Synthesis and DNA binding properties of pyrrole amino acid-containing peptides

Dimers of the pyrrole amino acid (Paa), 5-(aminomethyl)pyrrole-2-carboxylic acid, and its derivatives having Lys anchored on N- and C-termini bind in the minor groove of DNA with considerable apparent binding affinities. When the Lys unit is attached to the C-terminus, the resulting ligand binds to ds-DNA with twice the affinity, of the order of 10⁵, than the one carrying two positive charges at the same end.     

Synthesis of monofluorinated 1-(naphthalen-1-yl)piperazines

A series of regioisomerically monofluorinated 1-(naphthalen-1-yl)piperazines is described.     

Carbene-catalyzed enantioselective annulation of dinucleophilic hydrazones and bromoenals for access to aryl-dihydropyridazinones and related drugs

4,5-Dihydropyridazinones bearing an aryl substituent at the C6-position are important motifs in drug molecules. Herein, we developed an efficient protocol to access aryl-dihydropyridazinone molecules via carbene-catalyzed asymmetric annulation between dinucleophilic arylidene hydrazones and bromoenals. Key steps in this reaction include polarity-inversion of aryl aldehyde-derived hydrazones followed by chemo-selective reaction with enal-derived α,β-unsaturated acyl azolium intermediates. The aryl-dihydropyridazinone products accessed by our protocol can be readily transformed into drugs and bioactive molecules.

Polarity inversion of arylidene hydrazones to react with bromoenals via carbene organic catalysis is disclosed. The reaction enantioselectively affords 6-aryl-4,5-dihydropyridazinones and related drugs with proven commercial applications.     

Synthesis and human leukocyte elastase inhibitory activity of novel 2-spiro(2′,2′-diphenylcyclopropane) cephalosporin sulfones

A new series of 2-spiro(2,2-diphenylcyclopropane) cephalosporin sulfones was synthesizes as potent human leukocyte elastase inhibitors.SynPhar Laboratories Inc., #2 Taiho Alberta Centre, 4290-91A Street, Edmonton, Canada T6R 5V2. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1517–1523, November, 1998.     

Studies on monobactams II. Synthesis and β-lactamase inhibitory activity of 4α-methyl-3-[(thien-2-yl)-methylene]-2-azetidinone-1-sulfonate

Two monobactam derivatives, potassium 4-methyl-(3E)-[(thien-2-yl)methylene]-2-azetidinone-1-sulfonate and its (3Z)-isomer, were prepared and evaluated for their -lactamase inhibitory activities. These compounds were devoid of -lactamase inhibitory activity.SynPhar Laboratories Inc., #2, 4290-91A Street, Edmonton, Alberta T6E 5V2, Canada. Tokushima Research Institute, Taiho Pharmaceutical Co., Ltd., 224-2 Ebisuno Hiraishi, Kawauchi-cho, Tokushima 771-01, Japan. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1548–1552, November, 1998.     

Complexes of poly(ethylene glycol)-based cationic random copolymer and calf thymus DNA: a complete biophysical characterization

Complete biophysical characterization of complexes (polyplexes) of cationic polymers and DNA is needed to understand the mechanism underlying nonviral therapeutic gene transfer. In this article, we propose a new series of synthesized random cationic polymers (RCPs) from methoxy poly(ethylene glycol) monomethacrylate (MePEGMA) and (3-(methacryloylamino)propyl)trimethylammonium chloride with different mole ratios (32:68, 11:89, and 6:94) which could be used as a model system to address and answer the basic questions relating to the mechanism of the interaction of calf thymus DNA (CT-DNA) and cationic polymers. The solubility of the complexes of CT-DNA and RCP was followed by turbidity measurements. It has been observed that complexes of RCP with 68 mol % MePEGMA precipitate near the charge neutralization point, whereas complexes of the other two polymers are water-soluble and stable at all compositions. Dnase 1 digestion experiments show that DNA is inaccessible when it forms complexes with RCP. Ethidium bromide exclusion and gel electrophoretic mobility show that both polymers are capable of binding with CT-DNA. Atomic force microscopy images in conjunction with light scattering experiments showed that the complexes are spherical in nature and 75-100 nm in diameter. Circular dichroism spectroscopy studies indicated that the secondary structure of DNA in the complexes is not perturbed due to the presence of poly(ethylene glycol) segments in the polymer. Furthermore, we used a combination of spectroscopic and calorimetric techniques to determine complete thermodynamic profiles accompanying the helix-coil transition of CT-DNA in the complexes. UV and differential scanning calorimetry melting experiments revealed that DNA in the complexes is more stable than in the free state and the extent of stability depends on the polymer composition. Isothermal titration calorimetry experiments showed that the binding of these RCPs to CT-DNA is associated with small exothermic enthalpy changes. A complete thermodynamic profile showed that the RCP/DNA complex formation is entropically favorable. Much broader opportunities to vary the architecture of the polymers studied here make these systems promising in addressing various basic and practical problems in gene delivery systems.     

