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

Binding of Epstein-Barr virus nuclear antigen 1 to DNA: inhibition by distamycin and two novel distamycin analogues

Modulation of the interaction between cellular or viral transcription factors and target DNA sequences may represent a potential experimental strategy to control proliferation of neoplastic cells as well as virus DNA replication. Distamycin represents a likely candidate to mediate such modulation by pharmacological means. In order to obtain more detailed information on structure-activity relationships of these compounds, we have analysed the effects of distamycin and two distamycin analogues on the binding of a recombinant protein, the Epstein-Barr virus nuclear antigen 1 (EBNA-1) to its target sequence of Epstein-Barr virus, containing the 12 bp palindromic consensus TAGCATATGCTA. The sequence selectivity in the binding of distamycin to DNA was evaluated by footprinting experiments, while the effects of distamycins on DNA-protein interactions was analysed by means of electrophoretic mobility shift assay. The data presented in this paper suggest that distamycin and its analogues differentially inhibit the interaction between DNA-binding proteins and target DNA sequences

Croton macrostachys, a plant used in traditional medicine: purgative and inflammatory activity

Croton macrostachys seeds are widely used in Somalia as a purgative. in the present study, pharmacologic and chemical investigations confirm the laxative effect of the seeds and indicate the presence of phorbolesters. There appears to be no direct correlation between the phorbolester content and laxative effect

Synthesis of Two Distamycin Analogs and Their Binding Mode to d(CGCAAATTTGCG)2 in the 2:1 Solution Complexes as Determined by Two-Dimensional 1H-NMR

In the course of a study aimed at the synthesis of pyrrole amidine carboxamide DNA-binding agents as novel pharmacological agents, a series of carbamoyl analogues of distamycin, containing an increasing number of pyrrole units, have been obtained by total synthesis. The interaction of the tetrapyrrole carbamoyl 4 with the dodecamer d(CGCAAATTTGCG)(2) in comparison with that of the corresponding formylamino analogue 3 has been examined by high-resolution H-1-NMR and molecular modeling. Either ligand binds to DNA in one-drug and symmetric two-drug modes at low drug:DNA ratios, while at high ratios only the two-drug complex was observed. In this article, the structure of 2:1 drugs DNA complexes has been studied by NMR and molecular modeling, which indicate that the two analogues bind the DNA in a similar fashion, in the minor groove of the 5'-AATTT region. In both complexes the two drugs are symmetrically placed along the complementary strands of DNA with the pyrrole ring of one molecule in close contact with those of the other one. Although another region of five consecutive A-T base pairs is available, no evidence of sliding of drug molecules between different binding sites, as in the case of the 2:1 complex of distamycin with the same dodecamer, is observed, thus indicating that increasing the number of N-methylpyrrolecarboxamide units from three to four cases a lengthening of the recognition sequence