Top PDF Biological Activity of Pyrrole-Imidazole Polyamides in vivo

Biological Activity of Pyrrole-Imidazole Polyamides in vivo

Biological Activity of Pyrrole-Imidazole Polyamides in vivo

the promoter regions of enhancer and transcription factor binding elements within DNA sequences (Fig. 6.1B) (33). The binding of Py-Im PA compounds results in allosteric changes to the DNA helix that interferes with DNA-protein interactions and modifies gene expression (22). These compounds have multiple advantages for targeting gene transcription: they are cell permeable, localize to the nuclei, and recognize and bind to specific regions of the minor groove of double helical DNA with affinity similar to transcriptional factors, such as HIF (22). Previous studies show antitumor effects of Py-Im polyamides in xenografts (20, 26, 28, 30); however, the effects of Py-Im polyamide treatment on Multiple Myeloma models have not been examined. Herein we evaluate those effects using a Py-Im polyamide (HIF-PA) that is capable of displacing heterodimer from binding to its cognate DNA sequences and inhibiting hypoxia-mediated gene transcription including pro-angiogenic factors (33). The choice of compound is dictated by observed heightened expression of angiogenic factors, such as VEGF, increased angiogenesis within MM tumors, and a strong correlation of these characteristics with disease development and progression in the BM and poor patient prognosis (34-37). Currently used VEGF-targeting drugs, such as bevacizumab (Avastin) inhibit angiogenesis in MM tumors; however, only modest and transient anti-tumor effects were observed (38), calling into question the overall clinical effectiveness of using a mono-therapeutic strategy targeting angiogenesis to treat myeloma. One explanation for the underwhelming effects of bevacizumab could be explained by a concomitant increase of hypoxia resulting from the inhibition of angiogenesis (39). In this scenario, low pO 2 (a natural component of the BM niche) may
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Biological Activity, Lipoprotein binding Behavior, and In Vivo Disposition of Extracted and Native Forms of Salmonella typhimurium Lipopolysaccharides

Biological Activity, Lipoprotein binding Behavior, and In Vivo Disposition of Extracted and Native Forms of Salmonella typhimurium Lipopolysaccharides

Although phenol-extracted gram-negative bacterial lipopolysaccharides (LPS) have been used to study the properties of endotoxins for many years, nothing is known about the behavior of native (unextracted) LPS in vivo. Accordingly, we have compared extracted and native forms of LPS with regard to their biological activity, their ability to bind to plasma high density lipoproteins (HDL), and their fate after intravenous injection into rats. The LPS of Salmonella typhimurium G-30 were labeled with [ 3 H]galactose, and whole bacteria,

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Improving the Biological Activity of Pyrrole-Imidazole Polyamides

Improving the Biological Activity of Pyrrole-Imidazole Polyamides

sulforhodamine B colorimetric assay for cellular protein content as previously described. 22 All polyamide stock solutions were prepared in neat DMSO and dosed to give a final concentration of ≤ 0.3% DMSO. Briefly, cell lines were plated in 100 µL of the defined media at the following densities: A549 (1000 cells/well); LNCaP (5000 cells/well), HCT-116 (750 cells/well), MCF-7 (3000 cells/well). After 24 hr, polyamides were added to adhered cells in 100 µL of media by serial dilution. Quadruplicate wells were used for each polyamide concentration. After 72 hr, the medium was replaced with 100 µL fresh medium, and cells were allowed to recover for 24 hr. Following recovery, cells were fixed with 100 µL 10% trichloroacetic acid solution, washed, stained, and dried as described. For 48 and 72 hr polyamide treatments, the procedure was followed as above with A549 cells plated at 3000 and 2000 cells per well, respectively. After solubilization of the bound dye in 10 mM Tris (pH 8), the absorbance was measured at 490 nm on a Victor microplate reader (PerkinElmer). The data are charted as a percentage of untreated controls, corrected for background absorbance. IC 50 is defined as
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Biological Evaluation In Vivo of Synthesis of Silicated Apatites