Mechanism of N-vinylcarbazole polymerization on Co(II)–13X molecular sieve

Kinetics of polymerization of N-vinylcarbazole over Co(II)-13X molecular sieves in toluene have been studied. The rate of polymerization (R_p) has been found to be second order with respect to percent exchange level of Co(II) and also to the NVC concentration at all the reaction temperatures of 40, 50 and 60°C. The rate increases with decreasing pH of the original exchanging salt solution up to a pH of about 3.5, beyond which it falls. The overall activation energy of polymerization has been found to decrease with increase in monomer concentration, exchange level of Co(II), and the hydrogen ion concentration of the original exchange solution. Average degree of polymerization also follows a similar trend. A mechanism of polymerization involving simultaneous propagation on both metal ion Co(II) and proton on a zeolite surface has been suggested. The two propagation routes are characterized by an average activation energy of 10.36 kcal/mol and 5.40 kcal/mol on the metal ion and proton centers, respectively.     

HSAB principle applied to the time evolution of chemical reactions

Time evolution of various reactivity parameters such as electronegativity, hardness, and polarizability associated with a collision process between a proton and an X- atom/ion (X = He, Li(+), Be(2+), B(3+), C(4+)) in its ground ((1)S) and excited((1)P,(1)D,(1)F) electronic states as well as various complexions of a two-state ensemble is studied using time-dependent and excited-state density functional theory. This collision process may be considered to be a model mimicking the actual chemical reaction between an X-atom/ion and a proton to give rise to an XH(+) molecule. A favorable dynamical process is characterized by maximum hardness and minimum polarizability values according to the dynamical variants of the principles of maximum hardness and minimum polarizability. An electronic excitation or an increase in the excited-state contribution in a two-state ensemble makes the system softer and more polarizable, and the proton, being a hard acid, gradually prefers less to interact with X as has been discerned through the drop in maximum hardness value and the increase in the minimum polarizability value when the actual chemical process occurs. Among the noble gas elements, Xe is the most reactive. During the reaction: H(2) + H(+) --> H(3)(+) hardness maximizes and polarizability minimizes and H(2) is more reactive in its excited state. Regioselectivity of proton attack in the O-site of CO is clearly delineated wherein HOC(+) may eventually rearrange itself to go to the thermodynamically more stable HCO(+).     

Bead-bead interaction parameters in dissipative particle dynamics: relation to bead-size, solubility parameter, and surface tension

Dissipative particle dynamics (DPD) is a mesoscale modeling method for simulating equilibrium and dynamical properties of polymers in solution. The basic idea has been around for several decades in the form of bead-spring models. A few years ago, Groot and Warren established an important link between DPD and the Flory-Huggins chi-parameter theory for polymer solutions. We revisit the Groot-Warren theory and investigate the DPD interaction parameters as a function of bead size. In particular, we show a consistent scheme of computing the interfacial tension in a segregated binary mixture. Results for three systems chosen for illustration are in excellent agreement with experimental results. This opens the door for determining DPD interactions using interfacial tension as a fitting parameter.