Active Core Structure Research Articles

Recent reports on Pyridoxal derived Schiff base complexes

Abstract Pyridoxal and Pyridoxal 5-phosphate are two among the six aqua soluble vitamers of vitamin B6. They can form Schiff bases readily due to the presence of aldehyde group. Schiff bases can offer diverse coordination possibilities for many transition metals as has been found in a large volume of research till now. The coordination complexes thus formed gives insight into the active core structure and enzymatic activities of vit B6 containing enzymes. Apart from that, these complexes have been found useful as catalysts for synthesis of fine chemicals, as sensors and for their diverse biological activities.

Pyrazolodiazepine derivatives with agonist activity toward Drosophila RYamide receptor

The neuropeptide Y (NPY)-like signaling is conserved broadly in many animal species, and implicated in diverse biological functions, particularly those associated with feeding and metabolism. In Drosophila, three G protein coupled receptors (GPCRs) are closely related to the vertebrate NPY receptors: RYamide receptor (RYa-R) CG5811, neuropeptide F receptor (NPFR) CG1147 and short neuropeptide F receptor (sNPF-R) CG7395. Here, we screened 442 compounds of the pyrazolodiazepine analogs library, and identified four synthetic small compounds that activate the RYa-R, but not other two receptors. Their maximum activity is about 40% of the endogenous ligand, Drosophila RYamide-1, indicating they are partial agonists. Structural comparisons of these agonists identified an active core structure, characterized by phenylalanine and lysine fused pyrazolodiazepine skeletons, which can be utilized as a lead structure for further development of more potent drugs active on mammalian NPYRs. Identification of small compound agonists selective on RYa-R of the genetically amenable insect model will facilitate future efforts to understand biological functions of RYa-R, a GPCR conserved in many species.

Wave-Guiding Analysis of Annular Core Geometry Metal-Clad Semiconductor Nano-Lasers

Numerical modeling of cylindrical semiconductor nano-lasers has been undertaken accommodating local gain variations in the active region of the device. Analysis is performed using both the cylindrical transfer matrix method and the finite element method. Calculations have thereby been performed of the modal gain and the lasing condition for the device. The model has been applied to annular active core structures and a comparison has been made of the requirements for achieving lasing via the excitation of TE <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">01</sub> and TM <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">01</sub> modes. For representative structures, it is shown that TE and TM mode lasing can be supported in devices having cavity lengths in the order of 1 and 60 μm, respectively.

Cyclization Routes for the Synthesis of Functionalized Pyrano[2,3-b]indolones, Pyrazolo[3,4-b]indoles, and Furo[2,3-b]indoles

The synthesis of biologically active core structures containing pyrano[2,3-b]indol-2(9H)-ones, pyrano[2,3-b]indol-4(9H)-ones, pyrazolo[3,4-b]indoles, and furo[2,3-b]indoles are described. Pyrano[2,3-b]indol-2(9H)-ones are synthesized by three different metal-free syntheses (DCC, DMSO; CDI, DBU, CH2Cl2; or Mukaiyama’s reagent, Et3N, MeCN) and pyrano[2,3-b]indol-4(9H)-ones are prepared by one-pot or two-step synthesis. Pyrazolo[3,4-b]indoles are synthesized by Fischer indole type cyclization and McMurry coupling is employed for the synthesis of furo[2,3-b]indoles. All these core structures are synthesized from simple, common 3-acetylindol-2-ols.

ChemInform Abstract: Synthesis of Pyrido[2,3‐b]indoles and Pyrimidoindoles via Pd‐Catalyzed Amidation and Cyclization.

Biologically and pharmaceutically active core structures containing a new class of 4-hydroxy-α-carbolines, dihydropyrido[2,3-b]indoles, pyrimido[4,5-b] and [5,4-b]indoles have been synthesized in good yields via Pd-catalyzed amidation and cyclizations. The keto-enol tautomerism in 4-hydroxy-α-carbolines has been investigated by DFT calculations and spectroscopic techniques. The fluorescence studies of pyrimido[4,5-b] and [5,4-b]indoles were carried out with good quantum yields.

A phenotypic screening platform to identify small molecule modulators of Chlamydomonas reinhardtiigrowth, motility and photosynthesis

Chemical biology, the interfacial discipline of using small molecules as probes to investigate biology, is a powerful approach of developing specific, rapidly acting tools that can be applied across organisms. The single-celled alga Chlamydomonas reinhardtii is an excellent model system because of its photosynthetic ability, cilia-related motility and simple genetics. We report the results of an automated fitness screen of 5,445 small molecules and subsequent assays on motility/phototaxis and photosynthesis. Cheminformatic analysis revealed active core structures and was used to construct a naïve Bayes model that successfully predicts algal bioactive compounds.

