20 research outputs found
Biological activity and DNA sequence specificity of synthetic carbamoyl analogues of distamycin
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
An unusual rearrangement of Zofenopril, a new ACE inhibitor drug, under CID, MS, NMR and computational studies
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
550 Antitumour efficacy of MEN4901/T-0128, a new camptothecin derivative-carboxymethyldextran conjugate, in a panel of human gastrointestinal tumours xenografted in nude mice
Synthesis and DNA Binding Activities of Amidine Analogues of Oligo(N-Methylpyrrolecarboxamide) Antibiotics
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