensional structure analysis, epitope mapping and biochemical analysis. The X-ray crystal structure of the anti-MUC1 monoclonal antibody SN-101 complexed with the antigenic glycopeptide provides for the first time evidence that SN-101 recognises specifically the essential epitope by forming multiple hydrogen bonds both with the proximal peptide and GalNAc linked to the threonine residue, concurrently. Remarkably, the structure of the MUC1 glycopeptide in complex with SN-101 is identical to its solution NMR structure, an extended conformation induced by site-specific glycosylation. We demonstrate that this method accelerates dramatically the development of a new class of designated antibodies targeting a variety of “dynamic neoepitopes” elaborated by disease-specific O-glycosylation in the immunodominant mucin domains and mucin-like sequences found in intrinsically disordered regions of many proteins.

We developed new class of designated antibodies targeting of “dynamic neoepitopes” elaborated by disease-specific O-glycosylation at the immunodominant mucin domains.     

A straightforward modular approach to NLO-active beta-amino vinyl nitrothiophenes

Secondary amines add very efficiently to 2-ethynyl-5-nitrothiophene to give beta-amino vinyl nitrothiophenes, a novel class of push-pull chromophores. According to first HRS measurements these highly solvochromic compounds with relatively short dipole axes display remarkably high static first hyperpolarizabilities = 29-31 x 10(-)(30) esu.     

A straightforward and versatile synthetic approach to 1-azabicyclic alkaloids

A very straightforward route to 1-azabicyclo alkaloid scaffolds with several ring sizes is reported. The final bicyclic structures were built through a synthetic scheme that involved (i) the construction of dienic 4-piperidone systems by an imino-Diels-Alder reaction between aminotrienes and N-omega-vinylimines, in the presence of Yb(OTf)(3), and (ii) the ring-closing metathesis reaction of these cyclic dienes, under the influence of the first-generation Grubbs' Ru-complex catalyst. During this investigations, various polysubstituted azabicyclic ring skeletons, including several examples of the quinolizidine alkaloids, are reported, and their relative stereochemistry is adequately discussed.     

Clicking polymers: a straightforward approach to novel macromolecular architectures

Living/controlled polymerization techniques have enabled the synthesis of a large variety of different well-defined (co)polymer structures. In addition, the use of click chemistry in polymer science is a quickly emerging field of research since it allows the fast and simple creation of well-defined and complex polymeric structures in yields that were previously unattainable. In this critical review, the application of the azide-alkyne 1,3-dipolar cycloaddition for the construction of well-defined polymer architectures will be discussed in detail, providing a comprehensive overview for all disciplines related to polymeric materials.     

A straightforward approach to N-substituted-2H-indazol-2-amines through reductive cyclization

A versatile two-step, one-pot reaction to access N-substituted-2H-indazol-2-amine derivatives has been elaborated. A diverse set of analogues was obtained by a sequential hydrazone formation and reductive cyclization in moderate to good yields from readily available starting materials. The strategy tolerates a broad range of substitutions pattern and functional groups allowing further derivatizations.     

A straightforward route to spiroketals

A straightforward route to 1,7-dioxa-, 1,4,7-trioxa- and 1,4,7,10-tetraoxaspiro[5.5]undecanes, starting from commercially available 3-chloro-2(chloromethyl)prop-1-ene, is described.     

A straightforward approach towards thiazoles and endothiopeptides via Ugi reaction

Endothiopeptides can easily be obtained via Ugi reaction using thio acids as acid components. If isonitriles with an acetal group are applied, the endothiopeptides can directly be converted into thiazoles using TMSCl-NaI under microwave irradiation.     

A straightforward approach towards 5-substituted thiazolylpeptides via the thio-Ugi-reaction

A wide range of 5-substituted thiazoles are easily accessible via cross coupling of thiazolyl triflates. These activated thiazoles can be obtained by Ugi reactions using thioacids (thio-Ugi-reaction) and subsequent cyclisation of the endo thiopeptides formed with triflic anhydride. In addition, cyclisations with acyl halides give rise to 5-acyloxysubstituted derivatives.     

A straightforward approach towards cyclic peptides via ring-closing metathesis--scope and limitations

N- and C-terminal diallylated peptides are obtained by several approaches, such as peptide Claisen rearrangement, N- and O- allylation, and the Ugi reaction of allyl-protected components. These diallylated peptides are suitable substrates for ring-closing metathesis and the success of this cyclisation was investigated with respect to the ring size, the position of the allyl moieties and the reaction parameters. In general, excellent yields are obtained for cyclisation of allyl glycine subunits and N-allylated amides, while allyl esters and allyl carbamates often presented serious problems. However, yields of up to 73% were obtained under optimised conditions, and the new generated double bond is formed with excellent trans-selectivity.     