Synthesis of pyrido[2,3-b]indoles and pyrimidoindoles via Pd-catalyzed amidation and cyclization

Biologically and pharmaceutically active core structures containing a new class of 4-hydroxy-α-carbolines, dihydropyrido[2,3-b]indoles, pyrimido[4,5-b] and [5,4-b]indoles have been synthesized in good yields via Pd-catalyzed amidation and cyclizations. The keto-enol tautomerism in 4-hydroxy-α-carbolines has been investigated by DFT calculations and spectroscopic techniques. The fluorescence studies of pyrimido[4,5-b] and [5,4-b]indoles were carried out with good quantum yields.

Reduce to the Maximum: Truncated Natural Products as Powerful Modulators of Biological Processes

This account describes several examples from the literature, as well as from our own work, of efforts to reduce the structural complexity of natural products through truncation by organic synthesis. This process, sometimes called diverted total synthesis or function oriented synthesis, also aims to deliver improved compounds for clinical evaluation. The discussed examples from the literature of this type of chemical editing are the truncation of halichondrin B to E7389/eribulin, bryostatin 1 to the bryologs, migrastatin to the migrastatin core, macfarlandin E, and somatostatin (SRIF14) to L-363,301 and octreotide. From our work, efforts on the truncation of anguinomycin/leptomycin, farinosone C to tyrosinol propionamide, and anachelin to the anachelin chromophore are discussed. A hypothesis as to why nature retains apparently nonfunctional appendages on biologically active core structures (related to the pharmacophore) in such ‘less than perfect’ natural products is presented. It is proposed that such appendages are generated to increase chemotype plasticity, and that such plasticity might eventually lead to secondary benefits, such as improved physicochemical properties or additional bioactivity.

Facilitation of Hippocampal Synaptogenesis and Spatial Memory by C-Terminal Truncated Nle1-Angiotensin IV Analogs

Angiotensin IV (AngIV; Val(1)-Tyr(2)-Ile(3)-His(4)-Pro(5)-Phe(6))-related peptides have emerged as potential antidementia agents. However, their development as practical therapeutic agents has been impeded by a combination of metabolic instability, poor blood-brain barrier permeability, and an incomplete understanding of their mechanism of action. This study establishes the core structure contained within norleucine(1)-angiotensin IV (Nle(1)-AngIV) that is required for its procognitive activity. Results indicated that Nle(1)-AngIV-derived peptides as small as tetra- and tripeptides are capable of reversing scopolamine-induced deficits in Morris water maze performance. This identification of the active core structure contained within Nle(1)-AngIV represents an initial step in the development of AngIV-based procognitive drugs. The second objective of the study was to clarify the general mechanism of action of these peptides by assessing their ability to affect changes in dendritic spines. A correlation was observed between a peptide's procognitive activity and its capacity to increase spine numbers and enlarge spine head size. These data suggest that the procognitive activity of these molecules is attributable to their ability to augment synaptic connectivity.

Integrated twin modulator switches through MMI splitting and electroabsorption modulation

We present a 1 × 2 multimode interference splitter integrated with duo electroabsorption modulator based switches, one at each output arm. The material structure consists of an InGaAlAs/InGaAlAs multiple-quantum-well active core layer with a dual depletion region active core structure and a large optical cavity waveguide design. The switches exhibited an extinction ratio of up to 10 dB at a driving voltage-swing of 2.0 V.

Active core structure of terfestatin A, a new specific inhibitor of auxin signaling

The auxins, plant hormones, regulate many aspects of the growth and development of plants. Terfestatin A (TrfA), a novel auxin signaling inhibitor, was identified in a screen of Streptomyces sp. F40 extracts for inhibition of the expression of an auxin-inducible gene. However, the mode of action of TrfA has not been elucidated. To identify the active core structure, 25 derivatives of TrfA were synthesized and their inhibitory activities against auxin-inducible gene expression were evaluated. The structure–activity relationships revealed the essential active core structure of TrfA, 3-butoxy-4-methylbiphenyl-2,6-diol, which will lead to the design of biotin-tagged active TrfA.

