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Christian Bailly

Publications and source records attributed to Christian Bailly.

At least 73 records · Page 4Linked to original sources
PubMed2003

Lamellarin D: a novel potent inhibitor of topoisomerase I.

We report the identification and characterization of a novel potent inhibitor of DNA topoisomerase I: lamellarin D (LAM-D), initially isolated from a marine mollusk, Lamellaria sp., and subsequently identified from various ascidians. This alkaloid, which displays potent cytotoxic activities against multidrug-resistant tumor cell lines and is highly cytotoxic to prostate cancer cells, bears a 6H-[1]benzopyrano[4',3':4,5]pyrrolo[2,1-a]isoquinolin-one pentacyclic planar chromophore, whereas its synthetic 5,6-dehydro analogue, LAM-501, has a significantly tilted structure. DNA binding measurements by absorbance, fluorescence, and electric linear dichroism spectroscopy show that LAM-D is a weak DNA binder that intercalates between bp of the double helix. In contrast, the nonplanar analogue LAM-501 did not bind to DNA and failed to inhibit topoisomerase I. DNA intercalation may be required for the stabilization of topoisomerase I-DNA complexes by LAM-D. In the DNA relaxation assay, LAM-D strongly promoted the conversion of supercoiled DNA into nicked DNA in the presence of topoisomerase I. The marine product was approximately 5 times less efficient than camptothecin (CPT) at stabilizing topoisomerase I-DNA complexes, but interestingly, the two drugs exhibited slightly distinct sequence specificity profiles. Topoisomerase I-mediated DNA cleavage in the presence of LAM-D occurred at some sites common to CPT, but a few specific sites identified with CPT but not with LAM-D or conversely unique sites cleaved by LAM-D but not by CPT were detected. The distinct specificity profiles suggest that LAM-D and CPT interact differently with the topoisomerase I-DNA interface. A molecular modeling analysis provided structural information on the orientation of LAM-D within the topoisomerase I-DNA covalent complex. The marine alkaloid did not induce DNA cleavage by topoisomerase II. Immunoblotting experiments revealed that endogenous topoisomerase I was efficiently trapped on DNA by LAM-D in P388 and CEM leukemia cells. P388/CPT5 and CEM/C2 cell lines, both resistant to CPT and expressing a mutated top1 gene, were cross-resistant to LAM-D. Collectively, the results identify LAM-D as a novel lead candidate for the development of topoisomerase I-targeted antitumor agents.

Animals↗
PubMed2003

DNA sequence recognition by bispyrazinonaphthalimides antitumor agents.

Bifunctional DNA intercalating agents have long attracted considerable attention as anticancer agents. One of the lead compounds in this category is the dimeric antitumor drug elinafide, composed of two tricyclic naphthalimide chromophores separated by an aminoalkyl linker chain optimally designed to permit bisintercalation of the drug into DNA. In an effort to optimize the DNA recognition capacity, different series of elinafide analogues have been prepared by extending the surface of the planar drug chromophore which is important for DNA sequence recognition. We report here a detailed investigation of the DNA sequence preference of three tetracyclic monomeric or dimeric pyrazinonaphthalimide derivatives. Melting temperature measurements and surface plasmon resonance (SPR) studies indicate that the dimerization of the tetracyclic planar chromophore considerably augments the affinity of the drug for DNA, polynucleotides, or hairpin oligonucleotides and promotes selective interaction with G.C sites. The (CH(2))(2)NH(CH(2))(3)NH(CH(2))(2) connector stabilizes the drug-DNA complexes. The methylation of the two nitrogen atoms of this linker chain reduces the binding affinity and increases the dissociation rates of the drug-DNA complexes by a factor of 10. DNase I footprinting experiments were used to investigate the sequence selectivity of the drugs, demonstrating highly preferential binding to G.C-rich sequences. It also served to select a high-affinity site encompassing the sequence 5'-GACGGCCAG which was then introduced into a biotin-labeled hairpin oligonucleotide to accurately measure the binding parameters by SPR. The affinity constant of the unmethylated dimer for this sequence is 500 times higher than that of the monomer compound and approximately 10 times higher than that of the methylated dimer. The DNA groove accessibility was also probed with three related oligonucleotides carrying G --> c(7)G, G --> I, and C --> M substitutions. The level of drug binding to the two hairpin oligonucleotides containing 7-deazaguanine (c(7)G) or 5-methylcytosine (M) residues is unchanged or only slightly reduced compared to that of the unmodified target. In contrast, incorporation of inosine (I) residues considerably decreases the extent of drug binding or even abolishes the interaction as is the case with the monomer. The pyrazinonaphthalimide derivatives are thus much more sensitive to the deletion of the exocyclic guanine 2-amino group exposed in the minor groove of the duplex than to the modification of the major groove elements. The complementary SPR footprinting methodology combining site selection and quantitative DNA affinity analysis constitutes a reliable method for dissecting the DNA sequence selectivity profile of reversible DNA binding small molecules.