Stereoselective ring opening of meso bicyclic hydrazines: a straightforward approach to hydrazino cyclopentenic cores

The diastereoselective synthesis of hydrazinocyclopentenes 6 or 7 can be achieved in a straightforward manner from Diels-Alder adduct 4 using an acid-catalyzed rearrangement or a palladium-catalyzed allylic substitution reaction. In the latter case, enantioenriched compounds with ee values up to 58% can be obtained when an appropriate chiral ligand is used. [reaction: see text]     

Aldol-type reaction of a 4-pyrone: a straightforward approach to 4-pyrone-containing natural products

A straightforward approach to 4-pyrone-containing natural products has been developed, which includes an aldol-type reaction between 2,6-diethyl-3,5-dimethyl-4-pyrone and aldehydes. The counter cation of the carbanion of the pyrone was found to play an important role in this reaction.     

Arylbutyltellurides as precursors of dilithium arylthienylcyanocuprates in a straightforward approach to phenethylamine derivatives

The ring opening reaction of N-tosyl aziridines with dilithium arylthienylcyanocuprates generated from arylbutyltellurides produced phenethylamine derivatives in good to excellent yields.     

A straightforward approach to 2-azetidinones from imines and carboxylic acids using dimethyl sulfoxide and acetic anhydride

The direct synthesis of 2-azetidinones from imines and carboxylic acids under mild conditions is developed. Dimethyl sulfoxide (DMSO) can be activated by acetic anhydride and the resulting active species is used for the in situ generation of ketenes from carboxylic acids. This method is cheap, simple, convenient, and efficient and the products are easily isolated.     

A tandem Finkelstein-rearrangement-elimination reaction: a straightforward synthetic route to allyl esters

Allyl esters can be obtained by a Finkelstein-rearrangement-elimination reaction of 2-chloro-1-(chloromethyl)ethyl esters induced by NaI. Sodium iodide can be used below equivalence using a reductive agent as sodium thiosulfate. High yields are obtained with most of the diverse esters studied. The method described avoids the use of allyl alcohol as a reagent. 2-Chloro-1-(chloromethyl)ethyl esters are prepared from glycerol, the main by-product of biodiesel industry. The effectiveness of iodine as reagent to hydrolyze allyl esters is also confirmed.     

Cross-coupling of highly pyramidalized alkenes: A straightforward access to functionalized tetrasecododecahedradienes

The synthesis and chemical trapping of a highly pyramidalized pentacyclo[6.4.0.0(2,10).0(3,7).0(4,9)]dodec-8-ene containing ketal functions is reported. Its cross-coupling reaction with 3, 7-dimethyltricyclo[3.3.0.0(3,7)]oct-1(5)-ene followed by a [2 + 2] retrocycloaddition reaction gives a straightforward access to functionalized tetrasecododecahedradienes.     

A straightforward access to pyrrolidine-based ligands for asymmetric synthesis

A straightforward and flexible method for the preparation of ligands based on the pyrrolidine scaffold is presented. The synthetic strategy involves a diastereoselective allylation of phenylglycinol-derived imines, followed by a cyclization promoted by a hydrozirconation/halogenation sequence. Enantioselectivities of up to 84% ee in the asymmetric allylic allylation were obtained using these ligands.     

Synthesis of cucurbitine derivatives: facile straightforward approach to methyl 3-amino-4-aryl-1-methylpyrrolydine-3-carboxylates

A general three- or four-step synthesis of cis- and trans-substituted cucurbitine (3-aminopyrrolidine-3-carboxylic acid) derivatives from methyl 2-nitroacetate is reported. The first step utilizes a Knoevenagel condensation with five different aromatic imines or their corresponding aldehydes to form (Z/E)-mixtures of α-nitro acrylates. The second step gives rise to the pyrrolidine-core structures of the title compounds by a 1,3-dipolar cycloaddition reaction using an azomethine ylide. The last step consists of reduction of the nitro group to yield both diastereoisomers of the corresponding 4-aryl cucurbitine methyl esters.     

A chemical genetics approach for specific differentiation of stem cells to somatic cells: a new promising therapeutical approach

Cell replacement therapy of severe degenerative diseases such as diabetes, myocardial infarction and Parkinson's disease through transplantation of somatic cells generated from embryonic stem (ES) cells is currently receiving considerable attention for the therapeutic applications. ES cells harvested from the inner cell mass (ICM) of the early embryo, can proliferate indefinitely in vitro while retaining the ability to differentiate into all somatic cells thereby providing an unlimited renewable source of somatic cells. In this context, identifying soluble factors, in particular chemically synthesized small molecules, and signal cascades involved in specific differentiation processes toward a defined tissue specific cell type are crucial for optimizing the generation of somatic cells in vitro for therapeutic approaches. However, experimental models are required allowing rapid and "easy-to-handle" parallel screening of chemical libraries to achieve this goal. Recently, the forward chemical genetic screening strategy has been postulated to screen small molecules in cellular systems for a specific desired phenotypic effect. The current review is focused on the progress of ES cell research in the context of the chemical genetics to identify small molecules promoting specific differentiation of ES cells to desired cell phenotype. Chemical genetics in the context of the cell ES-based cell replacement therapy remains a challenge for the near future for several scientific fields including chemistry, molecular biology, medicinal physics and robotic technologies.