Central Core Structure Research Articles

Synthetic Strategies for the Synthesis and Transformation of Substituted Pyrrolinones as Advanced Intermediates for Rhazinilam Analogues

AbstractThe biaryl core structure of rhazinilam with its fixed dihedral angle is a pivotal element for its unique in vitro cytotoxic activity. Most of the related natural products are oxidized versions of rhazinilam. Replacing the sensitive pyrrole ring by a pyrrolinone ring is the basis of our initial strategy towards rhazinilam analogues. With this goal, variants of the sequence crossed Mukaiyama aldol reaction followed by the Staudinger reaction were studied. Reacting a suitably substituted acetophenone with O‐methyl O‐trimethylsilyl ketene acetal gave pyrrolinones 8a and 8b in good to excellent yields. These intermediates could be transformed in four high‐yielding steps into the pyrrolic precursors 7a–c containing all the atoms necessary for the construction of rings A, B, and C of rhazinilam. Our studies illustrate a lack of stability of these intermediates. Alternative synthetic approaches towards this central biaryl core structure are described.

“Old Friends in New Guise”: Exploiting Privileged Structures for Scaffold Re-Evolution/Refining

The attempts to increase novel drug productivity through creative discovery technologies have fallen short of producing the satisfactory results. For these reasons, evolved from the concept of drug repositioning, "privileged structure"-guided scaffold re-evolution/refining is a primary strategy to identify structurally novel chemotypes by modifying the central core structure and the side-chain of the existing active compounds, or to exploit undescribed bioactivites by making full use of readily derivatized motifs with well-established synthetic protocols. Herein, we review the basic tricks of exploiting privileged structures for scaffold re-evolution/refining. The power of this strategy is exemplified in the discovery of other new therapeutic applications by refining privileged structures in anti-viral agents.

Synergistic effect of cationic lipids with different polarheads, central core structures and hydrophobic tails on gene transfection efficiency.

Lipid-mediated delivery of DNA into cells holds great promise both for gene therapy and basic research applications. The primary approach to improving transfection efficiency is the design and synthesis of novel cationic lipids. Alternatively, using the synergistic effect of different cationic mixtures can provide another approach to increasing transfection efficiency. This paper describes the synergistic effect of lipids with different polarheads, central core structures and hydrophobic tails. The enhancement of cellular transfection into HEK293 cells was observed by combining two lipids having aminoglycerol and di(hydroxylethyl)amino core structures at a 1 : 1 weight ratio. Additionally, the liposome formation of these lipids with the helper lipid, 1,2-dioleoyl-propyl-3-phosphatidylethanolamine (DOPE), at the weight ratio of 1 : 1 can provide higher transfection efficiency into HEK293, MCF-7 and HeLa cells than Lipofectamine™ 2000. Our finding indicated that cationic liposomes comprised of a mixture of lipids with different polarheads, central core structures and hydrophobic tails should be very promising in liposome-mediated gene delivery in vitro and in vivo.

3-Biphenylimidazo[1,2-a]pyridines or [1,2-b]pyridazines and analogues, novel Flaviviridae inhibitors

Using Ttou 84 as starting point, a novel class of biphenyl derivatives of imidazo[1,2-a]pyridine and imidazo[1,2-b]pyridazine was designed to optimize the inhibitory properties on the replication of the bovine viral diarrhoea virus (BVDV) and hepatitis C virus (HCV). Three sites of pharmacomodulation were chosen i.e. positions 2, 3 and 6 on the central heterocyclic core structure. From the 49 analogues tested, only compound 18j (3-(2′-hydroxybiphen-3-yl)-2-(2-methoxyphenyl)-6-(thien-3-yl)imidazo[1,2-b]pyridazine) showed antiviral activity in the HCV replicon system reminiscent of selective inhibition (60–70% inhibition). Compound 4f (3-(biphen-3-yl)-2-(4-fluorophenyl)-6-phenylthioimidazo[1,2-a]pyridine) proved to be the most selective inhibitor of BVDV replication and showed no or only marginal cross-resistance with known inhibitors of pestivirus replication. The cross-resistance profile of 4f might indicate that 4f does not interact with the same binding site as BPIP, VP32947, AG110 or LZ37. From 42 analogues tested against both viruses, QSAR studies were discussed in regard to BVDV antiviral activity.

