PubMed Health⌕ Search

Biomedical subjects

Farial A Tanious

Publications and source records attributed to Farial A Tanious.

14 recordsLinked to original sources
PubMed2006

Synthesis and antiparasitic evaluation of bis-2,5-[4-guanidinophenyl]thiophenes.

A series of bis-2,5-[4-guanidinophenyl]thiophenes were prepared in a five step process starting from 2,5-bis[trimethylstannyl]thiophene. The compounds were evaluated in vitro against Trypanosoma brucei rhodesiense (T. b. r.), Plasmodium falciparum (P. f.), Leshmania donovani (L. d.) and Trypanasoma cruzi (T. c.), and in vivo against T. b. r. Certain compounds show promising in vitro activity against T. b. r. and P. f. and have superior in vivo activity against T. b. r. to that of pentamidine and furamidine.

Animals↗
PubMed2006

A high-throughput, high-resolution strategy for the study of site-selective DNA binding agents: analysis of a "highly twisted" benzimidazole-diamidine.

A general strategy for the rapid structural analysis of DNA binding ligands is described as it was applied to the study of RT29, a benzimidazole-diamidine compound containing a highly twisted diphenyl ether linkage. By combining the existing high-throughput fluorescent intercalator displacement (HT-FID) assay developed by Boger et al. and a high-resolution (HR) host-guest crystallographic technique, a system was produced that was capable of determining detailed structural information pertaining to RT29-DNA interactions within approximately 3 days. Our application of the HT/HR strategy immediately revealed that RT29 has a preference for 4-base pair (bp), A.T-rich sites (AATT) and a similar tolerance and affinity for three A-T-bp sites (such as ATTC) containing a G.C bp. On the basis of these selectivities, oligonucleotides were designed and the host-guest crystallographic method was used to generate diffraction quality crystals. Analysis of the resulting crystal structures revealed that the diphenyl ether moiety of RT29 undergoes conformational changes that allow it to adopt a crescent shape that now complements the minor groove structure. The presence of a G.C bp in the RT29 binding site of ATTC did not overly perturb its interaction with DNA-the compound adjusted to the nucleobases that were available through water-mediated interactions. Our analyses suggest that the HT/HR strategy may be used to expedite the screening of novel minor groove binding compounds leading to a direct, HR structural determination.

Base Pairing↗
PubMed2006

Trisubstituted acridines as G-quadruplex telomere targeting agents. Effects of extensions of the 3,6- and 9-side chains on quadruplex binding, telomerase activity, and cell proliferation.

The synthesis is reported of a group of 3,6,9-trisubstituted acridine compounds as telomeric quadruplex-stabilizing ligands with systematic variations at the 3-, 6-, and 9-positions. A new microwave-assisted methodology has been developed for trisubstituted acridine synthesis. Structure-activity relationships are reported using surface plasmon resonance and a fluorescence melting assay to examine quadruplex binding, together with a telomerase inhibition assay. These reveal relationships between G-quadruplex stabilization and telomerase inhibition and optimal 3,6- and 9-substituent side-chain lengths for maximal activity. Qualitative molecular modeling using molecular dynamics simulations has been undertaken on four quadruplex-DNA complexes. Long-term exposure of MCF7 cancer cells to a subset of the most active compounds, at doses lower than the IC(50) values, showed that one compound produced a marked decrease in population growth, accompanied by senescence, which is consistent with telomere targeting by this agent.

Acridines↗
PubMed2005

Synthesis, DNA affinity, and antiprotozoal activity of fused ring dicationic compounds and their prodrugs.

Dicationic guanidine, N-alkylguanidine, and reversed amidine derivatives of fused ring systems have been synthesized from their corresponding bis-amines. DNA binding studies suggest that the diguanidines and the N-alkyl diguanidines fluorenes bind in the minor groove in a manner similar to that of the previously reported dicationic carbazole derivatives. The diguanidines and the N-alkyl diguanidines showed promising in vitro activity against both Trypanosoma brucei rhodesiense and Plasmodium falciparum. Promising in vivo biological results were obtained for the dicationic N-isopropylguanidino-9H-fluorene, giving 4/4 cures of the treated animals in the STIB900 animal model for African trypanosomiasis. The N-methyl analogue showed high activity as well. In addition, with the goal of enhancing the oral bioavailability, two novel classes of potential guanidine prodrugs were prepared. The N-alkoxyguanidine derivatives were not effective as prodrugs. In contrast, a number of the carbamates showed promising activity. The value of the carbamate prodrugs was clearly demonstrated by the results, which gave 4/4 cures on oral administration in the STIB900 mouse model.

