Sara Drioli

Enantiomerically pure tetrahydro-5-oxo-2-furancarboxylic esters from dialkyl 2-oxoglutarates

Abstract Enantiomerically pure tetrahydro-5-oxo-2-furancarboxylic esters can be prepared either by enzymatic resolution of the racemic γ-lactones themselves or by bioreduction with bakers yeast of dialkyl 2-oxoglutarates and subsequent cyclization of the resulting dialkyl 2-hydroxyglutarates. The best results were obtained by the former route, by which the desired compounds were isolated in high enantiomeric excess. Bioreductions were less satisfactory. In fact the hydroxyester intermediates were initially formed as racemic mixtures and their final enantiomeric enrichment was reached by asymmetric destruction, occurring in the bioreaction medium, however at the same time large amounts of alkyl 4-hydroxybutanoates were formed as side products.

Conjugated PDT drug: Photosensitizing activity and tissue distribution of PEGylated pheophorbide a

The design of new photosensitizers with enhanced phototoxicity and pharmacokinetic properties remains a central challenge for cancer photodynamic therapy (PDT). In this study, Pheophorbide a (Pba) has been pegylated to methoxypolyethylene glycol (mPEG-Pba) to produce a soluble photosensitizer that exhibits a higher tissue distribution than free Pba. In vitro studies have shown that mPEG-Pba promotes a fairly strong photosensitizing effect in cancer cells, as previously observed for the unpegylated molecule. mPEG-Pba targets the mitochondria where, following photoactivation, ROS are produced which cause a cellular injury by lipid peroxidation. The effect of pegylation on the photosensitizer biodistribution has been examined in different selected organs of female mice, at different time points after intraperitoneal administration of the drug (50 µmol/Kg body weight). Other than free Pba, which showed a low tissue accumulation, mPEG-Pba has been detected in significant amounts (8 to 16 μg/ml) in liver, spleen, duodenum and kidney and, 3-5 hours after intraperitoneal injection, in moderate amounts (3 to 8 μg/ml) in brain and lung. In vivo optical imaging performed on living female C57/BL6 mice bearing a subcutaneous melanoma mass, showed that injected mPEG-Pba distributes all over the body, with an higher uptake in the tumor respect to free Pba. Our results indicate that although pegylation somewhat decreases the phototoxicity, it significantly increases the drug solubility and tissue distribution and tumor uptake of mPEG-Pba, making the conjugate an interesting photosensitizer for PDT.

A facile route to (+)- and (–)-trans-tetrahydro-5-oxo-2-pentylfuran-3-carboxylic acid, precursors of (+)- and (–)-methylenolactocin

The enantioselective synthesis of the title γ-lactone intermediates is easily achieved by employing Porcine pancreas lipase catalysed hydrolysis of the corresponding esters as the key step.

Synthesis, characterization, and optimization for in vivo delivery of a nonselective isopeptidase inhibitor as new antineoplastic agent

Bis-arylidenecycloalkanones structurally related to the nonselective isopeptidase inhibitor G5 were synthesized and tested for cytotoxic activity against glioblastoma cells. Cytotoxicities correlate well with Hammett σ constants for substituted arylidene groups, confirming the proposed inhibition mechanism. A new inhibitor (2c) based on the 4-hydroxycyclohexanone scaffold, which favors apoptosis over necrosis, was selected for further development. 2c inhibited representative deubiquitinases with micromolar IC50, and its proapoptotic activity was studied on several cancer cell lines. Inhibitor 2c was conjugated to PEG via dicarbamate and diester linkers. While the dicarbamate was inactive, the diester (2cPE) behaves like a prodrug and is converted into the active species 2c by secreted esterase activities. Finally, 2cPE was also tested in vivo on A549 lung carcinoma xenografts generated in mice. Intravenous treatment with 2cPE led to a significant reduction in primary tumor growth, without appreciable toxicity to mice.

Liquid‐Phase Synthesis and Characterization of a Conjugated Chimeric Oligonucleotide‐PEG‐Peptide

The preparation of a new chimeric conjugate in which a peptide and an oligonucleotide sequence are linked to the same, high-molecular weight poly(ethylene glycol) is reported. First, a new amino function was introduced on PEG selectively protected at the other OH extremity. Then, the peptide was synthesized at the amino-modified end, followed by removal of the OH-protecting group of PEG and synthesis of the oligonucleotide sequence. The final oligonucleotide deprotection was achieved without affecting the integrity of the peptide chain. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Pure, homo-bifunctional poly(ethylene glycol) orthogonally protected: synthesis and characterisation

New orthogonal reversible protections have been introduced on high-molecular weight, di-hydroxy PEGs. The introduction on the reaction intermediates of a removable carboxy group allows an efficient purification from all the undesired polymeric derivatives. A final, pure high-molecular weight DMT-PEG-Fmoc has been obtained.

Reactive PEGs for protein conjugation

Poly(ethylene glycol) (PEG) derivatives are the first choice of the water soluble, biocompatible polymers on hand for conjugation to proteins and polypeptides. This chapter deals with the PEG reagents that are available for the preparation of bioconjugates. The opportunities of different reactive groups on PEG are described and their different activities against the functional moieties of the amino acids are illustrated. Some attention is also given to the modification of the PEG backbone to increase its loading capacity and to eventually modify the stability of the conjugating bonds.

PNA Conjugated to High-Molecular Weight Poly(Ethylene Glycol): Synthesis and Properties

The conjugation of a bioactive, fluorescent PNA sequence to high-molecular weight poly(ethylene glycol) (PEG) is described and the properties of the PEG-PNA conjugate are evaluated.

Chemoenzymatic synthesis of optically active 4-methyl-tetrahydro-5-oxo-2-furancarboxylic acids and esters

Abstract Enantiomerically pure 4-methyl-tetrahydro-5-oxo-2-furancarboxylic acids and esters are prepared by enzymatic resolution of the chiral racemic esters. Their stereochemistry as well as their absolute configurations have been established by chemical correlation. The influence of the alkoxycarbonyl group at C-2 and that of the methyl group at C-4 on the sign of the Cotton effect in their CD spectra have been investigated. Formation of enantiomerically pure hydroxydiesters, precursors of the above-mentioned γ-lactones, by baker’s yeast reduction of the corresponding ketodiesters was unsatisfactory.

PEG-Ursolic Acid Conjugate: Synthesis and In Vitro Release Studies.

A highly water-soluble macromolecular compound of ursolic acid with monomethoxypoly(ethylene glycol) (mPEG) was prepared. The physicochemical properties and stabilities under different conditions were investigated. By PEG conjugation, greatly increased water solubility was obtained, and the results showed that this conjugate was a potential prodrug for the oral delivery of ursolic acid.