Cation-Specific Structural Accommodation within a Catalytic RNA

Metal ions facilitate the folding of the hairpin ribozyme but do not participate directly in catalysis. The metal complex cobalt(III) hexaammine supports folding and activity of the ribozyme and also mediates specific internucleotide photocrosslinks, several of which retain catalytic ability. These crosslinks imply that the active core structure organized by [Co(NH3)6]3+ is different from that organized by Mg2+ and that revealed in the crystal structure [Rupert, P. B., and Ferre-D'Amare, A. R. (2001) Nature 410, 780-786] (1). Residues U+2 and C+3 of the substrate, in particular, adopt different conformations in [Co(NH3)6]3+. U+2 is bulged out of loop A and stacked on residue G36, whereas the nucleotide at position +3 is stacked on G8, a nucleobase crucial for catalysis. Cleavage kinetics performed with +2 variants and a C+3 U variant correlate with the crosslinking observations. Variants that decreased cleavage rates in magnesium up to 70-fold showed only subtle decreases or even increases in observed rates when assayed in [Co(NH3)6]3+. Here, we propose a model of the [Co(NH3)6]3+-mediated catalytic core generated by MC-SYM that is consistent with these data.

Size of Hirudin Sequence Required To Fold into an Active Core Domain

The active core domain of hirudin contains three native disulfides (Cys6-Cys14,Cys16-Cys28, and Cys22-Cys39) and 49 amino acid residues (Hir1-49). This compact structure folds spontaneously, and its folding pathway has been elucidated recently [Chatrenet and Chang (1993) J. Biol. Chem. 268, 20988-20996]. The folding mechanisms of Hir1-35 and Hir1-43 were investigated in order to determine the minimum structural elements required to fold into this active core structure. Hir1-35 includes two native disulfides (Cys6-Cys14 and Cys16-Cys28) and an extra Cys22. When reduced/denatured Hir1-35 was allowed to fold, it folded into a collection of equilibrated 2-disulfide isomers. At least eight fractions of the 2-disulfide species have been observed. Structural analysis revealed that out of the 10 possible disulfide pairings, only five were detected to exist in the 2-disulfide isomers, and all have their half-cystines separated by less than 8-10 amino acid residues. One of the native disulfides, Cys16-Cys28, has not been found in any of those 2-disulfide species. On the other hand, the C-terminal extension of an octapeptide permitted reduced/denaturated Hir1-43 to fold into a defined active structure possessing the three native disulfides. These results also demonstrate that the folding mechanism of Hir1-35 resembles what occurs during the early stage of Hir1-43 (and Hir1-49) folding, which involves a process of nonspecific packing of unfolded polypeptide chains.

Contribution of structural elements to Thermus thermophilus ribonuclease P RNA function.

We have performed a deletion and mutational analysis of the catalytic ribonuclease (RNase) P RNA subunit from the extreme thermophilic eubacterium Thermus thermophilus HB8. Catalytic activity was reduced 600-fold when the terminal helix, connecting the 5' and 3' ends of the molecule, was destroyed by deleting 15 nucleotides from the 3' end. In comparison, the removal of a large portion (94 nucleotides, about one quarter of the RNA) of the upper loop region impaired function only to a relatively moderate extent (400-fold reduction in activity). The terminal helix appears to be crucial for the proper folding of RNase P RNA, possibly by orientating the adjacent universally conserved pseudoknot structure. The region containing the lower half of the pseudoknot structure was shown to be a key element for enzyme function, as was the region of nucleotides 328-335. Deleting a conserved hairpin (nucleotides 304-327) adjacent to this region and replacing the hairpin by a tetranucleotide sequence or a single cytidine reduced catalytic activity only 6-fold, whereas a simultaneous mutation of the five highly conserved nucleotides in the region of nucleotides 328-335 reduced catalytic activity by > 10(5)-fold. The two strictly conserved adenines 244 and 245 (nucleotides 248/249 in Escherichia coli RNase P RNA) were not as essential for enzyme function as suggested by previous data. However, additional disruption of two helical segments (nucleotides 235-242) adjacent to nucleotides 244 and 245 reduced activity by > 10(4)-fold, supporting the notion that nucleotides in this region are also part of the active core structure.(ABSTRACT TRUNCATED AT 250 WORDS)

A 225 K dalton glycoprotein is the active core structure of the sperm-binding factor of the sea urchin, Anthocidaris crassispina

Fab fragments against 225 000 D glycoprotein (225 K), 87 000 D protein (87 K) and 80 000 D glycoprotein (80 K) of partially purified sperm-binding factor of Anthocidaris crassispina were prepared, and their effects upon fertilizability of dejellied homologous and heterologous eggs examined. Only the 225 K Fab impaired the fertilizability of homologous, not heterologous eggs by decreasing their sperm-binding capacity. It was concluded that 225 K glycoprotein is the active core structure of the sperm-binding factor of this species. The possible participation of the other two proteins as residual ingredients of the sperm-binding factor was also discussed. Immunofluorescence studies showed that 225 K core protein is localized on the whole surface of unfertilized eggs and of fully-grown oocytes. The fluorescence disappeared following fertilization.