Animals↗
PubMed2005

New triple-helix DNA stabilizing agents.

Several substituted quinolin-4-amines and heteroaromatic analogs were synthesized and evaluated for interaction with triplex polydA.2polydT and duplex polydA.polydT by using UV-thermal melting experiments. Excellent triple-helix DNA ligands with high affinity toward T.A.T triplets and triple/duplex selectivity were designed through a rational approach.

DNA↗
PubMed2005

Molecular determinants for DNA minor groove recognition: design of a bis-guanidinium derivative of ethidium that is highly selective for AT-rich DNA sequences.

The phenanthridinium dye ethidium bromide is a prototypical DNA intercalating agent. For decades, this anti-trypanosomal agent has been known to intercalate into nucleic acids, with little preference for particular sequences. Only polydA-polydT tracts are relatively refractory to ethidium intercalation. In an effort to tune the sequence selectivity of known DNA binding agents, we report here the synthesis and detailed characterization of the mode of binding to DNA of a novel ethidium derivative possessing two guanidinium groups at positions 3 and 8. This compound, DB950, binds to DNA much more tightly than ethidium and exhibits distinct DNA-dependent absorption and fluorescence properties. The study of the mode of binding to DNA by means of circular and electric linear dichroism revealed that, unlike ethidium, DB950 forms minor groove complexes with AT sequences. Accurate quantification of binding affinities by surface plasmon resonance using A(n)T(n) hairpin oligomer indicated that the interaction of DB950 is over 10-50 times stronger than that of ethidium and comparable to that of the known minor groove binder furamidine. DB950 interacts weakly with GC sites by intercalation. DNase I footprinting experiments performed with different DNA fragments established that DB950 presents a pronounced selectivity for AT-rich sites, identical with that of furamidine. The replacement of the amino groups of ethidium with guanidinium groups has resulted in a marked gain of both affinity and sequence selectivity. DB950 provides protection against DNase I cleavage at AT-containing sites which frequently correspond to regions of enhanced cleavage in the presence of ethidium. Although DB950 maintains a planar phenanthridinium chromophore, the compound no longer intercalates at AT sites. The guanidinium groups of DB950, just like the amidinium group of furamidine (DB75), are the critical determinants for recognition of AT binding sites in DNA. The chemical modulation of the ethidium exocyclic amines is a profitable option to tune the nucleic acid recognition properties of phenylphenanthridinium dyes.

Base Sequence↗
PubMed2005

Dications that target the DNA minor groove: compound design and preparation, DNA interactions, cellular distribution and biological activity.

Fluorescence microscopy of trypanosomes from drug treated mice shows that biologically active heterocyclic diamidines that target the DNA minor groove bind rapidly and specifically to parasite kinetoplast DNA (k-DNA). The observation that the kinetoplast is destroyed, generally within 24 hours, after drug treatment is very important for understanding the biological mechanism, and suggests that the diamidines may be inhibiting some critical opening/closing step of circular k-DNA. Given the uncertainties in the biological mechanism, we have taken an empirical approach to generating a variety of synthetic compounds and DNA minor groove interactions for development of improved and new biological activities. Furamidine, DB75, is a diphenyl-diamidine that has the curvature to match the DNA minor groove as expected in the classical groove interaction model. Surprisingly, a linear diamidine with a nitrogen rich linker has significantly stronger binding than furamidine due to favorable linker and water-mediated DNA interactions. The water interaction is very dependant on compound structure since other linear compounds do not have similar interactions. Change of one phenyl of furamidine to a benzimidazole does not significantly enhance DNA binding but additional conversion of the furan to a thiophene (DB818) yields a compound with ten times stronger binding. Structural analysis shows that DB818 has a very favorable curvature for optimizing minor groove interactions. It is clear that there are many ways for compounds to bind to k-DNA and exert specific effects on kinetoplast replication and/or transcription that are required to obtain an active compound.

Animals↗
PubMed2004

Dicationic biphenyl benzimidazole derivatives as antiprotozoal agents.

