NMR Structure Implications of Enhanced Efficacy of Obestatin Fragment Analogs

Obestatin is a more recently discovered hormone that is encoded by the ghrelin gene and produced in the stomach and gut. We report NMR analysis on synthetic Obestatin (OB23), a 23 residue peptide, along with three overlapping fragments of the same in methanol solvent as a first step towards structure activity relationship. Selective substitutions on the promising N-terminal and middle fragments of obestatin have been carried out in order to improve the efficacy and potency. In the N-terminal fragment two peptides were obtained by the replacement of Gly (8) with a-aminoisobutyric acid (Aib, U) and Phe (F5) with Cyclohexylalanine (Cha). In case of the middle fragment both Gly (3) and Gly (8) were replaced with Aib residues. The rationale being, these unusual amino acids could provide protection from immediate degradation and aid structure stabilization. Our previous studies showed that the N-terminal and the middle fragment were unstructured and hence this substitution would directly evaluate the effect of structure on the activity of these fragment analogs. Detailed NMR analysis clearly demonstrates formation of helical secondary structure in all the peptide analogues and provides justification for relative activities reported by our group previously (Nagaraj et al. 2009).

Molecular structures and antiproliferative activity of side-chain saturated and homologated analogs of 2-chloro-3-(n-alkylamino)-1,4-napthoquinone

Side chain homologated derivatives of 2-chloro-3-(n-alkylamino)-1,4-naphthoquinone {n-alkyl: pentyl; L-5, hexyl; L-6, heptyl; L-7 and octyl; L-8} have been synthesized and characterized by elemental analysis, FT-IR, H-1 NMR, UV-visible spectroscopy and LC-MS. Compounds, L-4, n-alkyl: butyl; L-4}, L-6 and L-8 have been characterized by single crystal X-ray diffraction studies. The single crystal X-ray structures reveal that L-4 and L-8 crystallizes in P2(1) space group, while L-6 in P2(1)/c space group. Molecules of L-4 and L-8 from polymeric chains through C-H center dot center dot center dot O and N-H center dot center dot center dot O close contacts. L-6 is a dimer formed by N-H center dot center dot center dot O interaction. Slipped pi-pi stacking interactions are observed between quinonoid and benzenoid rings of L-4 and L-8. Orientations of alkyl group in L-4 and L-8 is on same side of the chain and polymeric chains run opposite to one another to form zip like structure to the alkyl groups. Antiproliferative activities of L-1 to L-8{n-alkyl: methyl; L-1, ethyl; L-2, propyl; L-3 and butyl; L-4} were studied in cancer cells of colon (COLO205), brain (U87MG) and pancreas (MIAPaCa2) where L-1, L-2 and L-3 were active in MIAPaCa2 (L-1 = 1-2 > L-3) and COLO205 (L-2 = L-3 > L-1) and inactive in U87MG. From antiproliferative studies with compounds L-1 to L-8 it can be concluded that homologation of 2-chloro-3-(n-alkylamino)-1,4-napthoquinone with saturated methyl groups yielded tissue specific compounds such as L-2 (for MIAPaCa2) and L-3 (for COLO205) with optimal activity. (c) 2013 Elsevier B.V. All rights reserved.

sigma-Ferrier rearrangement of carbohydrate derived vinylcyclopropanes: a facile approach to oxepane analogs

This article presents our work on the sigma-Ferrier ring-expansion of carbohydrate derived vinylcyclopropanes (VCPs) under electrophilic conditions mediated by chloramine-T and a phase-transfer catalyst. The present work serves as the first example on the studies of the reactivity of carbohydrate VCPs towards the synthesis of densely functionalized oxepane analogues. The work elaborates on a reasonable mechanism for the product formation and our observations on the diastereoselectivity based on control experiments and gas-phase calculations. (C) 2014 Elsevier Ltd. All rights reserved.