Adenine↗
PubMed2003

Synthesis and pharmacological evaluation of novel non-lactone analogues of camptothecin.

Ten novel camptothecin (CPT) derivatives devoid of the lactone function in the E-ring were synthesized and evaluated as anticancer agents. Several of these CPT analogues bearing a five-membered E-ring are potent inhibitors of the DNA relaxation and cleavage reactions catalyzed by topoisomerase I and exhibit promising cytotoxic activities with IC(50) values in the nM range. This is the first successful design of lactone-free CPT, providing thus a new avenue to the development of topoisomerase I targeted antitumor agents.

Animals↗
PubMed2003

Rebeccamycin analogues bearing amine substituents or other groups on the sugar moiety.

In the course of structure-activity relationship studies on rebeccamycin analogues, a series of compounds bearing an amino function on the sugar moiety were synthesized with the aim of improving the solubility and interaction with the macromolecular target(s). The syntheses of amino derivatives and the corresponding chloro, iodo and azido intermediates are described. Their interaction with DNA and effects on human DNA topoisomerases I and II were investigated. Their antimicrobial activities against two Gram-positive bacteria, Bacillus cereus and Streptomyces chartreusis, a Gram-negative bacterium Escherichia coli and a yeast Candida albicans were also determined. 6'-Amino compound 7 and 6'-N-methylamino 14 very efficiently inhibit the growth of E. coli. The introduction of an amino group at the 6'-position strongly enhances the capacity of the drugs to interact with DNA but almost abolishes their poisoning effect on topoisomerase I. Unlike the vast majority of rebeccamycin analogues previously studied, the newly designed compounds do not stimulate DNA cleavage by topoisomerase I. The enhanced capacity of the 6'-amino glycosyl rebeccamycin derivatives to bind to DNA likely account for the improved biological profiles. DNA and topoisomerase I represent two independent targets which can both be used for the development of antitumor rebeccamycin derivatives.

Amines↗
PubMed2003

Spatial organization of topoisomerase I-mediated DNA cleavage induced by camptothecin-oligonucleotide conjugates.

Triple helix-forming oligonucleotides covalently linked to topoisomerase I inhibitors, in particular the antitumor agent camptothecin, trigger topoisomerase I-mediated DNA cleavage selectively in the proximity of the binding site of the oligonucleotide vector. In the present study, we have performed a systematic analysis of the DNA cleavage efficiency as a function of the positioning of the camptothecin derivative, either on the 3' or the 5' side of the triplex, and the location of the cleavage site. A previously identified cleavage site was inserted at different positions within two triplex site-containing 59 bp duplexes. Sequence-specific DNA cleavage by topoisomerase I occurs only with triplex conjugates bearing the inhibitor at the 3'-end of the oligonucleotide and on the oligopyrimidine strand of the duplex. The lack of targeted cleavage on the 5' side is attributed to the structural differences of the 3' and 5' duplex-triplex DNA junctions. The changes induced in the double helix by the triple-helical structure interfere with the action of the enzyme according to a preferred spatial organization. Camptothecin conjugates of oligonucleotides provide efficient tools to probe the organization of the topoisomerase I-DNA complex and will be useful to understand the functioning of topoisomerase I in living cells.