Biological Evaluation In Vivo of Synthesis of Silicated Apatites

The biological study allows us to evaluate the biological properties of calcium phosphate apatite silicated to assess both the efficiency and the performance of these biomaterials as bone substitutes. The in vivo results indicate bone ingrowth into the spaces between the surrounding bone and our product SiHa. We also noted that the SiHa biomaterial is well accepted in the host tissue, with no evidence of inflammatory cells, there is a good fixation of our product. The absolute percentage of bone ingrowth coverage and bone mineral apposition rate for SiHa implant was significantly interesting. These results have established that silicium plays an active role in bone formation and calcification. Finally this study shows clearly, that the biological activity/response of apatite is significantly enhanced by the substitution of low levels of silicate ions into the Ha lattice [33].
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Targeted Derepression of the Human Immunodeficiency Virus Type 1 Long Terminal Repeat by Pyrrole-Imidazole Polyamides

Targeted Derepression of the Human Immunodeficiency Virus Type 1 Long Terminal Repeat by Pyrrole-Imidazole Polyamides

FIG. 2. Polyamides block binding of LSF to the RCS in vivo. ChIP assays show an increase of acetylated histone H4 near Nuc-1 of the LTR after treatment with TSA and a decrease in LSF at this region of the LTR after exposure to RCS-binding polyamides. (A) PCR ampli- fication of the 5⬘ LTR or ␤-actin promoter performed by using cell extracts (⫺) and cells exposed to TSA (⫹). Shown are products of ChIP and PCR amplification of the 5⬘ LTR or ␤-actin promoter using anti-acetylated histone H4 or mock immunoprecipitation (IP) with rabbit immunoglobulin G (IgG) and control PCR amplification of the 5⬘ LTR or ␤-actin promoter using extract prior to immunoprecipita- tion. Results are representative of three independent experiments. (B) ChIP with anti-LSF. PCR products of extracts of untreated cells, cells exposed to TSA, and polyamides 1 and 4, 2 and 4, M1 and M3/4, or M2 and M3/4. Shown are products of ChIP and PCR amplification of the 5⬘ LTR using anti-LSF or mock immunoprecipitation with rabbit immunoglobulin G and control PCR amplification of the 5⬘ LTR or ␤-actin promoter using extract prior to immunoprecipitation. PCR amplification of the ␤-actin promoter with extract following immuno- precipitation with anti-LSF yielded no product (data not shown). These two experiments are representative of four independent exper- iments.
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Preclinical Study of DNA-Recognized Peptide Pyrrole-Imidazole Polyamide Targeting Human TGF-β1 Promoter for Progressive Renal Diseases in Common Marmoset

Preclinical Study of DNA-Recognized Peptide Pyrrole-Imidazole Polyamide Targeting Human TGF-β1 Promoter for Progressive Renal Diseases in Common Marmoset

Recently some groups have developed alkylating PI polyamides as anticancer agents [28-30]. DNA alkylating agents can damage cellular DNA and lead to anticancer activity. Since the non-specific DNA alkylation damages normal cells, alkylating PI polyamides can damage cancer cells in sequence-specific alkylation for cancer genes [31]. However, the off-target effects of the alkylating PI polyamides by binding and alkylating to non-target genes have been concerned as practical medicines. On the other hand, we have developed non-alkylating PI polyamides as a gene silencer to block transcription factor binding on the target gene. Transcriptional silencing PI polyamides may also have off-target effects by non-specific binding on a non-target gene. However, transcriptional silencing PI polyamides simply suppress the transcriptionally activated gene function in a disease state, even when binding to non-target genes, indicating that the non-alkylating PI polyamides might have low side effects and high specificity. In conclusion, in the present study we examined the effects of low-dose treatment with a PI polyamide targeting hTGF-b1 that was injected once a day in common marmoset models of chronic nephropathy induced by CsA and UUO, as a preclinical study. The synthetic PI polyamide targeting hTGF-b1 effectively improved nephropathy in common marmosets. These results indicate that the PI polyamide will be developed as a medicine that may provide a radical cure for progressive renal diseases.
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Synthesis and biological evaluation of new nanosized aromatic polyamides containing amido- and sulfonamidopyrimidines pendant structures

Synthesis and biological evaluation of new nanosized aromatic polyamides containing amido- and sulfonamidopyrimidines pendant structures

