Three successive and regiocontroled palladium cross-coupling reactions to easily synthesize novel series of 2,4,6-tris(het)aryl pyrido[1',2':1,5]pyrazolo[3,4-d]pyrimidines.

The first access to tris(het)arylated pyrido[1',2':1,5]pyrazolo[3,4-d]pyrimidine derivatives is reported. The series were generated from 4-chloroaminopyridinium, which afforded the key intermediate bearing three leaving groups, i.e. a C-2 methylsulfanyl, a lactame carbonyl group in C-4 and a chlorine atom in C-6. The regioselective reactions led to the tris(het)aryl derivatives with satisfying to high yields. The three successive cross-coupling reactions occurred first in C-6 by the displacement of chlorine, next in C-4 position by a sequential Pd-catalyzed phosphonium coupling and finally in C-2 under a Pd/Cu-catalyzed desulfitative cross-coupling reaction. The optimization and scope of each reaction are discussed and the original compounds characterized.

EVALUATION OF ANTIOXIDANT ACTIVITY OF SOME IMINES DERIVATIVES OF L-ARGININE.

UNLABELLED: L-Arginine is an a-amino acid which plays important roles in different diseases or processes, such as Alzheimer disease, inflammatory process, healing and tissue regeneration and it also could be useful as an anti-atherosclerotic agent. AIM: Considering the large amount of studies on the beneficial effects of different antioxidants, this paper is focused on the evaluation of the antioxidant potential of some imine derivatives, synthesized by the authors and described in a previous article. MATERIAL AND METHODS: The evaluation of the antioxidant power was performed using phosphomolydenum-reducing antioxidant power (PRAP) and ferric reducing antioxidant power (FRAP) assays, tests described in the literature and which are used with some minor modifications. RESULTS: It was found that most of the imine derivatives are more active than the L-Arginine in the PPAP and FRAP assays. The most active derivative was the compound obtained by condensation of L-arginine with 2,3-dihydroxybenzaldehyde (2k) and 2-nitrobenzaldehyde (2g). CONCLUSIONS: Following the described protocol, some imine derivatives of L-arginine were evaluated in terms of antioxidant potential using in vitro methods. The most favorable influence was obtained by the aromatic substitution with nitro and hydroxyl, the corresponding derivatives being the most active derivatives compared to L-arginine.

PET tracers for imaging brain α7 nicotinic receptors: an update.

Positron emission tomography (PET) molecular imaging of brain targets is a powerful tool to diagnose, follow up, and develop treatments and personalized medicine for a number of acute and chronic brain disorders. The availability of ß+ emitter tracers labelled with [(11)C] or [(18)F] having optimal characteristics of affinity and selectivity for alpha-7 nicotinic receptors (α7R) has received considerable attention, due to the major implication of these receptors in brain functions. The aim of this review is to identify the interest and need for the in vivo exploration of α7R by PET molecular imaging, which tools are currently available for this and how to progress.

Recent advances in the chemistry and biology of pyridopyrimidines.

The interest in pyridopyrimidine cores for pharmaceutical products makes this scaffold a highly useful building block for organic chemistry. These derivatives have found applications in various areas of medicine such as anticancer, CNS, fungicidal, antiviral, anti-inflammatory, antimicrobial, and antibacterial therapies. This review mainly focuses on the progress achieved since 2004 in the chemistry and biological activity of pyridopyrimidines.

Synthesis, characterization and antioxidant activity of some new thiazolidin-4-one derivatives.

AIM: To design new thiazolidin-4-ones derivatives and to evaluate their potential antioxidant effects using in vitro methods. MATERIAL AND METHODS: New ethyl esters of the 2-(R-phenyl)-4-oxo-thiazolidin-3-yl propionic acid were synthesized using "one step reaction" between different aromatic aldehydes, thioglycolic acid and beta-alanine ethyl ester hydrochloride. The antioxidant potential of the synthesized compounds was evaluated using the DPPH radical scavenging assay and phosphomolybdenum method. RESULTS: Eight thiazolidine-4-one derivatives were obtained in good yields and high purity. The structure of the synthesized compounds was confirmed using IR spectroscopy. The evaluation of antioxidant activity showed that 2-[(4-NO2)-phenyl]-4-oxo-thiazolidin-3-yl propionic acid ethyl ester (compound 16) was the most active compound. For this derivative the DPPH radical scavenger activity (I% = 91.63% +/- 0.77) and the total antioxidant capacity (absorbance = 1.0691 +/- 0.0763) were similar with that of ascorbic acid used as standard antioxidant. CONCLUSIONS: The antioxidant activity of the thiazolidine-4-one derivatives depends on the nature of the phenyl ring substituents, the NO2 and OH radicals having the most significant influence.

Development and optimization of the synthesis of new thiazolidin-4-one derivatives of ibuprofen.