Base Sequence↗
PubMed2003

Structure-activity relationships and mechanism of action of antitumor benzo[b]pyrano[3,2-h]acridin-7-one acronycine analogues.

The cytotoxic and antitumor activities of cis-1,2-diacyloxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one derivatives 3, 6-9 were strongly correlated with their ability to give covalent adducts with purified, as well as genomic, DNA. Such adducts involve reaction between the exocyclic N-2 amino group of guanines exposed in the minor groove of double helical DNA and the leaving ester group at the benzylic position 1 of the drug. A transesterification process of the ester group from position 2 to position 1 in aqueous medium accounted for the intense activity of the cis-1-hydroxy-2-acyloxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one derivatives 10-13. Compounds without acyloxy or hydroxy group at position 1, such as 15, 17, 18, and 22, were inert with respect to DNA and almost devoid of significant cytotoxic activity. Condensation of 5-amino-2,2-dimethyl-2H-chromene (26) with 3-bromo-2-naphthoic acid (27), followed by cyclization, gave access to 6-demethoxy analogues. Diacetate 32 and cyclic carbonate 33, both belonging to the latter series, were less reactive toward DNA and less cytotoxic than their 6-methoxy counterparts 3 and 34. DNA alkylation appears thus to play an important role in the antitumor properties of benzo[b]pyrano[3,2-h]acridin-7-one derivatives.

Acridines↗
PubMed2003

Anti-proliferative and apoptotic effects of anandamide in human prostatic cancer cell lines: implication of epidermal growth factor receptor down-regulation and ceramide production.

BACKGROUND: Anandamide (ANA) is an endogenous lipid which acts as a cannabinoid receptor ligand and with potent anticarcinogenic activity in several cancer cell types. METHODS: The inhibitory effect of ANA on the epidermal growth factor receptor (EGFR) levels expressed on the EGF-stimulated prostatic cancer cells LNCaP, DU145, and PC3 was estimated by ELISA tests. The anti-proliferative and cytotoxic effects of ANA were also evaluated on these human prostatic cancer cell lines by growth tests, flow cytometric analyses, trypan blue dye exclusion assays combined with the Papanicolaou cytological staining method. RESULTS: ANA induced a decrease of EGFR levels on LNCaP, DU145, and PC3 prostatic cancer cells by acting through cannabinoid CB(1) receptor subtype and this leaded to an inhibition of the EGF-stimulated growth of these cells. Moreover, the G(1) arrest of metastatic DU145 and PC3 growth was accompanied by a massive cell death by apoptosis and/or necrosis while LNCaP cells were less sensitive to cytotoxic effects of ANA. The apoptotic/necrotic responses induced by ANA on these prostatic cancer cells were also potentiated by the acidic ceramidase inhibitor, N-oleoylethanolamine and partially inhibited by the specific ceramide synthetase inhibitor, fumonisin B1 indicating that these cytotoxic actions of ANA might be induced via the cellular ceramide production. CONCLUSIONS: The potent anti-proliferative and cytotoxic effects of ANA on metastatic prostatic cancer cells might provide basis for the design of new therapeutic agents for effective treatment of recurrent and invasive prostatic cancers.

Apoptosis↗
PubMed2003

Sequence-selective targeting of long stretches of the DNA minor groove by a novel dimeric bis-benzimidazole.