An Attempted Substitute Study of Total Skin Electron Therapy Technique by Using Helical Photon Tomotherapy with Helical Irradiation of the Total Skin Treatment: A Phantom Result

An anthropomorphic phantom was used to investigate a treatment technique and analyze the dose distributions for helical irradiation of the total skin (HITS) by helical tomotherapy (HT). Hypothetical bolus of thicknesses of 0, 10, and 15 mm was added around the phantom body to account for the dose homogeneity and setup uncertainty. A central core structure was assigned as a “complete block” to force the dose tangential delivery. HITS technique with prescribed dose (D p) of 36 Gy in 36 fractions was generated. The radiochromic EBT2 films were used for the dose measurements. The target region with 95.0% of the D p received by more than 95% of the PTV was obtained. The calculated mean doses for the organs at risk (OARs) were 4.69, 3.10, 3.20, and 2.94 Gy for the lung, heart, liver, and kidneys, respectively. The measurement doses on a phantom surface for a plan with 10 mm hypothetical bolus and bolus thicknesses of 0, 1, 2, and 3 mm are 89.5%, 111.4%, 116.9%, and 117.7% of D p, respectively. HITS can provide an accurate and uniform treatment dose in the skin with limited doses to OARs and is safe to replace a total skin electron beam regimen.

Synthesis and Antibacterial Evaluation of a Novel Series of 2‐(1,2‐Dihydro‐3‐oxo‐3H‐pyrazol‐2‐yl)benzothiazoles

The 2-(1,2-dihydro-3-oxo-3H-pyrazol-2-yl)benzothiazole scaffold was selected as a central core structure for the discovery of novel antibacterial compounds. A systematic variation of the substituents on the oxo-pyrazole moiety, as well as on the benzo moiety, led to the creation of a small and focused library of benzothiazoles that was subjected to antibacterial screening. In a first round of screening, activity of the compounds against six representative microorganisms was established. For the most potent congeners, MIC values against S. aureus and P. aeruginosa were determined. The structure-activity relationship study clearly revealed that subtle structural variations influence the antibacterial activity to a large extent. The most potent congeners displayed MIC values of 3.30 μM.

Construction of Supramolecular Helices and Breaking the Helicity by Forming Supramolecular β-Sheet Structures Using Suitable Self-Assembling Pseudopeptide Building Blocks

Bis-valine derivatives of malonamide (Guha, S.; Drew, M. G. B. Small 2008, 4, 1993−2005) and a bis-valine derivative of 1,1-cyclopropane dicarboxamide were used as building blocks for the construction of supramolecular helical structures. The six-membered intramolecular hydrogen-bonded scaffold is formed, and this acts as a unique supramolecular synthon for the construction of a pseudopeptide-based supramolecular helical structure. However, in absence of this intramolecular hydrogen bond, intermolecular hydrogen bonds are formed among the peptide strands. This leads to a supramolecular β-sheet structure. Proper selection of the supramolecular synthon (six-membered intramolecular hydrogen-bonded scaffold) promotes supramolecular helix formation, and a deviation from this molecular structure dictates the disruption of supramolecular helicity. In this study, six crystal structures have been used to demonstrate that a change in the central angle and/or the central core structure of dicarboxamides can be used ...