UNLABELLED: Ibuprofen, an important nonsteroidal anti-inflammatory agent, is one of the most prescribed drugs for the treatment of pain and inflammation from various rheumatic diseases, but some side effects can occur on long-term use. AIM: The method for synthesis optimization of new derivatives of Ibuprofen with thiazolidin-4-one moiety, with improved pharmacological and toxicological profile. MATERIAL AND METHODS: To optimize the derivatization method of free carboxyl group of Ibuprofen (2-(4-isobutylphenyl)propionic acid) the reaction conditions were varied (reagent ratio, catalyst, reaction medium). RESULTS: The most favorable method was proved to be the reaction between ibuprofen hydrazone and mercaptoacetic acid, in excess, at 80-85 degrees C, for 6 h with 96% conversion rate. CONCLUSIONS: The synthesis of 2-phenyl-3-[2-(4-(isobutyl)phenyl)-2-methyl]acetamido-thiazolidin-4-one derivative was optimized in view of applying it as a general procedure for the synthesis of other derivatives with related structure. The chemical structure and molecular weight of the synthesized compound were confirmed by spectral methods (IR, 1H NMR, 13C NMR, HR-MS).

Aggressive behavior induced by the steroid sulfatase inhibitor COUMATE and by DHEAS in CBA/H mice.

The steroid sulfatase enzyme (STS) regulates the formation of dehydroepiandrosterone (DHEA) from dehydroepiandrosterone-sulfate (DHEAS). DHEAS is a well-known negative allosteric modulator of the GABA(A) receptor-gated chloride channels. It is classified as an excitatory neurosteroid. The implication of GABA(A) receptor activity in aggressive behavior in rodents is well-documented. In addition a genetic correlation between STS level in the liver and aggressive behavior across 12 strains of mice suggest that STS activity could be involved in aggression in mice. We assessed herein whether COUMATE (an STS inhibitor) and DHEAS modulate aggression in CBA/H mice. We hypothesized that inhibiting STS activity in vivo followed by DHEAS injections which increase the level of sulfated steroid that cross the blood-brain barrier and then modulate neurotransmitter receptors could modify the attack behavior in mice. COUMATE (10 mg/kg) was administrated p.o. alone or in combination with the neurosteroid DHEAS (0-50 mg/kg) i.p. Animals were thereafter tested for aggression. A single dose of COUMATE significantly inhibited STS activity both in the brain (70.57%) and in the liver (87%) 24 h following administration. Behavioral tests showed that the inhibitor and DHEAS enhanced aggressive behavior when animals were simultaneously subjected to both molecules. These results confirm the correlation between aggressive behavior and STS concentration in mice. In addition, we confirm that the steroid metabolism can modulate the behavior in rodents.

DNA interaction and cytotoxicity of a new series of indolo[2,3-b]quinoxaline and pyridopyrazino[2,3-b]indole derivatives.

Absorption, melting temperature and linear dichroism measurements were performed to investigate the interaction with DNA of a series of 16 tricyclic and tetracyclic compounds related to the antiviral agent B-220. The relative DNA affinity of the test compounds containing an indolo[2,3-b]quinoxaline, pyridopyrazino[2,3-b]indoles or pyrazino[2,3-b]indole planar chromophore varies significantly depending on the nature of the side chain grafted onto the indole nitrogen. Compounds with a dimethylaminoethyl chain strongly bind to DNA and exhibit a preference for GC-rich DNA sequences, as revealed by DNase I footprinting. Weaker DNA interactions were detected with those bearing a morpholinoethyl side chain. The incorporation of a 2,3-dihydroxypropyl side chain does not reinforce the DNA interaction compared with the unsubstituted analogues. Both the DNA relaxation assay and cytotoxicity study using two human leukemia cell lines sensitive (HL-60) or resistant (HL-60/MX2) to the antitumor drug mitoxantrone, indicate that topoisomerase II is not a privileged target for the test compounds which only weakly interfere with the catalytic activity of the DNA cleaving enzyme. Cytometry studies showed that the most cytotoxic compounds induce a massive accumulation of cells in the G2/M phase of the cell cycle. Collectively, the data show a relationship between DNA binding and cytotoxicity in the indolo[2,3-b]quinoxaline series.

Synthesis, cytotoxicity, DNA interaction and topoisomerase II inhibition properties of tetrahydropyrrolo[3,4-a]carbazole-1,3-dione and tetrahydropyrido-[3,2-b]pyrrolo[3,4-g]indole-1,3-dione derivatives.

Three tetrahydropyrrolo[3,4-a]carbazole-1,3-diones (6--8) and two tetrahydropyrido[3,2-b]pyrrolo[3,4-g]indole-1,3-diones (11--12) have been synthesized. Their interaction with DNA was probed by absorption and thermal melting studies. Compounds 8 and 12 both equipped with a hydroxyethyl-aminoethyl side-chain demonstrated higher affinities for poly(dA-dT)(2) than compounds 6, 7 and 11 bearing a dimethylaminoethyl side-chain. Circular and electric linear dichroism measurements showed that all five drugs behave as typical DNA intercalating agents. A plasmid cleavage assay was used to evaluate the capacity of the drugs to inhibit human topoisomerase II. Compounds 8 and 12 which bind strongly to DNA were found to stabilize DNA-topoisomerase II covalent complexes but their topoisomerase II inhibitory properties do not correlate with their cytotoxic potential. Compounds 6 and 7 are essentially inactive whereas compounds 8, 11 and 12 exhibit a high toxicity to P388 murine leukemia cells and provoke a marked accumulation in the G2/M phase of the cell cycle. These compounds form a new class of DNA-targeted antitumor agents.