A dimeric bis-benzimidazole molecule has been designed by computer modeling to bind to a DNA sequence via the DNA minor groove that covers a complete turn of B-DNA. A series of bis-benzimidazole dimers incorporating a -O-(CH(2))(n)()-X-CH(2))(n)()-O- linker, with n = 2 or 3 and X = O or N(+)H(Me), were screened for their capacity to fit the DNA minor groove. The modeling studies enabled an optimal linker to be devised (n = 3, X = N(+)H(Me)), and the synthesis of the predicted "best" molecule, N-methyl-N,N-bis-3,3-[4'-[5' '-(2' "-p-methoxyphenyl)-5' "-1H-benzimidazolyl]-2' '-1H-benzimidazolyl]phenoxypropylamine (5), is reported. The optimized linker permits the two symmetric bis-benzimidazole motifs to maintain hydrogen-bonded contacts with the floor of the DNA minor groove. DNase I footprinting studies have shown that this ligand binds with high affinity to sequences representing approximately a complete turn of B-DNA, represented by the [A.T](4)-[G.C]-[A.T](4) motif, and only poorly to sequences of half this site size, in accord with the computer modeling studies. Compound 5 does not show acute cellular cytotoxicity, in contrast with its monomeric bis-benzimidazole precursors, yet is rapidly taken up into cells.

Base Sequence↗
PubMed2003

Indolocarbazole glycosides in inactive conformations.

Indolocarbazole glycosides related to rebeccamycin represent a promising category of antitumor agents targeting DNA and topoisomerase I. These drugs prefer to adopt a closed conformation with an intramolecular hydrogen bond between the indole NH group and the pyranose oxygen atom. Three pairs of indolocarbazole monoglycosides bearing an NH or an N-methyl indole moiety were synthesized and their biological properties investigated at the molecular and cellular level. Replacing the indole NH proton with a methyl group reduces DNA interaction and abolishes activity against DNA topoisomerase I. Surface plasmon resonance studies performed with a pair of water-soluble indolocarbazole glycosides and two hairpin oligonucleotides containing an [AT]4 or a [CG]4 sequence indicate that both the NH and the N-methyl derivative maintain a relatively high affinity for DNA (Keq = 2 - 6 x 10(5) M(-1)) but the incorporation of the methyl group restricts access to the DNA. The number of ligand binding sites (n) on the oligonucleotides is about twice as high for the NH compound compared to its N-methyl analogue. Modeling and 1H NMR studies demonstrate that addition of the N-methyl group drives a radical change in conformation in which the orientation of the aglycone relative to the beta-glucoside is reversed. The loss of the closed conformation by the N-methyl derivatives perturbs thir ability to access DNA binding sites and prevents the drug from inhibiting topoisomerase I. As a consequence, the NH compounds exhibit potent cytotoxicity against CEM leukemia cells with an IC50 value in the 1 microM range, whereas the N-methyl analogues are 10 to 100 times less cytotoxic. These studies offer circumstantial evidence supporting the importance of the closed conformation in the interaction of indolocarbazole glycosides with their molecular targets, DNA and topoisomerase I.

Anti-Bacterial Agents↗
PubMed2003

Selective recognition of G-qQuadruplex telomeric DNA by a bis(quinacridine) macrocycle.

The interaction of G-quadruplex DNA with the macrocyclic compound BOQ1, which possesses two dibenzophenanthroline (quinacridine) subunits, has been investigated by a variety of methods. The oligonucleotide 5'-A(GGGT(2)A)(3)G(3), which mimics the human telomeric repeat sequence and forms an intramolecular quadruplex, was used as one model system. Equilibrium binding constants measured by biosensor surface plasmon resonance (SPR) methods indicate a high affinity of the macrocycle for the quadruplex conformation (K > 1 x 10(7) M(-)(1)) with two equivalent binding sites. The affinity of BOQ1 for DNA duplexes is at least 1 order of magnitude lower. In addition, the macrocycle is more selective than the monomeric control compound (MOQ2), which is not able to discriminate between the two DNA structures (K(duplex) approximately K(quadruplex) approximately 10(6) M(-)(1)). Strong binding of BOQ1 to G4 DNA sequences was confirmed by fluorometric titrations with a tetraplex-forming oligonucleotide. Competition dialysis experiments with a panel of different DNA structures, from single strands to quadruplexes, clearly established the quadruplex binding specificity of BOQ1. Fluorescence resonance energy transfer (FRET) T(m) experiments with a doubly labeled oligonucleotide also revealed a strong stabilization of the G4 conformation in the presence of BOQ1 (DeltaT(m) = +28 degrees C). This DeltaT(m) value is one of the highest values measured for a G-quadruplex ligand and is significantly higher than observed for the monomer control compounds (DeltaT(m) = +10-12 degrees C). Gel mobility shift assays indicated that the macrocycle efficiently induces the formation of G-tetraplexes. Strong inhibition of telomerase was observed in the submicromolar range (IC(50) = 0.13 microM). These results indicate that macrocycles represent an exciting new development opportunity for targeting DNA quadruplexes.

