g-factors of the ground state rotational band of158Dy

Theg-factors of the four lowest states of the ground state rotational band of¹⁵⁸Dy have been determined asg(2 ₁ ⁺ )=+0.362(23),g(4 ₁ ^su+ )=+0.340(20),g(6 ₁ ^su+ )=+0.207(36) andg(8 ₁ ^su+ )=+0.21(11). Theg-factors of the 2⁺ and 4⁺ states were measured by the IPAC method with radioactive samples of 2.4 h¹⁵⁸Er in external magnetic fields. To investigate the higher states, for the first time an on-line γ—γ IPAC experiment was performed with the reaction¹⁵⁶Gd(α, 2n)¹⁵⁸Dy by use of the static hyperfine field of DyGd.     

Contribution of cyclodextrins in the development of different pharmaceutical formulations of a new matrix metalloproteinase inhibitor

Ro 28-2653 is a new synthetic inhibitor of matrix metalloproteinases. The ability of these enzymes to degrade various components of the extracellular matrix seems to play a major role in tumors progression and is potentially effective against bronchial remodeling in asthma and BPCO. Ro 28-2653 is very poorly soluble in water. This low solubility estimated at about 0.56 μg/ml in water at 25 °C gives rise to difficulties in pharmaceutical formulation of oral, injectable or nebulizable solutions. The purpose of our study is to prepare and to characterize inclusion complexes between Ro 28-2653 and cyclodextrins and to investigate the biopharmaceutical repercussion of the inclusion of the active substance. The complex formation was investigated by phase solubility studies. ¹H-NMR spectroscopy and molecular modeling studies were carried out to elucidate the structure of the inclusion complex between Ro 28-2653 and cyclodextrin. Oral, intravenous and nebulizable solutions of Ro 28-2653 were developed with cyclodextrin. The in vivo studies were performed on healthy sheep for the pharmacokinetic evaluation of the oral and intravenous formulations while the nebulization of the complex solution was studied by using an asthma model in mouse.     

Inclusion Complexes of Cyproterone Acetate with Cyclodextrins in Aqueous Solution

Cyproterone acetate (CPA) is a steroidal antiandrogen with a progestogenic activity. Given that this molecule has a very poor water solubility (2.1 g/mL), different cyclodextrins (CDs) were tested to form inclusion complexes and to increase solubility. Two different techniques were compared to study the affinity between CPA and CDs: phase-solubility studies and NMR spectroscopy. The stoichiometry and the stability constant could be determined for most complexes with the aid of phase-solubility studies. The greatest increase in solubility was achieved with the methylated -CDs, but hydroxypropylated - and -CDs also gave enhanced solubilities. ¹H-NMR studies showed a solubility increase similar to that found with phase-solubility studies. The proof of inclusion in the2,6-dimethyl--CD (DIMEB) was shown by ¹H-NMR and t-ROESY spectra.     

Radical S‐Adenosyl Methionine Epimerases: Regioselective Introduction of Diverse D‐Amino Acid Patterns into Peptide Natural Products

PoyD is a radical S‐adenosyl methionine epimerase that introduces multiple D ‐configured amino acids at alternating positions into the highly complex marine peptides polytheonamide A and B. This novel post‐translational modification contributes to the ability of the polytheonamides to form unimolecular minimalistic ion channels and its cytotoxic activity at picomolar levels. Using a genome mining approach we have identified additional PoyD homologues in various bacteria. Three enzymes were expressed in E. coli with their cognate as well as engineered peptide precursors and shown to introduce diverse D ‐amino acid patterns into all‐L peptides. The data reveal a family of architecturally and functionally distinct enzymes that exhibit high regioselectivity, substrate promiscuity, and irreversible action and thus provide attractive opportunities for peptide engineering.     

Genome Mining of Oxidation Modules in trans-Acyltransferase Polyketide Synthases Reveals a Culturable Source for Lobatamides

Bacterial trans-acyltransferase polyketide synthases (trans-AT PKSs) are multimodular megaenzymes that biosynthesize many bioactive natural products. They contain a remarkable range of domains and module types that introduce different substituents into growing polyketide chains. As one such modification, we recently reported Baeyer–Villiger-type oxygen insertion into nascent polyketide backbones, thereby generating malonyl thioester intermediates. In this work, genome mining focusing on architecturally diverse oxidation modules in trans-AT PKSs led us to the culturable plant symbiont Gynuella sunshinyii, which harbors two distinct modules in one orphan PKS. The PKS product was revealed to be lobatamide A, a potent cytotoxin previously only known from a marine tunicate. Biochemical studies show that one module generates glycolyl thioester intermediates, while the other is proposed to be involved in oxime formation. The data suggest varied roles of oxygenation modules in the biosynthesis of polyketide scaffolds and support the importance of trans-AT PKSs in the specialized metabolism of symbiotic bacteria.     

Genome Mining of Oxidation Modules in trans‐Acyltransferase Polyketide Synthases Reveals a Culturable Source for Lobatamides

Bacterial trans‐acyltransferase polyketide synthases (trans‐AT PKSs) are multimodular megaenzymes that biosynthesize many bioactive natural products. They contain a remarkable range of domains and module types that introduce different substituents into growing polyketide chains. As one such modification, we recently reported Baeyer–Villiger‐type oxygen insertion into nascent polyketide backbones, thereby generating malonyl thioester intermediates. In this work, genome mining focusing on architecturally diverse oxidation modules in trans‐AT PKSs led us to the culturable plant symbiont Gynuella sunshinyii, which harbors two distinct modules in one orphan PKS. The PKS product was revealed to be lobatamide A, a potent cytotoxin previously only known from a marine tunicate. Biochemical studies show that one module generates glycolyl thioester intermediates, while the other is proposed to be involved in oxime formation. The data suggest varied roles of oxygenation modules in the biosynthesis of polyketide scaffolds and support the importance of trans‐AT PKSs in the specialized metabolism of symbiotic bacteria.     

Lectin-Mediated Drug Targeting: Discrimination of Carbohydrate-Mediated Cellular Uptake between Tumor and Liver Cells with Neoglycoconjugates Carrying Fucose Epitopes Regioselectively Modified in the 3-Position

The circumvention of efficient "carbohydrate traps" in the liver is required for targeting glycoconjugates on tumor cells. As shown in the model system of bovine serum albumin (BSA) conjugates, the nature of R(1)-R(3) of the fucose epitope plays an important role in the discrimination of cellular uptake between tumor and liver cells as well as in the cytotoxic activity.