Change Is in the Air: The Hypoxic Induction of Phenotype Switching in Melanoma

Melanoma cells can switch from a highly proliferative, less invasive state to a highly invasive, less proliferative state, a phenomenon termed phenotype switching. This results in a highly heterogenous tumor, where a slow-growing, aggressive population of cells may resist tumor therapy, and it predicts tumor recurrence. Here we discuss the observation made by Widmer et al. that hypoxia may drive phenotype switching

Interaction between double helix DNA fragments and the new antitumor agent sabarubicin, Men10755

Amongthe disaccharide derivatives of the antitumor anthracycline doxorubicin, sabarubicin (Men10755) is more active and less cytotoxic than doxorubicin. It showed a strong in vivo antitumor activity in all preclinical models examined, in conjunction with a better tolerability, and is now in phase II clinical trials. The interaction of sabarubicin andMen10749(a similar disaccharidewith a different configuration at C-40 of the proximal sugar) with the hexanucleotides d(CGTACG)2 and d(CGATCG)2 was studied by a combined use of 2D-1Hand 31PNMRtechniques. Both 1Hand 31P chemical shifts of imino protons and phosphates allowed to established the intercalation sites between the CG base pairs, as it occurs for other anthracyclines of the series. The dissociation rate constants (koff) of the slow step of the intercalation process were measured for Men10755 and Men10749, by NMR NOE-exchange experiments. The increase of koff , with respect of doxorubicin, showed that the intercalation process is significantly faster for both drugs, leading to an average residence time for sabarubicin into d(CGTACG)2 sixfold shorter than for doxorubicin. This could give account of both higher cytoplasmic/nuclear ratio and lower cellular uptake of sabarubicin in comparison with doxorubicin and accordingly of the lower cytotoxicity of these disaccharide analogues. A relevant number of NOE interactions allowed the structure of the complexes in solution to be derived through restrained MD calculations. NMR-DOSY experiments were performed with several drug/oligonucleotide mixtures in order to determine the structure and the dimension of the aggregates

Funzionalizzazione del C-3’ delle cefalosporine Δ2 e Δ3

Viene descritta la reazione dei Δ3 – C3’ bromo derivati della cefalosporine con alcooli. Si ottengono 3’-acilossimetilcefalosporine con buone rese e senza isomerizzazione del doppio legame; la reazione è più lenta rispetto all'analoga trasformazione descritta per i derivati Δ2

Studies related to cephalosporins. Part1. Solvolytic reactions of 3-bromomethyl cephems with alcohols and phenols

3-Bromomethyl-3 cephems are solvolysed by alcohols, similarly to the Δ2 isomers. The yields are fairly good and this reaction represents a straightforward route to obntain 3-alcoxymethyl-3-cephems. Both 3-bromomethyl-2-cephems and 3-bromomethyl-3-isomers reactr with a variety of phenols under solvolytic conditions, giving only C-substitution products. This reaction represent the sole example of c-alkylation of phenols by an allylic bromide under such mild conditions