Sulfonamides have been used in therapeutics for many years [13, 14]. The sulfonamide derivatives have been reported to show substantial antitumor activity in  vitro and/or in vivo [15–18], HIV protease inhibitors [19, 20] and cell entry [21]. The polysulfonamide is an active agent that shields the toxic polycations. The copolymers possess higher activity toward fungi than against bacteria and being more gram positive rather than gram negative as it is common. A novel strategy for cancer treatment based on a new class of inhibitors bearing fluorescent tails is currently an active research area for use therapeu- tic and imaging agents for poorly responsive tumors to classical chemo- and radiotherapies. For instance, a bio- active novel fluorescent fluoro poly(amide–sulfonamide) s possessed distinctive structure as well as unique prop- erties were reported [22].
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Activity of Py Im Polyamides in Anti Androgen Resistant Prostate Cancer Models

Activity of Py Im Polyamides in Anti Androgen Resistant Prostate Cancer Models

Pyrrole imidazole (Py-Im) polyamides are non-covalent, sequence specific DNA binders that can alter DNA architecture. (1, 2) Upon high affinity binding to the DNA minor groove, the molecules cause a 4 angstrom widening of the minor groove walls and a corresponding compression of the opposing major groove. (3, 4) Despite the relatively large molecular weight of Py-Im polyamides, these molecules are cell permeable and localize to the cell nucleus to affect endogenous gene expression.(5–10) Due to their modular sequence specificity, Py-Im polyamides can be synthesized to target DNA sequences of similar size to a protein-DNA interaction site and therefore used to antagonize gene expression driven by specific transcription factors. (7, 9–13) One such transcription factor that has been studied previously is the androgen receptor (AR). (9)
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Synthesis and study of biological activity of some new Imidazole derivatives

Abdul Jabar Kh. Atia | Mohammed fraj Al-Marjani | Muayad Abbood Qaban

Synthesis and study of biological activity of some new Imidazole derivatives Abdul Jabar Kh. Atia | Mohammed fraj Al-Marjani | Muayad Abbood Qaban

In recent years, heterocyclic compounds had been received considerable attention due to their pharmacological and pesticidal importance [1-9]. The simplest of five - membered heterocyclic compounds are pyrrole , furan and thiophene , each of which contains a single hetero atom [10]. Benzothiophene [11] a class of heterocyclic compounds containing a benzene ring fused with five membered aromatic ring made up of one sulfur as heteroatom with formula C 8 H 6 S.

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Synthesis and Biological Studies of DNA binding Cyclic Py Im Polyamides

Synthesis and Biological Studies of DNA binding Cyclic Py Im Polyamides

The selective modulation of eukaryotic gene expression by small molecules may have important implications in the field of chemical biology and human medicine. Pyrrole-imidazole polyamides are a class of synthetic ligands that can be programmed to bind the minor groove of specific DNA sequences. 1 Antiparallel, side-by-side N-methylpyrrole (Py) and N- methylimidazole (Im) carboxamides (Im/Py) pairs distinguish G·C from C·G base pairs, N- methyl-3-hydroxypyrrole (Hp)/Py shows specificity for T·A over A·T, whereas Py/Py pairs are specific for both T·A and A·T. 2–5 By linking two strands of these heterocyclic oligomers via a - amino butyric acid (GABA) turn unit, hairpin Py-Im polyamides can be programmed to bind a large library of DNA sequences with affinities comparable to natural DNA-binding proteins. 6–8 Hairpin polyamides have been shown to localize to the nuclei of living cells, and regulate endogenous gene expression by disrupting protein / DNA interfaces. 9–17 Cyclic polyamides containing a second GABA turn unit exhibit further enhanced DNA binding properties. 18–21 We have recently demonstrated their gene regulatory effects on AR-activated gene expression in prostate cancer models. 22
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Comparative Analysis of the Antineoplastic Activity of C60 Fullerene with 5 Fluorouracil and Pyrrole Derivative In Vivo

Comparative Analysis of the Antineoplastic Activity of C60 Fullerene with 5 Fluorouracil and Pyrrole Derivative In Vivo

[5] and can be transferred into the water by means of special procedures [6–8]. These properties enable fuller- ene to utilize in biological objects due to their ability to easily penetrate the cell lipid membrane [9–12]. At low (near-physiological) concentrations, C 60 fullerenes dem-

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Programming Protein Patterns on DNA Nanostructures with Pyrrole Imidazole Polyamides

