Synthesis,Antitumor, and DNA Binding Behavior of Novel 4-(2-Hydroxyquinolin-3-yl)-6-Phenyl-5, 6 Dihydropyrimidin Derivatives in Aqueous Medium

This article deals with the synthesis of 4-(2-hydroxyquinolin-3-yl)-6-phenyl-5,6-dihydropyrimidin derivatives (2a–f), on condensation with various aromatic aldehydes and ketones in aqueous ethanolic NaOH solution yielding the corresponding chalcones (3). These chalcones were further reacted with thiourea/urea in the presence of a base, which led to the formation of the titled derivatives (2a–f). The newly synthesized heterocyles were characterized by elemental analysis, FTIR, ¹HNMR, and electronic and mass spectral data. The compounds (2a and 2b) were evulated for in vitro cyctotoxicity against human breast adenocarcinoma cell (MCF-7). In MTT cytotoxicity studies, both quinolinde derivatives were found most effective. The binding interaction behavior of the compound (2a) and (2d) with calf thymus-DNA (CT-DNA) was studied by electronic spectra, viscosity measurements, and thermal denaturation studies. On binding to CT-DNA, the absorption spectrum underwent bathochromic and hypochromic shifts. The binding constant (K_b) observed 4.3 × 10⁵ M^?1 for (2a), and 3.8 × 10⁵ M^?1 for (2d) suggested that compound (2a) binds more strongly with base pairs than (2d).     

An Extracellullar Nuclease from Bacillus Firmus VKPACU-1: Specificity and Mode of Action

An extracellular nuclease from Bacillus firmus VKPACU-1 was multifunctional enzyme, this nuclease hydrolyzed poly U rapidly and more preferentially than the other homopolyribonucleotides. Hydrolysis of RNA this enzyme released mononucleotides in the order 5′UMP > 5′AMP > 5′GMP where as in hydrolysis of DNA the mononucleotides in the order of 5′dAMP > 5′dGMP > 5′dTMP and oligonucleotides. Uridylic linkages in RNA and adenylic linkages in DNA were preferentially cleaved by the nuclease. Nuclease produced oligonucleotides having only 3’ hydroxyl and 5’ phosphate termini. Present nuclease hydrolyzed RNA and DNA released oligonucleotides as major end products and mononucleotides, suggesting an endo mode of action.     

Analysis of DNA Sequencing Reaction Products Made with 7-Halo-7-deaza-2′-deoxyguanosine-5′-triphosphate

Abstract

7-Chloro- and 7- Iodo-7-Deaza-2′-Deoxyguanosine-5′-Triphosphates were employed as substrates replacing dGTP, dITP, or 7-Deaza-2′-Deoxyguanosine-5′-Triphosphate in sequencing reactions with Thermo Sequenase^TM. Analysis of the reaction products by denaturing gel electrophoresis indicates DNA containing these halogenated analogs can form strong secondary structures.     

Uniform Band Intensities in Fluorescent Dye Terminator Sequencing

Abstract

The use of Cyanine dye (Cy^TM 5 and Cy5.5) labeled dideoxy terminators with Thermo Sequenase^TM DNA polymerase in DNA sequencing provides uniform band intensity, improved sequence read-length, and accuracy. It also greatly improves the ability to detect single base heterozygotes with dye-terminator sequencing method.     

Synthesis of Iodoaminoimidazole Arabinoside (IAIA): A Potential Reductive Metabolite of the Spect Imaging Agent,Iodoazomycin Arabinoside (IAZA)

Abstract

The stereospecific synthesis of 1-(5-deoxy-5-iodo-α-D-arabino-furanosyl)-2-aminoimidazole (iodoaminoimidazole arabinoside: IAIA, 2) is described. The reaction of the protected sugar bromide (8) and trifluoroacetamidoimidazole (10B) gave the coupled product (11B), which gave the free nucleoside (4) on deblocking. It was identical with AIA obtained by reduction of AZA (azomycin arabinoside), whose anomeric configuration was found to be a by the X-ray crystallography.     

A New Solid Phase Method for the Synthesis of Oligonucleotides with Terminal -3′-Phosphate

Abstract

A novel method for the synthesis of oligonucleotides with terminal-3′-phosphate using universal CPG polymer support is described.     

Synthesis,In Vitro Biological Stability,and Anti-HIV Activity of 5-Halo (or Methoxy)-6-Alkoxy (Azido or Hydroxy)-5,6-Dihydro-2′,3′-Didehydro-3′-Deoxythymidine Diastereomers as Potential Prodrugs of 2′,3′-Didehydro-3′-deoxythymidine (D4T)