Acridines↗
PubMed2003

Chromophore-modified bisnaphthalimides: DNA recognition, topoisomerase inhibition, and cytotoxic properties of two mono- and bisfuronaphthalimides.

Bisnaphthalimides represent a promising group of DNA-targeted anticancer agents. In this series, the lead compounds elinafide and bisnafide have reached clinical trials, and the search for more potent analogues remains a priority. In the course of a medicinal chemistry program aimed at discovering novel antitumor drugs based on the naphthalimide skeleton, different dimeric molecules containing two tetracyclic neutral DNA intercalating chromophores were synthesized. The naphthalimide unit has been fused to a benzene ring (azonafide derivatives), an imidazole, a pyrazine, or, as reported here, a furan ring which increases the planar surface of the chromophore and enhances its stacking properties. We report a detailed investigation of the DNA binding capacity of the dimeric molecule MCI3335 composed of two furonaphthalimide units connected by a 12 A long amino alkyl linker [(CH(2))(2)-NH-(CH(2))(3)-NH-(CH(2))(2)] identical to that of elinafide. Qualitative and quantitative binding studies, in particular using surface plasmon resonance, establish that the dimer binds considerably more tightly to DNA (up to 1000 times) than the corresponding monomer and exhibits a higher sequence selectivity for GC-rich sequences. DNase I footprinting experiments attest that the dimer, and to a lesser extent the monomer, preferentially intercalate at GC sites. The strong binding interaction between the drugs and DNA perturbs the relaxation of supercoiled DNA by topoisomerases, but the test compounds do not promote DNA cleavage by topoisomerase I or II. Despite the lack of poisoning effect toward topoisomerase II, MCI3335 displays a very high cytotoxicity toward CEM human leukemia cells, with an IC(50) in the low nanomolar range, approximately 4 times inferior to that of the reference drug elinafide. Confocal microscopy observations indicate that the monomer shows a stronger tendency to accumulate in the cell nuclei than the dimer. The extremely high cytotoxic potential of MCI3335 is attributed to its enhanced capacity to bind to DNA and to inhibit DNA synthesis, as evidenced by flow cytometry experiments using the BrdU assay. The results provide novel mechanistic information that furthers the understanding of the structure-activity relationships in the bisnaphthalimide series and identify MCI3335 as a novel lead compound for further preclinical investigations.

Base Sequence↗
PubMed2003

4-Hydroxymethyl-3-aminoacridine derivatives as a new family of anticancer agents.

3-Amino- and 3-alkylamino-4-hydroxymethylacridines bearing various substituents on the C ring have been prepared by regioselective electrophilic aromatic substitution of the corresponding 3-aminoacridines and ring opening of the dihydrooxazinoacridine key intermediates. Most of the new compounds show potent cytotoxic activities against murine L1210 (leukemia), human A549 (lung), and HT29 (colon) cancer cell lines. The most cytotoxic molecules, 1 and 13, are active at nanomolar concentrations. As predicted for acridine derivatives, the new compounds intercalate in DNA, but interestingly they do not interfere with topoisomerase I and II activities. The mode of action remains uncertain because intracellular distribution indicated very different behaviors for 1 and 13. Compound 13 is uniformly distributed in the cell both in the cytoplasm and in the nucleus, whereas compound 1 is essentially localized in cytoplasmic granules.