Programming Protein Patterns on DNA Nanostructures with Pyrrole Imidazole Polyamides

In order for DNA-binding molecules to be useful tools for gene regulation, they must be able to access DNA in biological systems. DNA in eukaryotic organisms exists in a highly condensed form as chromatin. The nucleosome core particle (NCP) represents the most basic unit of the higher order structure chromatin. The NCP consists of 147 bp of DNA wrapped twice around an octamer of histone proteins. The histone octamer contains two copies each of histones H2A, H2B, H3, and H4. One of the most interesting features of the NCP is the alignment between the major and minor-grooves of the two gyres of DNA. These aligned minor-grooves separated by a small gap between the gyres of DNA create a “super groove”, consisting of 14-16 bp of DNA that is accessible for recognition. Each of these supergrooves bring sequence elements that are 80 bp apart in the linear DNA strand into close spatial proximity. As a result, supergrooves create a recognition platform that exists solely in the context of the NCP.
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Synthesis of Bioactive Molecule Fluoro Substituted Benzothiazole Comprising Quinazolinyl Imidazole for Biological and Pharmacological Screening

Synthesis of Bioactive Molecule Fluoro Substituted Benzothiazole Comprising Quinazolinyl Imidazole for Biological and Pharmacological Screening

effective chemotherapeutic agents to be employed systemically for the prevention and cure of bacterial infectiont in human beings. The introduction of trimethaprim and sulphamethoxazole has resulted in creased use of sulfonamide for the treatment of specific microbial infection. Benzothiazoles with sulphonyl group, imdazolone etc were reported to posses various pharmacological activity of clinical importance.

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The chemistry and biological significance of imidazole, benzimidazole, benzoxazole, tetrazole and quinazolinone nucleus

The chemistry and biological significance of imidazole, benzimidazole, benzoxazole, tetrazole and quinazolinone nucleus

Benzoxazole is an aromatic organic compound with a benzene fused oxazole ring structure. Substituted benzoxazole derivatives and their analogues such as benzimidazoles and benzothiazoles have been the aim of many researchers for many years, because they constitute an important class of heterocyclic compounds. The structural variations of these compounds are that different substituents can be incorporated on the benzene ring and diverse heterocycles and other active groups can be introduced at the 2-position in order to create good biological activity. The substitution at second position in benzoxazole skeleton is influential for the biological activity of the molecule Jauhari et al., (2008) 11 . Benzoxazole derivatives are biologically significant compounds and known to exhibit various biological activities such as anticancer, antimicrobial, anti HIV and dopamine D4 agonists Kumar et al., (2002) 12 . Benzoxazoles are also interesting fluorescent probes which show high Stokes shift and present thermal and photophysical stability due to an excited state intramolecular proton transfer mechanism Holler et al., (2002) 13 . Since they interfere with biosynthesis of coloured carotenoids by inhibiting the enzyme phytoene desaturase, they are studied as potential bleaching herbicides Laber et al., (1999) 14 . Benzoxazoles can be considered as structural bioisosteres of naturally occurring nucleotides such as adenine and guanine, which allow them to interact easily with the biopolymers of a living system. They have shown low toxicity in warm-blooded animals Dunwell et al., (1977) 15 . Benzoxazoles have a number of optical applications such as photoluminescents Claussen, et al., (1981) 16 , whitening agents and dye laser Reser, et al., (1972) 17 . Benzoxazoles have found applications as intermediates for organic synthesis Fery-Forgues et al., (1993) 18 .
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Synthesis and biological screening of some Pyridine and Pyrrole derivatives of
Pyrazolo [3, 4 c] pyrazoles

Synthesis and biological screening of some Pyridine and Pyrrole derivatives of Pyrazolo [3, 4 c] pyrazoles

the tested compounds 5a, 5b and 5d, showed good activity against A.niger and 3d, 5c have shows moderate activity against A.niger. Compounds 3a, 4d, 5c and 5d have shown very good activity and compound 3cand 5b have shown moderate activity against candida albicans due to the above synthesized compounds exibit very good activity of against antibacterial and antifungal activity.