Abstract

A new class of 5-halo (or methoxy)-6-alkoxy (azido or hydroxy)-5,6-dihydro-2′,3′-didehydro-3′-deoxythymidines (4–17) were investigated as potential anti-AIDS drugs. These 5,6-dihydro derivatives, which are also potential prodmgs of 2′,3′-didehydro-3′-deoxythymidine (D4T) were designed to have properties which would enhance their duration of action, lipophilicity and cephalic delivery to the central nervous system. The 5,6-dihydro derivatives of D4T (4–15), which differ in configuration at the C-5 and C-6 positions, were synthesized by the regiospecific addition of XR (X = Br, Cl, I; R = OMe, OEt, N₃, OH) to the 5,6-olefinic bond of D4T. These 5,6-disubstituted-5,6-dihydro analogs of D4T are more lipophilic (P = 0.70 – 4.0 range) than D4T (P = 0.12) and are stable to E. coli thymidine phosphorylase. Regeneration of the 5,6-olefinic bond to give D4T, upon incubation of the 5-bromo- and 5-iodo-6-methoxy-5,6-dihydro derivatives (6, 7, 10, 11) with glutathione or a mouse liver soluble enzyme fraction, was extensive (50–95%). The most potent anti-HIV-1 agents, 5-iodo-6-methoxy (10, 11), 5-bromo-6-azido (14, 15) and 5-methoxy-6-hydroxy (16, 17) derivatives of D4T, exhibited anti-HIV activities comparable to D4T.

     

Chemoenzymatic Synthesis of 3′-Deoxy-3′-(4-Substituted-Triazol-1-YL)-5-Methyluridine

An efficient protocol has been developed for the synthesis of a small library of 3′-deoxy-3′-(4-substituted-triazol-1-yl)-5-methyluridine using Cu(I)-catalyzed Huisgen–Sharpless–Meldal 1,3-dipolar cycloaddition reaction of 3′-azido-3′-deoxy-5-methyluridine with different alkynes under optimized condition in an overall yields of 76%–92%. Here, the azido precursor compound, i.e., 3′-azido-3′-deoxy-5-methyluridine was chemoenzymatically synthesized from D-xylose in good yield. Some of the alkynes used in cycloaddition reaction were synthesized by the reaction of hydroxycoumarins or naphthols with propargyl bromide in acetone using K₂CO₃in excellent yields. All synthesized compounds were unambiguously identified on the basis of their spectral (IR, ¹H-, ¹³C NMR spectra, and high-resolution mass spectra) data analysis.     

DNA-Binding and Photocleavage Properties of Ru(II) Polypyridyl Complexes with DNA and Their Toxicity Studies on Eukaryotic Microorganisms

Four Ru(II) polypyridyl complexes, [Ru(bpy)₂(7-NO₂-dppz)]²⁺, [Ru(bpy)₂(7-CH₃-dppz)]²⁺, [Ru(phen)₂(7-NO₂-dppz)]²⁺, and [Ru(phen)₂(7-CH₃-dppz)]²⁺ (bpy = 2,2′-bipyridine, phen = 1,10-phenanthroline), (7-Nitro-dppz = 7-Nitro dipyrido[3,2-a:2′-3′-c]phenazine, 7-CH₃-dppz = 7-Methyl dipyrido[3,2-a:2′-3′-c]phenazine), have been synthesized and characterized by IR, UV, elemental analysis, ¹H NMR, ¹³C-NMR, and mass spectroscopy. The DNA-binding properties of the four complexes were investigated by spectroscopic and viscosity measurements. The results suggest that all four complexes bind to DNA via an intercalative mode. Under irradiation at 365 nm, all four complexes were found to promote the photocleavage of plasmid pBR 322 DNA. Toxicological effects of the selected complexes were performed on industrially important yeasts (eukaryotic microorganisms).     

Development of Novel Elastic Vesicle-Based Topical Formulation of Cetirizine Dihydrochloride for Treatment of Atopic Dermatitis

Cetirizine is a piperazine-derived second-generation antihistaminic drug recommended for treatment of pruritus associated with atopic dermatitis. The present investigation encompasses development of a nanosized novel elastic vesicle-based topical formulation of cetirizine dihydrochloride using combination of Phospholipon® 90G and edge activators with an aim to have targeted peripheral H₁ antihistaminic activity. The formulation was optimized with respect to phospholipid/drug/charge inducer ratio along with type and concentration of edge activator. The optimized formulation was found to be satisfactory with respect to stability, drug content, entrapment efficiency, pH, viscosity, vesicular size, spreadability, and morphological characteristics. The ex vivo permeation studies through mice skin were performed using Franz diffusion cell assembly. It was found that the mean cumulative percentage amount permeated in 8 h was almost twice (60.001 ± 0.332) as compared to conventional cream (33.268 ± 0.795) and aqueous solution of drug (32.616 ± 0.969), suggesting better penetration and permeation of cetirizine from the novel vesicular delivery system. Further, therapeutic efficacy of optimized formulation was assessed against oxazolone-induced atopic dermatitis in mice. It was observed that the developed formulation was highly efficacious in reducing the itching score (4.75 itches per 20 min) compared to conventional cream (9.75 itches per 20 min) with profound reduction in dermal eosinophil count and erythema score. To conclude, a novel vesicular, dermally safe, and nontoxic topical formulation of cetirizine was successfully developed and may be used to treat atopic dermatitis after clinical investigation.KEY WORDS: atopic dermatitis, cetirizine, elastic vesicles, oxazolone, topical