A series of copper complexes of bis(hydroxysalicylidene)ethylenediamine (hydroxy-salens) have
been synthesized. The hydroxy group in the ortho, meta, or para position on each salicylidene unit was added
to reinforce the stability of the copper complex and to create a hydroquinone system cooperating with the
copper redox system to facilitate the spontaneous formation of oxidizing CuIII species. Cyclic voltammetry
and ESR spectroscopy in combination with electrochemistry and spin trapping experiments have been used to
characterize the structure and the redox state of the hydroxy-salen−copper complexes and to evidence the
production of oxygen-based free radicals. A complete set of magnetic values were determined. In addition, we
studied the capacity of complexes 3a,b,c to cleave DNA in the absence of activating agents. The meta isomer
3b does not generate oxygen radicals, and as a result it cannot cleave DNA. In sharp contrast, the para isomer
3c and to a lower extent the ortho isomer 3a exhibit nuclease activities in relation to their capacities to produce
oxygen radicals. Electrochemistry provides unequivocal evidence for the formation of CuIII species with
compounds 3a and 3c, but not with 3b. The nuclease activity correlates well with the ability of the hydroxy-salens to form the oxidizing CuIII species. The redox properties and therefore the DNA cleaving activities of
the complexes depend crucially on the position of the OH groups which contribute significantly to stabilize
the square planar copper complexes. The present work supports the hypothesis that a hydroquinone system
can cooperate with a redox metal system to trigger DNA cleavage. The design of metallo(hydroxy-salens)
provides an original route for the development of self-activated chemical nucleases.
This review article illustrates the growing use of azaindole derivatives as kinase inhibitors and their contribution to drug discovery and innovation. The different protein kinases which have served as targets and the known molecules which have emerged from medicinal chemistry and Fragment-Based Drug Discovery (FBDD) programs are presented. The various synthetic routes used to access these compounds and the chemical pathways leading to their synthesis are also discussed. An analysis of their mode of binding based on X-ray crystallography data gives structural insights for the design of more potent and selective inhibitors.
An original procedure for efficient synthesis of a functionalized
salen·copper complex is reported.
The mode of binding to DNA of the salen·CuII
complex was investigated by viscometry as well as
by absorption, circular, and linear dichroism spectroscopy. The
complex can induce DNA strand
breakage in the presence of a reducing agent as revealed by a plasmid
cleavage assay. The
spectroscopic and biochemical data indicate that the
salen·CuII complex induces
single-stranded
breaks via an interaction within one of the grooves of the double
helix.
We here report the synthesis and biological evaluation of new phenylcarbazole derivatives designed as potential anticancer agents. Indole and hydroxyindole were used to generate three scaffolds that were successively exploited to introduce various substituents on the maleimide moiety. The synthesis includes a final intramolecular key Heck-type reaction, which was carried out with a triflate derivative or with a bromophenyl derivative. Each step was optimized and the complete chemical strategy is detailed. Several compounds showed a marked cytotoxicity against CEM human leukemia cells with IC(50) values in the 10-100 nM range. Precise structure-activity relationships were delineated. Cell cycle analysis, topoisomerase I inhibition, and interaction with DNA were evaluated, and inhibition of CDK activity was also investigated. Although binding of the drugs to DNA likely contributes to the cytotoxic action, the exact molecular targets of these molecules remain undiscovered. The efficient chemical routes reported here for the design of highly cytotoxic compounds provide novel opportunities to identify antitumor agents in the phenylcarbazole series.
Bis(hydroxy)salen.Fe complexes were designed as self-activated chemical nucleases. The presence of a hy-droxyl group on the two salicylidene moieties serve to form a hydroquinone system cooperating with the iron redox system to facilitate spontaneous formation of free radicals. We compared the DNA binding and cleaving properties of the ortho -, meta- and para -(bishydroxy) salen.Fe complexes with that of the corresponding chelate lacking the hydroxyl groups. DNA melting temperature studies indicated that the para complex exhibits the highest affinity for DNA. In addition, this para compound was considerably more potent at cleaving supercoiled plasmid DNA than the regio-isomeric ortho - and meta -hydroxy-salen.Fe complexes, even in the absence of a reducing agent, such as dithiothreitol used to activate the metal complex. The DNA cleaving activity of the para isomer is both time and concentration dependent and the complexed iron atom is absolutely essential for the sequence uniform cleavage of DNA. From a mechanistic point of view, electron spin resonance measurements suggest that DNA contributes positively to the activation of the semi-quinone system and the production of ligand radical species responsible for subsequent strand scission in the absence of a reducing agent. The para -hydroxy-salen.Fe complex has been used for detecting sequence-specific drug-DNA interactions. Specific binding of Hoechst 33258 to AT sequences and chromomycin to GC sequences were shown. The para -bis(hydroxy)salen.Fe derivative complements the tool box of footprinting reagents which can be utilised to produce efficient cleavage of DNA.
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