Acridines↗
PubMed2003

Highly cytotoxic benzo[c]pyrido[2,3,4-kl]acridines.

Several benzo[c]pyrido[2,3,4-kl]acridines bearing different substituents on the A and E rings were synthesized and evaluated for their capacity to bind to DNA and to inhibit DNA topoisomerases. Potent cytotoxic compounds were discovered but no strict correlation with their DNA binding affinity and effects on topoisomerases were observed. DNA is one but not the unique target of these compounds.

Acridines↗
PubMed2003

Sequence-specific minor groove binding by bis-benzimidazoles: water molecules in ligand recognition.

The binding of two symmetric bis-benzimidazole compounds, 2,2-bis-[4'-(3"-dimethylamino-1"-propyloxy)phenyl]-5,5-bi-1H-benzimidazole and its piperidinpropylphenyl analog, to the minor groove of DNA, have been studied by DNA footprinting, surface plasmon resonance (SPR) methods and molecular dynamics simulations in explicit solvent. The footprinting and SPR methods find that the former compound has enhanced affinity and selectivity for AT sequences in DNA. The molecular modeling studies have suggested that, due to the presence of the oxygen atom in each side chain of the former compound, a water molecule is immobilized and effectively bridges between side chain and DNA base edges via hydrogen bonding interactions. This additional contribution to ligand-DNA interactions would be expected to result in enhanced DNA affinity, as is observed.

Base Sequence↗
PubMed2003

Mechanically linked polycarbonate.

The synthesis, by solid-state copolymerization, and characterization of the first polycatenanes based on a commercial polymer are reported. Various amounts of a benzylic amide [2]catenane, the corresponding macrocycle, and a rigid bisphenol fluorene derivative have been quantitatively and homogeneously incorporated into bisphenol A polycarbonate. The resulting copolymers were characterized by size exclusion chromatography coupled with viscosimetry, (1)H NMR, differential scanning calorimetry, and dynamic mechanical analysis. The unexpectedly small influence of [2]catenane incorporation on the glass transition temperature of the copolymers points to remarkable internal mobility of the catenane comonomer rings. A new relaxation linked to the flexible catenane units is also observed. The studies represent a detailed structural characterization of a polymer containing small amounts of mechanical linkages in its backbone and demonstrate that significant effects can be induced by doping conventional polymers with small percentages (2-6% of repeat units) of flexible catenanes.

Journal Article↗
PubMed2003

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.

Antineoplastic Agents↗
PubMed2003

Syntheses and antiproliferative activities of 7-azarebeccamycin analogues bearing one 7-azaindole moiety.

Rebeccamycin analogues containing one azaindole unit, with and without a methyl group on the imide nitrogen and with the sugar moiety coupled either to the indole nitrogen or to the azaindole nitrogen were synthesized. To increase the solubility and induce stronger interactions with the target macromolecules, a bromo or nitro substitutent was introduced on the indole unit. The DNA binding and topoisomerase I inhibition properties were investigated together with the antiproliferative activities toward nine tumor cell lines. In addition, the effect of the compounds on the cell cycle of L1210 leukemia cells was examined. The nonaza analogues were found to be cytotoxic against all cell lines of the panel whereas the aza-analogues showed a selective action toward certain cell lines. They strongly inhibited the proliferation of SK-N-MC neuroblastoma, A431 epidermoid carcinoma and NCI-H69 small cell lung carcinoma cells, but showed little or no cytotoxic effect against IGROV ovary carcinoma, HT29 colon carcinoma, and A549 non small cell lung carcinoma cells. Whatever their cytotoxicity profile, all compounds induce similar cell cycle effects, with a marked G2+M block observed with L1210 leukemia cells. The data suggest that the molecular mechanism of action of the aza-analogue derivatives is different from that of rebeccamycin.

Aminoglycosides↗