On the Relevance of the Met-turn Methionine in Metzincins

The metzincins are a clan of metallopeptidases consisting of families that share a series of structural elements. Among them is the Met-turn, a tight 1,4-turn found directly below the zinc-binding site, which is structurally and spatially conserved and invariantly shows a methionine at position 3 in all metzincins identified. The reason for this conservation has been a matter of debate since its discovery. We have studied this structural element in Methanosarcina acetivorans ulilysin, the structural prototype of the pappalysin family, by generating 10 mutants that replaced methionine with proteogenic amino acids. We compared recombinant overexpression yields, autolytic and tryptic activation, proteolytic activity, thermal stability, and three-dimensional structure with those of the wild type. All forms were soluble and could be purified, although with varying yields, and three variants underwent autolysis, could be activated by trypsin, and displayed significant proteolytic activity. All variants were analyzed for the thermal stability of their zymogens. None of the mutants analyzed proved more stable or active than the wild type. Both bulky and small side chains, as well as hydrophilic ones, showed diminished thermal stability. Two mutants, leucine and cysteine, crystallized and showed three-dimensional structures that were indistinguishable from the wild type. These studies reveal that the Met-turn acts as a plug that snugly inserts laterally into a core structure created by the protein segment engaged in zinc binding and thus contributes to its structural integrity, which is indispensable for function. Replacement of the methionine with residues that deviate in size, side-chain conformation, and chemical properties impairs the plug-core interaction and prejudices molecular stability and activity.

Nanostructure of PEO–polyurethane–PEO triblock copolymer micelles in water

Novel hydrophilic triblock copolymers which form micelles in aqueous solution were studied by static and dynamic light scattering (SLS and DLS), small angle neutron scattering (SANS) and densitometry. The polymers were symmetric A–B–A block copolymers having two poly(ethylene oxide) (PEO) tail blocks and a polyurethane (PU) center segment that contained pendant carboxylic acids. The aggregation number of the micelles decreased with increasing PEO mass content. When attempting to fit the SANS data it was found that no single model was suitable over the entire range of block lengths and PEO mass concentrations investigated here. For the polymer with the highest aggregation number, the data were fitted with a triblock model consisting of a homogeneous core with a corona of non-interacting Gaussian chains for which only two free parameters were required: the radius of the core and the radius of gyration of the corona. In this case, the core was found to be effectively dry. At lower aggregation numbers, a star polymer model generated significantly better fits, suggesting the absence of any identifiable central core structure. Good agreement was found between the sizes measured by DLS, SANS and theoretical predictions of micelle size from a density distribution theory. These results show that when significant changes in aggregation number occur, the nanostructure of the micelle can change substantially even for polymers that are remarkably similar.

Recent CB1 cannabinoid receptor antagonists and inverse agonists

AbstractAntagonists or inverse agonists of the cannabinoid CB1 receptor (CB1R) reported from the 2006–2007 period are reviewed. The compounds are either variations of the archetypical cannabinoid CB1 inverse agonist rimonabant (SR141716) or are other structures less obviously related to the archetype. Many of the former class replace the core pyrazole ring of rimonabant with other ring systems to display/arrange the appended binding/activity elements. A structure‐activity relationship evolves from bioassays of these compounds that also provides a more detailed understanding of the molecular mechanism of the binding to and stabilization of the active and inactive states of the constitutively active CB1R. In addition to diverse variations of the core ring and appended substituents, conformationally constrained analogs with high affinity were revealed, a number of which do not fit a one‐to‐one atom correspondence with the putatively active conformations of the rimonabant template and other active analogs. Diphenylmethyl analogs were a repeated motif in structures where core rings were either absent or played less restrictive roles in structures pursuing higher conformational freedom. Bicyclic nitrogen heterocyclic ring systems as the central core structures were reported, as were linear structures including phenyl ureas and taranabant analogs. Finally, peptides in the hemopressin class were presented as CB1 antagonists. Drug Dev Res 70:601–615, 2009. © 2009 Wiley‐Liss, Inc.

