Miguel F. Braña

Synthesis, biological evaluation and DNA binding properties of novel mono and bisnaphthalimides

A novel series of mono and bisnaphthalimides was synthesized and their antiproliferative activities were evaluated against three tumor cell lines. Bisnaphthalimides 3 and 4, bearing a pyrazine ring fused to the naphthalimide system, showed activities in the order of 10(-8) microM, similar to elinafide. DNA binding properties and the ability to induce DNA damage were studied for some of the most active compounds.

Bis-naphthalimides. 2. Synthesis and biological activity of 5,6-acenaphthalimidoalkyl-1,8-naphthalimidoalkyl amines

Summary A series of non-symmetric bis-naphthalimides bearing a conveniently substituted 1,8-naphthalimide and a 5,6-acenaphthalimide chromophore was synthesized and in vitro activities were determined. Although previous studies suggested that the presence of the acenaphthalimide system in the structure enhances aqueous solubility, we found that these compounds were no more soluble or cytotoxic than the homologous symmetric series.

Synthesis and antitumour activity of new dendritic polyamines-(imide-DNA-intercalator) conjugates: potent Lck inhibitors.

A series of dendritic polyamines-(imide-DNA-intercalators) conjugates with different connectivity in their basic chain were synthesised and evaluated as antitumour compounds. Although their antiproliferative activity against HT-29 was not significant, conjugates 13 and 16 showed a promising profile as inhibitors of Lck.

Synthesis and biological evaluation of analogues of butyrolactone I and molecular model of its interaction with CDK2

A series of analogues of butyrolactone I, a natural product isolated from Aspergillus terreus that selectively inhibits the CDK2 and CDK1 kinases and that has been found to exhibit an interesting antiproliferative activity, have been synthesized. Its antitumor activity has been tested. Molecular models of the complex between butyrolactone I and the CDK2 active site have been built using a combination of conformational search and automated docking techniques. The stability of the resulting complexes has been assessed by molecular dynamics simulations and the experimental results obtained for the synthesized analogues are rationalized based on the molecular models.

Chemoselective Michael reactions on pyroglutamates. Expeditious synthesis of spiro-bis-γ-lactams as β-turn peptidomimetics

Abstract Starting from pyroglutamic acid, the synthesis of spiro-bis-γ-lactams, using as key step a chemoselective Michael reaction of pyroglutamates is reported. Thus, the reaction of N -BOC- l -methyl pyroglutamate with LiHMDS gives the enolates at C4 which react with several Michael acceptors. On the other hand, N -benzyl- l -methyl pyroglutamate reacts under the same conditions, to give the ester enolate which reacts with Michael acceptors leading to quaternized derivatives. The synthesis of the bicyclic spirolactams results from a reduction of the nitro group present in these derivatives which directly gives the spiro compounds. These final compounds may act as β-turn mimetics, as they have torsion angles which are in the range of β-turns of type II and II′.

Synthesis and biological evaluation of novel bisindolylmaleimides that inhibit vascular endothelial cell proliferation.

A novel class of bisindolylmaleimides were synthesized and antiproliferative activities (HUVECs and three tumor cell lines) of these compounds were investigated. Two water-soluble derivatives, 10 and 12, possessing a dimethylaminoalkoxy side chain in their structure, showed interesting activity and selectivity on HUVECs proliferation.

Synthesis, cytotoxic activities and proposed mode of binding of a series of bis([(9-oxo-9,10-dihydroacridine-4-carbonyl)amino]alkyl) alkylamines.

A series of bis([(9-oxo-9,10-dihydroacridine-4-carbonyl)amino]alkyl) alkylamines have been prepared and their antiproliferative properties have been tested against HT-29 cell lines. Compounds 6b and 6d showed an interesting cytotoxic profile and were subjected to further cytotoxic evaluation, DNA binding properties and molecular modelling studies. The evaluation of the cytotoxic activity of compounds 6b and 6d against pairs of cisplatin-sensitive and -resistant ovarian tumour cells shows that both compounds may be endowed with interesting antitumour properties because they are able to circumvent cisplatin resistance in A2780cisR, CH1cisR and Pam 212-ras tumour cells. On the other hand, DNA binding data indicate that compounds 6b and 6d are able to intercalate stronger than acridine within the double helix. Both compounds displace ethidium bromide with an efficiency ten times higher than acridine from several linear double-stranded DNAs and induce 43 degrees unwinding in supercoiled pBR322 DNA while acridine unwinds pBR322 DNA by only 24 degrees. Altogether these data indicate that the significant conformational changes induced by compounds 6b and 6d in the double helix are due to a bis-intercalative DNA binding mode. We propose that binding to DNA through bisintercalation might be at least in part responsible for the remarkable cytotoxic properties of these acridine derivatives. The complex of 6b with d(GCGCGC)(2) in the four possible orientations that the ligand can adopt when binding to the DNA hexamer have been modelled and subjected to molecular dynamics simulations with the aim of evaluating the binding preferences of this bisintercalating agent into the DNA molecule. The predictions suggest that 6b binds to d(GCGCGC)(2) with a parallel orientation of the chromophores relative to each other and with a preference for binding through the minor groove of the hexamer. The possible relevance of these findings to the process of bisintercalation and the antitumour profile of these compounds is discussed in this paper.

ON THE CHEMOSELECTIVITY OF PYROGLUTAMATES IN REACTIONS WITH INDOLE DERIVATIVES

Abstract Control of the chemoselectivity of reactions of pyroglutamates is determined by the nature of the nitrogen protecting group. Alkylation, aldol and Michael reactions of indole derivatives are explored.

Reaction of N-(4-pyridylmethyl)-amide N-oxides with acetic anhydride

Abstract Reaction of N-(4-pyridylmethyl)-benzamide N-oxides with acetic anhydride yielded dimerization compounds. This dimerization occurs at the atom attached to the pyridine ring.

Synthesis of a new bicyclic tetrahydropyridine system related to enediyne antibiotics

Abstract The synthesis of model compounds 1 and 2 related to dynemicin A is described.