Search

The recombinant catalase-peroxidase HPI from E. coli was used as an alternative enzyme in polymerization reactions for the production of (-) epicatechin oligomers and their biological activity was characterized. The enzyme was prepared in two forms: a purified and an immobilized form. Both were tested for their activity in oxidative polymerization reactions, and their stability and reusability were assessed. The polymerization reactions were followed by SEC-HPLC analyses, and the substrate was completely converted into one or more polymerization products depending on the reactions conditions. Results showed that the utilized conditions allowed for the isolation of some oligomers of different molecular weight: the oligomers containing 6 and 7 units of epicatechin substrate are the heaviest ones. Epicatechin was also used in reactions catalyzed by HRP in the same reaction conditions for comparison. In addition, one selected oligomer obtained by HPI enzyme catalysis was shown to act as in vitro inhibitor of tumor cell growth, like one oligomer deriving from epicatechin by HRP catalysis. These data confirm that epicatechin oligomeric form is more effective than its monomer in biological activity and suggest the use of HPI as an alternative enzyme in reactions for the production of epicatechin oligomers

Several synthetic combretastatin A4 (CA-4) derivatives were recently prepared to increase the drug efficacy and stability of the natural product isolated from the South African tree Combretum caffrum. A group of ten 3-amino-2-azetidinone derivatives, as combretastatin A4 analogues, was selected through docking experiments, synthesized and tested for their anti-proliferative activity against the colon cancer SW48 cell line. These molecules, through the formation of amide bonds in position 3, allow the synthesis of various derivatives that can modulate the activity with great resistance to hydrolytic conditions. The cyclization to obtain the 3-aminoazetidinone ring is highly diastereoselective and provides a trans biologically active isomer under mild reaction conditions with better yields than the 3-hydroxy-2-azetidinone synthesis. All compounds showed IC50values ranging between 14.0 and 564.2 nM, and the most active compound showed inhibitory activity against tubulin polymerization in vitro, being a potential therapeutic agent against colon cancer.

A series of Z and E combretastatin A-4 analogs bearing different substituents (OH, F, NO2, NH2, B(OH)2) in the 3′ position were synthesized. These derivatives and Z and E combretastatin A-1 were analysed by monitoring their ability to inhibit cell growth in Saccharomyces cerevisiae. Combretastatin A-1 (2a), A-4 (2b) and compound 2c were found to inhibit yeast growth. Moreover, combretatstatin A-4 (2b) and compound 2c induced a G1 arrest by affecting the synthesis of Clb5 protein, the principal S-phase cyclin. The G1 arrest is coincident with the activation of the stress activated kinase Snf1.

Summary: The anticancer activity of a novel pure 1,4-Diaryl-2-azetidinone (1), endowed with a higher solubility than the well known Combretastatin A4, is tested in mice. We previously reported that Compound (1) showed specific antiproliferative activity against duodenal and colon cancer cells, inducing activation of AMP-activated protein kinase and apoptosis. Here we estimate that the maximum tolerated dose in a mouse model is 40 mg/kg; the drug is well tolerated both in single dose and in repeated administration schedules. The drug displays a significant antitumor activity and a tumor growth delay when administered at the MTD both in single and fractionated i.v. administration in a mouse xenograft model of colorectal cancer. Arrest of tumor growth and relapse after drug suspension are parallel to modification in glucose demand as shown by PET studies with [18∈F] FDG. These data strongly support Compound (1) as a promising molecule for in vivo treatment of colorectal cancer.

A series of novel 1,4-diaryl-2-azetidinones were synthesized and evaluated for antiproliferative activity, cell cycle effects and apoptosis induction. Strong cytotoxicity was observed with the best compounds (±)-trans-20, (±)-trans-21 as well as enantiomers (+)-trans-20 and (+)-trans-21, which exhibited IC50 values of 3-13 nM against duodenal adenocarcinoma cells. They induced inhibition of tubulin polymerization and subsequent G2/M arrest. This effect was accompanied by activation of AMP-activated protein kinase (AMPK), activation of caspase-3 and induction of apoptosis. Additionally, the most potent compounds displayed antiproliferative activity against different colon cancer cell lines, opening the route to a new class of potential therapeutic agents against colon cancer.

The synthesis of a new DO3A-based macrocyclic ligand bearing a 8-hydroxyquinoline residue together with the prepn. of its Eu3+ and Er3+ neutral complexes are described. In a previous report [F. Rizzo, A. Papagni, F. Meinardi, R. Tubino, M. Ottonelli, G.F. Musso, G. Dellepiane, Synth. Met. 147 (2004) 143], we have shown that lanthanide complexes display very high stability combined with a good luminescence in aq. soln. under UV radiation, which indicate an energy transfer process from the excited 8-hydroxyquinoline moiety to the metal. In this work, we correlate the ability to transfer the energy from the sensitizer to lanthanide ion with pH behavior of the antenna. Furthermore, the variation of pH in Eu3+ complex supports the hypothesis of presence of charge-transfer transitions. The good soly. and sensitized emission in different solvents (org. and water) are very important aspects for their technol. applications as luminescent probes or NIR-emitting devices.