Ferroelectric and Antiferroelectric Behavior in Chiral Bent-shaped Molecules with an Asymmetric Central Naphthalene Core

A new series of chiral bent-shaped liquid crystals with an asymmetric central core based on 1,6- dihydroxynaphthalene and chiral terminal chain prepared from (S)-(?)-2-methyl-1-butanol, 1,6-naphthalene bis[4-(4-alkoxyphenyliminomethyl)]benzoates [N(1,6)-n-O-PIMB(n-2)*-(n-4)O (n = 8-11)] were synthesized. Their mesomorphic properties and phase structures were investigated by means of electro-optical, polarization reversal current, and second harmonic generation measurements in order to confirm the relationship between the molecular structure and phase structure. All odd n (n = 9 and 11) compounds, N(1,6)-9-O-PIMB7*-5O and N(1,6)-11-O-PIMB9*-7O exhibit antiferroelectric phase, whereas even n (n = 8 and 10) compounds was flexible, N(1,6)-10-O-PIMB8*-6O exhibits the ferroelectric phase but N(1,6)-8-O-PIMB6*-4O exhibits the antiferroelectric phase. These results come from the decrease of the closed packing efficiency within a layer and the lack of uniform interlayer interaction between adjacent layers, which were caused by the asymmetrical naphthalene central core. Thus, we concluded that the structure of central core as well as the terminal chain plays an important role for the emergence of particular polar ordering in phase structures.

Cytotoxic small molecule dimers and their inhibitory activity against human breast cancer cells

Small molecules based upon natural product dimers that exhibit cytotoxic activity were synthesized and evaluated for their anti-proliferative activity in human breast cancer cell lines. A central isophthalic core structure linking aromatic amines containing 3,5-disubstitutions produced the most active compounds. This series of compounds was found to be more active against the estrogen receptor positive cell line MCF-7 than the estrogen receptor negative cell line, SKBr3.

Bearing strength of steel coupling beam connections embedded reinforced concrete shear walls

In high multistory reinforced concrete buildings, coupled shear walls can provide an efficient structural system to resist horizontal force due to wind and seismic effects. Coupled shear walls are usually built over the whole height of the building and are laid out either as a series of walls coupled by beams and/or slabs or as a central core structure with openings to accommodate doors, elevator wells, windows and corridors. A number of recent studies have focused on examining the seismic response of concrete, steel, and composite coupling beams. However, since no specific equations are available for computing the bearing strength of steel coupling beam–wall connections, it is necessary to develop such strength equations. There were carried out analytical and experimental studies to develop the strength equations of steel coupling beams–concrete wall connections. Experiments were conducted to determine the factors influencing the bearing strength and to verify the strength equations of the steel coupling beam–wall connections. The proposed equations were in good agreement with both test results and other test data from the literature.

The Steel Coupling Beam-Wall Connections Strength

In high multistory reinforced concrete buildings, coupled shear walls can provide an efficient structural system to resist horizontal force due to wind and seismic effects. Coupled shear walls are usually built over the whole height of the building and re laid out either as a series of walls coupled by beams and/or slabs or a central core structure with openings to accommodate doors, elevators walls, windows and corridors. A number of recent studies have focused on examining the seismic response of concrete, steel, and composite coupling beams. However, since no specific equations are available for computing the bearing strength of steel coupling beam-wall connections, it is necessary to develop such strength equations. There were carried out analytical and experimental studies to develop the strength equations of steel coupling beam-connections. Experiments were conducted to determine the factors influencing the bearing strength of the steel coupling beam-wall connection. The results of the proposed equations were in good agreement with both test results and other test data from the literature. Finally, this paper provides background for design guidelines that include a design model to calculate the bearing strength of steel coupling beam-wall connections.