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Synthesis and Evaluation of N-substituted Imidazole Derivatives for Antimicrobial Activity

Synthesis and Evaluation of N-substituted Imidazole Derivatives for Antimicrobial Activity

evaluated for the antimicrobial activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, Candida albicans and Aspergillus niger by determination of MIC (minimum inhibitory concentration) using tube dilution method. Compound (1b) was found to be the most active antimicrobial compound amongst others in the series.

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A REVIEW ON THE BIOLOGICAL APPLICATIONS OF IMIDAZOLE, THIAZOLE AND THEIR DERIVATIVESSyed Muzaffar Ahmad1 and Mohd Syeed ShahDOWNLOAD/VIEW

A REVIEW ON THE BIOLOGICAL APPLICATIONS OF IMIDAZOLE, THIAZOLE AND THEIR DERIVATIVESSyed Muzaffar Ahmad1 and Mohd Syeed ShahDOWNLOAD/VIEW

Thiazoles are important class of heterocyclic compounds, found in many potent biologically active molecules such as Sulfathiazol (antimicrobial drug), Ritonavir (antiretroviral drug), Abafungin (antifungal drug) with trade name Abasol cream and Bleomycine and Tiazofurin (antineoplastic drug)[16]. In recent times, the applications of thiazoles were found in drug development for the treatment of allergies, hypertension, inflammation, schizophrenia, bacterial, HIV infections, hypnotics and more recently for the treatment of pain, as fibrinogen receptor antagonists with antithrombotic activity and as new inhibitors of bacterial DNA gyrase B [17-19].
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Synthesis of some new pyrrole derivatives and their antimicrobial activity

Synthesis of some new pyrrole derivatives and their antimicrobial activity

Synthesis of5,5'-(3,5-dimethyl-1H-pyrrole-2,4-diyl)bis(4-amino-4H-1,2,4-triazole-3-thiol)(4) A mixture of 5,5'-(3,5-dimethyl-1H-pyrrole-2,4-diyl)bis(1,3,4-oxadiazole-2-thiol)(3) (2.95 g, 0.01 mol) and hydrazine hydrate (0.8 mL, 0.02 mol) in ethanol, the reaction mixture was heated and refluxed for 24 h. Then, the reaction mixture was cooled at room temperature. This crude product was filtered off, washed with ethanol, and recrystallized from ethanol.

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Optimized dispersion of nanoparticles for biological in vitro and in vivo studies

Optimized dispersion of nanoparticles for biological in vitro and in vivo studies

Nanoparticles can come in contact with the human body through inhalation but also through ingestion, dermal deposition, or by medical applications through injection [5]. Nanoparticles having entered the body through inha- lation can translocate into the systemic circulation, reach various remote organs, and affect their function [6]. For investigations of the in vivo effects of nanoparticles in the circulation and for measuring the effects of nanoparti- cles on different types of cells in vitro, nanoparticles have to be dispersed in physiological solutions. However, par- ticles in solutions with physiological salt concentrations and pH values form micrometer-sized coarse agglomer- ates [7-9]. Coarse agglomerates of nanoparticles have been shown to exert different biological effects as com- pared to well-dispersed nanoparticles [9-12]. Therefore, investigating the biological effects of nanoscaled particles with dispersions containing coarse agglomerates is not appropriate. Previously, different methods have been published on how to avoid the formation of coarse agglomerates of nanoparticles dispersed in physiological solutions. The importance of the correct ultrasound energy as well as the use of dispersion stabilizers was emphasized for the optimal deagglomeration of nanopar- ticles [13]. Pulmonary surfactant, Tween, bronchoalveolar lavage fluid, albumin, or serum were used as dispersion stabilizers in physiological solutions [8,9,11]. Sonication preceding the addition of a dispersion stabilizer to the nanoparticle dispersion has been shown to be more effec- tive than sonication afterwards [7]. However, most of these studies have investigated only one aspect of the par- ticle dispersion method or tested only one nanoparticle type. For practical use in nanotoxicology experiments, a complete method including all these aspects and working on a wide range of different types of nanoparticles is nec- essary.
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Biochemical and Biological in vivo Functions of Dna2p in Saccharomyces cerevisiae

Biochemical and Biological in vivo Functions of Dna2p in Saccharomyces cerevisiae

Several known helicases yeast SCSI, the Werner syndrome helicase, and the bacterial RecE,C,D enzymel are associated with nuclease activities, although none of the known helicase/nuclease[r]

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