Synthesis and characterization of new 1,1′-diester,diketone, and dinitrile derivatives of 2,2′-biimidazole

Substituted 1,1′-diester, diketone and dinitrile derivatives are prepared from 2,2′-biimidazole. The reactions involved include: Michael addition with halogenated olefins; nucleophilic substitution with ketones, nitriles, and esters; and condensation with amines.     

α-CGRP disrupts amylin fibrillization and regulates insulin secretion: implications on diabetes and migraine

Despite being relatively benign and not an indicative signature of toxicity, fibril formation and fibrillar structures continue to be key factors in assessing the structure–function relationship in protein aggregation diseases. The inability to capture molecular cross-talk among key players at the tissue level before fibril formation greatly accounts for the missing link toward the development of an efficacious therapeutic intervention for Type II diabetes mellitus (T2DM). We show that human α-calcitonin gene-related peptide (α-CGRP) remodeled amylin fibrillization. Furthermore, while CGRP and/or amylin monomers reduce the secretion of both mouse Ins1 and Ins2 proteins, CGRP oligomers have a reverse effect on Ins1. Genetically reduced Ins2, the orthologous version of human insulin, has been shown to enhance insulin sensitivity and extend the life-span in old female mice. Beyond the mechanistic insights, our data suggest that CGRP regulates insulin secretion and lowers the risk of T2DM. Our result rationalizes how migraine might be protective against T2DM. We envision the new paradigm of CGRP : amylin interactions as a pivotal aspect for T2DM diagnostics and therapeutics. Maintaining a low level of amylin while increasing the level of CGRP could become a viable approach toward T2DM prevention and treatment.

CGRP concentration is elevated in migraine conditions. The protective effect of migraine against type 2 diabetes is attributed to the ability of CGRP to remodel human amylin aggregation and to suppress the secretion of mouse insulin 2 (the orthologue of human insulin).     

Heteroatom derivatives of indene: V. Vibrational spectra of benzimidazole

Infrared and Raman measurements for benzimidazole are presented and discussed, including its argon-matrix infrared spectrum. To assist in the assignment, benzimidazole's harmonic force fields for the 321G* and 631G* levels were scaled by scaled factors derived by fitting the respective computed force fields of other indene derivatives to previously reported experimental vibrational frequencies. Comparison to the best set of experimental wavenumbers, usually taken from the matrix, shows mean 321G* and 631G* deviations of 7.0 and 5.8 cm⁻¹ for the planar modes, and 14.0 and 6.8 cm⁻¹ for the nonplanar modes, respectively, with much of the error residing in imino-hydrogen group modes. Standard entropies are derived with the matrix wavenumbers and the methods of statistical mechanics. An attempt to determine standard entropies by calorimetric methods was unsuccessful. The triple-point temperature T_tp and enthalpy of fusion Δ¹_crH_m only are reported.     

Synthesis and Characterization of Polymers Derived from the Copolymerization of 1,1′-Dihydroxyethyl-2,2′-Biimidazole and the Diglycidyl Ether of Bisphenol A

Abstract

1,1′-Dihydroxyethyl-2,2′-biimidazole has been used as a copolymerizing monomer with the diglycidyl ether of bisphenol A in the preparation of biimidazole-containing epoxy polymers. Polymerization reactions were studied in bulk, with and without catalyst, and in N,N-dimethylforma-mide and anisole solvents, with and without catalyst. FT-IR and NMR spectra, molecular weight, thermal and solubility characteristics were obtained. Polymers isolated as amorphous light brown solids were found to be only sparingly soluble in THF or in highly polar nitrogen-containing solvents (DMF, NMP, pyridine). These materials exhibited molecular weights up to 37 000 for SnC1₄-catalyzed polymerization carried out in DMF. A glass-transition temperature of 391°C was observed for polymers obtained under uncatalyzed solventless conditions. The glass transition temperature was 373°C for product obtained under SnC1₄-catalyzed, solventless conditions. Thermogravimetric analysis in air of polymers obtained under varying solvent and catalyst conditions showed less than 25% weight loss below 330°C and greater than 75% weight loss above 400°C.     

Engineering strategy to improve peptide analogs: from structure-based computational design to tumor homing

We present a chemical strategy to engineer analogs of the tumor-homing peptide CREKA (Cys-Arg-Glu-Lys-Ala), which binds to fibrin and fibrin-associated clotted plasma proteins in tumor vessels (Simberg et al. in Proc Natl Acad Sci USA 104:932–936, 2007) with improved ability to inhibit tumor growth. Computer modeling using a combination of simulated annealing and molecular dynamics were carried out to design targeted replacements aimed at enhancing the stability of the bioactive conformation of CREKA. Because this conformation presents a pocket-like shape with the charged groups of Arg, Glu and Lys pointing outward, non-proteinogenic amino acids α-methyl and N-methyl derivatives of Arg, Glu and Lys were selected, rationally designed and incorporated into CREKA analogs. The stabilization of the bioactive conformation predicted by the modeling for the different CREKA analogs matched the tumor fluorescence results, with tumor accumulation increasing with stabilization. Here we report the modeling, synthetic procedures, and new biological assays used to test the efficacy and utility of the analogs. Combined, our results show how studies based on multi-disciplinary collaboration can converge and lead to useful biomedical advances.     

Activation and Retention: A Magnetic Resonance Probe for the Detection of Acute Thrombosis

Blood‐clot formation that results in the complete occlusion of a blood vessel (thrombosis) often leads to serious life‐threatening events, such as strokes and heart attacks. As the composition of a thrombus changes as it matures, new imaging methods that are capable of distinguishing new clots from old clots may yield important diagnostic and prognostic information. To address this need, an activatable magnetic resonance (MR) probe that is responsive to a key biochemical process associated with recently formed clots has been developed.     

Large-amplitude plasma wave generation with a high-intensity short-pulse beat wave

A short-pulse laser beat wave scheme for advanced particle accelerator applications is examined. A short, intense (3-ps, >10(18)-W cm(-2)) two-frequency laser pulse is produced by use of a modified chirped-pulse amplification scheme and is shown to produce relativistic plasma waves during interactions with low-density plasmas. The generation of plasma waves was observed by measurement of forward Raman scattering. Resonance was found to occur at an electron density many times that expected, owing to ponderomotive displacement of plasma within the focal region.     

How to Make Drugs Orally Active: A Substrate Template for Peptide Transporter PepT1

By building key structural features into hydrophilic drugs, they can be recognized by the PepT1 transporter system of the small intestine and rendered orally active. The model shown provides, for the first time, a 3D template for all known substrates of PepT1.