A series of biphenyl benzimidazoles diamidines 6a-i were synthesized from their respective diamidoximes, through the bis-O-acetoxyamidoxime followed by hydrogenation in glacial acetic acid/ethanol in the presence of Pd-C. The target compounds contain hydroxy and/or methoxy substituted 1,3-phenyl groups as the central spacer between the two amidino bearing aryl groups. All of the diamidines showed strong DNA affinities as judged by high DeltaTm values with poly(dA.dT)2, which varied with structure and is discussed. Seven of the nine new diamidines gave in vitro IC50 values of approximately 30 nM or less versus Trypanosoma brucei rhodesiense (T.b.r.). Generally the diamidines were less active versus Plasmodium falciparum (P.f.), however one compound exhibited excellent activity with an IC50 value of 2.1 nM. Five of the nine diamidines exhibited excellent in vivo activity in the trypanosomal STIB900 mouse model giving 3/4 or 4/4 cures at dosage of 20 mg/kg i.p. and three showed similar efficacy at dosage of 10 mg/kg or lower.

Animals↗
PubMed2004

Novel dicationic imidazo[1,2-a]pyridines and 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridines as antiprotozoal agents.

2-[5-(4-Amidinophenyl)-furan-2-yl]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-6-carboxamidine acetate salt (7) was synthesized from 2-[5-(4-cyanophenyl)-furan-2-yl]-imidazo[1,2-a]pyridine-6-carbonitrile (4a), through the bis-O-acetoxyamidoxime followed by hydrogenation in glacial acetic acid. Compound 4a was obtained in four steps starting with two successive brominations of 2-acetylfuran first with N-bromosuccinimide, and second with bromine to form alpha-bromo-2-acetyl-5-bromofuran (2) in a moderate yield. The product (3a), of the condensation reaction between 6-amino-nicotinonitrile and 2, undergoes Suzuki coupling with 4-cyanophenylboronic acid to furnish 4a in good yield. Acetate salt of 2-[5-(4-amidinophenyl)-furan-2-yl]-imidazo[1,2-a]pyridine-6-carboxamidine (8a) was obtained from 4a, through the bis-O-acetoxyamidoxime followed by hydrogenation in a mixture of ethanol/ethyl acetate. N-Methoxy-2-(5-[4-(N-methoxyamidino)-phenyl]-furan-2-yl)-imidazo[1,2-a]pyridine-6-carboxamidine (6) was prepared via methylation of the respective diamidoxime 5a with dimethyl sulfate. By these approaches eight new diamidines and four potential prodrugs were prepared. All of the diamidines showed strong DNA affinities as judged by high DeltaT(m) values. Six of the eight diamidines gave in vitro IC(50) values of 63 nM or less vs T. b. rhodesiense with two exhibiting values of 6 nM and 1 nM. Also, six of the eight diamidines gave in vitro IC(50) values of 88 nM or less vs P. falciparum with two exhibiting values of 14 nM. Excellent in vivo activity in the trypanosomal STIB900 mouse model was found for five of the diamidines on ip dosage; these compounds gave 4/4 cures in this model. The oral activity of the prodrugs was modest with only one showing 2/4 cures in the same mouse model.

Animals↗
PubMed2004

DNA sequence dependent monomer-dimer binding modulation of asymmetric benzimidazole derivatives.

A number of studies indicate that DNA sequences such as AATT and TTAA have significantly different physical and interaction properties. To probe these interaction differences in detail and determine the influence of charge, we have synthesized three bisbenzimidazole derivatives, a diamidine, DB185, and monoamidines, DB183 and DB210, that are related to the well-known minor groove agent, Hoechst 33258. Footprinting studies with several natural and designed DNA fragments indicate that the synthetic compounds bind at AT sequences in the minor groove and interact more weakly at sites with TpA steps relative to sites without such steps. Circular dichroism spectroscopy also indicates that the compounds bind in the DNA minor groove. Surprisingly, Tm studies as a function of ratio indicate that the monoamidines bind to TTAA sequences as dimers, whereas the diamidine binds as a monomer. Biosensor-surface plasmon resonance (SPR) studies allowed us to quantitate the interaction differences in more detail. SPR results clearly show that the monoamidine compounds bind to the TTAA sequence in a cooperative 2:1 complex but bind as monomers to AATT. The dication binds to both sequences in monomer complexes but the binding to AATT is significantly stronger than binding to TTAA. Molecular dynamics simulations indicate that the AATT sequence has a narrow time-average minor groove width that is a very good receptor site for the bisbenzimidazole compounds. The groove in TTAA sequences is wider and the width must be reduced to form a favorable monomer complex. The monocations thus form cooperative dimers that stack in an antiparallel orientation and closely fit the structure of the TTAA minor groove. The amidine groups in the dimer are oriented in the 5' direction of the strand to which they are closest. Charge repulsion in the dication apparently keeps it from forming the dimer. It instead reduces the TTAA groove width, in an induced fit process, sufficiently to form a minor groove complex. The dimer-binding mode of DB183 and DB210 is a new DNA recognition motif and offers novel design concepts for selective targeting of DNA sequences with a wider minor groove, including those with TpA steps.