Plaques of Alzheimer’s disease originate from cysts of Borrelia burgdorferi, the Lyme disease spirochete

Here is hypothesized a truly revolutionary notion that rounded cystic forms of Borrelia burgdorferi are the root cause of the rounded structures called plaques in the Alzheimer brain. Rounded "plaques' in high density in brain tissue are emblematic of Alzheimer's disease (AD). Plaques may be conceptualized as rounded "pock mark-like" areas of brain tissue injury. In this century, in brain tissue of AD, plaques are Amyloid Plaques according to the most up to date textbooks. In the last century, however, Dr. Alois Alzheimer did not require amyloid as the pathogenesis for either the disease or for the origin of its plaques. Surely, amyloid is an event in AD, but it may not be the primal cause of AD. Indeed in plaques, amyloid is regularly represented by the "congophilic core" structure which is so named because the waxy amyloid material binds the congo red stain and is congophilic. However an accepted subset of plaques in AD is devoid of a congophilic amyloid core region (these plaques "cotton wool" type plaques, lack a central congophilic core structure). Furthermore, there is "plaque diversity" in Alzheimer's; small, medium and large plaques parallel variable cystic diameters for Borrelia burgdorferi. Perturbations of AD plaque structure (i.e. young plaques devoid of a central core and older plaques with or without a central core structure) offer room for an alternate pathway for explanation of ontogeny of the plaque structures. If amyloid is not required to initiate all of the possible plaques in Alzheimer's, is it possible that amyloid just a by product of a more fundamental primal path to dementia? If a byproduct status is assigned to amyloid in the realm of plaque formation, then is amyloid also an epiphenomenon rather than a primary pathogenesis for Alzheimer's disease. In the "anatomy is destiny" model, cysts of borrelia are always round. Why then not accept roundness as a fundamental "structure determines function" argument for the answer to the mystery of why Alzheimer plaques are always round? Parataxis causality, a concept borrowed from philosophy, is the error that comes from linking two events, which occur contemporaneously or in close proximity to one another with a cause and effect relationship. Parataxis tells us that what appears to be cause and effect in the couplet "amyloid plaque" merely by a proximity relationship may be "spurious causality" which is a cognitive dead end.

Three-dimensional reconstruction and analysis of structure characteristics on senile plaques of Alzheimer’s disease

Alzheimer’s disease is a progressive neurodegenerative disorder characterized by the presence of senile plaques primarily composed of amyloid β in brain. Abnormal secretion and aggregation of amyloid β are the key events in pathogenesis of Alzheimer’s disease. Reduction of amyloid β production and inhibition of amyloid β aggregation to form senile plaques are hopeful strategies for the treatment and prevention of Alzheimer’s disease. In the present study, the silver and immunohistochemical staining methods were applied to discover senile plaques in the hippocampus of Alzheimer’s disease patients, and then images were processed and three-dimensionally reconstructed by Matlab and AVS software. The structure characteristics of senile plaques were measured through correlation function calculation and fractal dimension by a computer-aided method. Diffuse plaque had no amyloid center, but classic plaque presented compact central core structure; two types of plaques were both of porous structure, but the sizes of their pores were significantly different. Furthermore, there was difference in fractal dimension value between the diffuse plaque and classic plaque in the two staining methods. The comparison of structure characteristics between two types of plaques indicated that they developed independently. Establishment of the methods for reconstructing the three-dimensional structure of senile plaque and analyzing their structure characteristics is helpful for further study on the aggregation mechanism of senile plaque.

The 1.1-Å Structure of the Spindle Checkpoint Protein Bub3p Reveals Functional Regions

Bub3p is a protein that mediates the spindle checkpoint, a signaling pathway that ensures correct chromosome segregation in organisms ranging from yeast to mammals. It is known to function by co-localizing at least two other proteins, Mad3p and the protein kinase Bub1p, to the kinetochore of chromosomes that are not properly attached to mitotic spindles, ultimately resulting in cell cycle arrest. Prior sequence analysis suggested that Bub3p was composed of three or four WD repeats (also known as WD40 and beta-transducin repeats), short sequence motifs appearing in clusters of 4-16 found in many hundreds of eukaryotic proteins that fold into four-stranded blade-like sheets. We have determined the crystal structure of Bub3p from Saccharomyces cerevisiae at 1.1 angstrom and a crystallographic R-factor of 15.3%, revealing seven authentic repeats. In light of this, it appears that many of these repeats therefore remain hidden in sequences of other proteins. Analysis of random and site-directed mutants identifies the surface of Bub3p involved in checkpoint function through binding of Bub1p and Mad3p. Sequence alignments indicate that these surfaces are mostly conserved across Bub3 proteins from diverse species. A structural comparison with other proteins containing WD repeats suggests that these folds may bind partner proteins using similar surface areas on the top and sides of the propeller. The sequences composing these regions are the most divergent within the repeat across all WD repeat proteins and could potentially be modulated to provide specificity in partner protein binding without perturbation of the core structure.