DNA but not topoisomerases is a target for a cytotoxic benzo[5,6]cyclohepta[b]indol-6-one derivative.

The interaction of a newly designed benzocycloheptaindol-6-one derivative with DNA has been investigated by complementary spectroscopic techniques including absorption, circular and linear dichroism. Footprinting measurements were performed to delineate the sequence-selectivity of the drug-DNA interaction and a plasmid relaxation assay was used to study the effects of the drug on human DNA topoisomerases I and II. The results clearly indicated that the test compound behaves as a typical DNA intercalating agent but does not stimulate DNA cleavage by topoisomerases. At the cellular level, the cytometry measurements showed that the drug provoked a marked accumulation of HL60 human leukemia cells in the G2/M phase of the cell cycle. DNA is thus identified as a valid target for this new series of drugs particularly toxic to human (HL60) and murine (P388) leukemia cells.

DNA cleavage by hydroxy-salicylidene-ethylendiamine-iron complexes.

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.

Synthesis, DNA binding, topoisomerase II inhibition and cytotoxicity of two guanidine-containing anthracene-9,10-diones.

Two anthraquinone derivatives of the anticancer drugs mitoxantrone and ametantrone were examined for their ability to bind to DNA and to modulate the formation of topoisomerase-DNA cleavable complexes in vitro. The guanidinium groups introduced at the termini of the two aminoethylamino side chains of mitoxantrone can reinforce the interaction with DNA as judged from thermal denaturation studies with calf thymus DNA and polynucleotides. Footprinting experiments indicate that the binding to DNA of compound SR107 lacking the 5,8-hydroxyl substituents is essentially nonspecific whereas its congener SR 103 interacts preferentially with GC-rich sequences, particularly those containing 5'-(A/T)CG sites. Compound SR103, which bears two hydroxyl groups on the anthraquinone chromophore, promotes the cleavage of DNA by topoisomerase II and is cytotoxic toward human KB carcinoma cells in vitro. In contrast, the analogue SR107, which lacks OH groups, has no effect on topoisomerase II and is not cytotoxic.

Synthesis, DNA binding, and cleaving properties of an ellipticine-salen.copper conjugate.

The synthesis of a DNA-cutting agent that conjugates an ellipticine chromophore and a copper complex of bis(salicylidene)ethylenediamine, referred to as a salen, is reported. The presence of the salen.Cu complex allows cleavage of DNA via oxygen-based radicals, and the ellipticine moiety serves as a DNA anchor. Spectroscopic measurements indicate that the intercalation geometry of the ellipticine chromophore is preserved with the hybrid. The cleavage is much more efficient with the conjugate than with the Schiff base copper complex alone.

Salen-anthraquinone conjugates. Synthesis, DNA-binding and cleaving properties, effects on topoisomerases and cytotoxicity.

A series of amidoethylamino-anthraquinone derivatives bearing either one or two salen (bis(salicylidene)ethylenediamine) moieties complexed with CuII or NiII have been synthesized, and their DNA-binding and cleaving properties examined. The effects of the mono- and di-substituted anthracenedione-salen conjugates on DNA cleavage mediated by topoisomerases I and II have also been determined, as well as their cytotoxicity toward human KB cells. The anthraquinone-salen. NiII conjugates bind to GC-rich sequences in DNA, but do not cleave the macromolecule. By contrast, the anthraquinone-salen. CuII hybrids do not recognize particular nucleotide sequences but efficiently induce single-strand breaks in DNA after activation. The 5,8-dihydroxy-anthraquinone conjugates are more cytotoxic and more potent toward topoisomerase II than the non-hydroxylated analogues, but they are less cytotoxic than the salen-free anthraquinones. The attachment of a salen. CuII complex to the anthraquinone chromophore can confer DNA cleaving properties in vitro, but this is at the expense of cytotoxic activity. Anthraquinone-salen. CuII complexes may find useful employ as footprinting probes for investigating ligand-DNA interactions.

DNA recognition by two mitoxantrone analogues: influence of the hydroxyl groups.

The clinically useful anticancer drug mitoxantrone intercalates preferentially into 5'-(A/T)CG and 5'-(A/T)CA sites on DNA. The 5,8 hydroxyl substituents on its anthracenedione chromophore are available to interact with the double helix. Footprinting experiments with two anthraquinone derivatives structurally related to mitoxantrone and ametantrone have been undertaken to assess the influence of the hydroxyl groups on the DNA recognition process. The results confirm that they do play a role in the recognition of preferred nucleotide sequences and suggest that the binding of anthraquinones to a 5'-(A/T)CG site is dependent on the presence of the 5,8 hydroxyl substitutes whereas binding to 5'-(A/T)CA sites appears to proceed just as well without them.