Benzimidazoles↗
PubMed2003

Synthesis and antiprotozoal activity of aza-analogues of furamidine.

6-[5-(4-Amidinophenyl)furan-2-yl]nicotinamidine (8a) was synthesized from 6-[5-(4-cyanophenyl)furan-2-yl]nicotinonitrile (4a), through the bis-O-acetoxyamidoxime followed by hydrogenation. Compound 4a was prepared via selective bromination of 6-(furan-2-yl)nicotinonitrile (2a) with N-bromosuccinimide, followed by Suzuki coupling with 4-cyanophenylboronic acid. In a similar way, diamidines 8b and 8c were prepared from the dicyano derivatives 4c and 4d, respectively. N-Methoxy-6-[5-[4-(N-methoxyamidino)phenyl]-furan-2-yl]-nicotinamidine (6a) was prepared via methylation of the respective diamidoxime 5a with dimethylsulfate. Prodrugs 6b and 6c were also prepared by methylation of the respective diamidoximes 5b and 5d. The symmetrical diamidines 14a,b were synthesized through the corresponding bis-O-acetoxyamidoxime followed by hydrogenation. The key compounds 11a,b were conveniently obtained by Stille coupling between 2,5-bis(tri-n-butylstannyl)furan and the corresponding heteroaryl halides. These compounds have been evaluated in vitro for activity against Trypanosoma b.rhodesiense (T. b. r.) and P. falciparum (P. f.). The diamidines 8a, 8c, and 14b gave IC(50) values versus T. b. r. of less than 10 nM. Against P. f. 8a, 8b, and 14b exhibited IC(50) values less than 10 nM. In an in vivo mouse model for T. b. r. four compounds 6a, 6c, 6d, and 8a were curative. Compound 6a produced cures at an oral dosage of 5 mg/kg.

Animals↗
PubMed2003

Trisubstituted acridine derivatives as potent and selective telomerase inhibitors.

The synthesis and evaluation for telomerase-inhibitory and quadruplex DNA binding properties of three related series of rationally designed trisubstituted acridine derivatives are described. These are substituted on the acridine ring at the 2,6,9; 2,7,9; and 3,6,9 positions. The ability of several of the most potent compounds to interact with and stabilize an intramolecular G-quadruplex DNA was evaluated by surface plasmon resonance methods, and affinities were found to correlate with potency in a telomerase assay. The interactions of a number of compounds with a parallel quadruplex DNA structure were simulated by molecular modeling methods. The calculated interaction energies were compared with telomerase activity and showed generally consistent correlations between quadruplex affinity and telomerase inhibition. These data support a model for the action of these compounds that involves the stabilization of intermediate quadruplex structures that inhibit the elongation of telomeric DNA by telomerase in tumor cells.

Acridines↗
PubMed2003

Bis-4-aminoquinolines: novel triple-helix DNA intercalators and antagonists of immunostimulatory CpG-oligodeoxynucleotides.

Six dimeric 2-(2-naphthyl)quinolin-4-amines with a linker between the amino groups and eight dimeric 2-(4-anilino)quinolin-4-amines linked between the anilino groups were synthesized and evaluated for their interaction with duplex/triplex DNA's and as antagonists of immunostimulatory oligodeoxynucleotides with a CpG-motif (CpG-ODN). The most powerful triple-helix DNA intercalator known to date, with high affinity toward T.A.T triplets and triplex/duplex selectivity, was found. The potent antagonism of immunostimulatory CpG-ODN by several bis-4-aminoquinolines is not related to their DNA interactions.

Adjuvants, Immunologic↗