2 Millimeter Dust around NGC 7538 — IRS 1, 2, and 3: I. Unfilled Structure of Dust Cloud

Abstract A 2-mm continuum mapping observation around NGC 7538 — IRS 1, 2, and 3 was made by the Nobeyama Bolometer Array (NOBA) with a spatial resolution of 12$^{\prime\prime}$. An extended source of $\sim {32{}^{\mathrm {\prime \prime }}} \times {44{}^{\mathrm {\prime \prime }}}$ ($\Delta\alpha \times \Delta\delta$), having a hardly resolved central core structure, was observed. The core gives a flux density of $3.1 \,\mathrm{Jy} \pm 1 \,\mathrm{Jy}$, and is clearly identified with the free-free emission from the compact H II regions. A smooth and extended source gives an integrated flux density of $5 \,\mathrm{Jy} \pm 1.5 \,\mathrm{Jy}$, and an intensity spectrum of $\nu^{3}$–$\nu^{3.5}$ in the millimeter wave region. The fitting of a gray body function to the observational data shows that an absorption index, $\beta$, of 1.8–2.0, a dust filling factor, $\eta$, of 0.3–0.5, and a dust temperature, $T_\mathrm{d}$, of 34 K–45 K are reasonable parameters for this 2-mm extended dust. Astronomical silicate grains were examined for a dust model. The total dust mass and luminosity were obtained as $M_\mathrm{d} \simeq 0.85 \times 10^{2} \,{{{M}_{\odot}}}$ and $L_\mathrm{d} \simeq 2.2 \times 10^{5} \,{{{L}_{\odot}}}$, respectively. The extent of 2-mm dust emission partly coincides with those of the 100-$/mu$ m map, of the 57-$/mu$ m map, and of the total intensity of the wing parts of the CO ($J = 1-0$) line emission of the region. The absorbing silicate dust layer must be distinct from the extended 2-mm dust, and must arise on smaller scales than the extended 2-mm dust.

High throughput synthesis and screening: the partner of genomics for discovery of new chemicals for agriculture

Abstract As new targets for herbicide action are identified from genomics research, large and diverse chemical collections and high-throughput assays will be required to maximize the probability of identifying compounds with activity at these targets. The new technology of combinatorial synthesis and high-throughput, miniaturized, in vitro screening, which has become an integral part of pharmaceutical discovery, is now being applied to discover new herbicides, insecticides, and fungicides. Depending on the synthesis design, the products of a combinatorial synthesis, referred to as a library, may be either unbiased or biased toward an intended target. Unbiased libraries are generally prepared to maximize chemical diversity around a central core structure or scaffold. Often containing 10,000 to 30,000 compounds each, these libraries are encoded and prepared by a combinatorial methodology known as mix-and-split, which produces compounds as mixtures. The preparation of these large libraries requires robust sy...

Circumnuclear Regions and their Barred Host Galaxies

In this paper we present first results from an observational study of the connection between the global parameters of barred galaxies and the appearance of structures, such as dust lanes and star-forming rings in their circumnuclear regions. We combine near-infrared imaging of the central small-scale core structure with optical imaging of the large-scale discs of these barred galaxies. We present more detailed studies of two of our sample galaxies, NGC1530 and NGC 3504, for which we relate the presence and morphology of dust lanes (with different curvature radii) to the strength of the bar. A relation where strong bars lead to straight dust lanes and ovals or weak bars to curved dust lanes is expected theoretically and is borne out by our preliminary imaging results.