Identifying and interpreting stratification in sedimentary rocks on Mars : insight from Rover and orbital observations and terrestrial field analogs

Sedimentary rocks on Mars provide insight into past aqueous and atmospheric processes, climate regimes, and potential habitability. The stratigraphic architecture of sedimentary rocks on Mars is similar to that of Earth, indicating that the processes that govern deposition and erosion on Mars can be reasonably inferred through reference to analogous terrestrial systems. This dissertation aims to understand Martian surface processes through the use of (1) ground-based observations from the Mars Exploration Rovers, (2) orbital data from the High Resolution Imaging Science Experiment onboard the Mars Reconnaissance Orbiter, and (3) the use of terrestrial field analogs to understand bedforms and sediment transport on Mars. Chapters 1 and 2 trace the history of aqueous activity at Meridiani Planum, through the reconstruction of eolian bedforms at Victoria crater, and the identification of a potential mudstone facies at Santa Maria crater. Chapter 3 uses Terrestrial Laser Scanning to study cross-bedding in pyroclastic surge deposits on Earth in order to understand sediment transport in these events and to establish criteria for their identification on Mars. The final chapter analyzes stratal geometries in the Martian North Polar Layered Deposits using tools for sequence stratigraphic analysis, to better constrain past surface processes and past climate conditions on Mars.

On Ultrafast Time-Domain TeraHertz Spectroscopy in the Condensed Phase: Linear Spectroscopic Measurements of Hydrogen-Bond Dynamics of Astrochemical Ice Analogs and Nonlinear TeraHertz Kerr Effect Measurements of Vibrational Quantum Beats

Much of the chemistry that affects life on planet Earth occurs in the condensed phase. The TeraHertz (THz) or far-infrared (far-IR) region of the electromagnetic spectrum (from 0.1 THz to 10 THz, 3 cm^-1 to 300 cm^-1, or 3000 μm to 30 μm) has been shown to provide unique possibilities in the study of condensed-phase processes. The goal of this work is to expand the possibilities available in the THz region and undertake new investigations of fundamental interest to chemistry. Since we are fundamentally interested in condensed-phase processes, this thesis focuses on two areas where THz spectroscopy can provide new understanding: astrochemistry and solvation science. To advance these fields, we had to develop new instrumentation that would enable the experiments necessary to answer new questions in either astrochemistry or solvation science. We first developed a new experimental setup capable of studying astrochemical ice analogs in both the TeraHertz (THz), or far-Infrared (far-IR), region (0.3 - 7.5 THz; 10 - 250 cm^-1) and the mid-IR (400 - 4000 cm^-1). The importance of astrochemical ices lies in their key role in the formation of complex organic molecules, such as amino acids and sugars in space. Thus, the instruments are capable of performing variety of spectroscopic studies that can provide especially relevant laboratory data to support astronomical observations from telescopes such as the Herschel Space Telescope, the Stratospheric Observatory for Infrared Astronomy (SOFIA), and the Atacama Large Millimeter Array (ALMA). The experimental apparatus uses a THz time-domain spectrometer, with a 1750/875 nm plasma source and a GaP detector crystal, to cover the bandwidth mentioned above with ~10 GHz (~0.3 cm^-1) resolution.

Using the above instrumentation, experimental spectra of astrochemical ice analogs of water and carbon dioxide in pure, mixed, and layered ices were collected at different temperatures under high vacuum conditions with the goal of investigating the structure of the ice. We tentatively observe a new feature in both amorphous solid water and crystalline water at 33 cm^-1 (1 THz). In addition, our studies of mixed and layered ices show how it is possible to identify the location of carbon dioxide as it segregates within the ice by observing its effect on the THz spectrum of water ice. The THz spectra of mixed and layered ices are further analyzed by fitting their spectra features to those of pure amorphous solid water and crystalline water ice to quantify the effects of temperature changes on structure. From the results of this work, it appears that THz spectroscopy is potentially well suited to study thermal transformations within the ice.

To advance the study of liquids with THz spectroscopy, we developed a new ultrafast nonlinear THz spectroscopic technique: heterodyne-detected, ultrafast THz Kerr effect (TKE) spectroscopy. We implemented a heterodyne-detection scheme into a TKE spectrometer that uses a stilbazoiumbased THz emitter, 4-N,N-dimethylamino-4-N-methyl-stilbazolium 2,4,6-trimethylbenzenesulfonate (DSTMS), and high numerical aperture optics which generates THz electric field in excess of 300 kV/cm, in the sample. This allows us to report the first measurement of quantum beats at terahertz (THz) frequencies that result from vibrational coherences initiated by the nonlinear, dipolar interaction of a broadband, high-energy, (sub)picosecond THz pulse with the sample. Our instrument improves on both the frequency coverage, and sensitivity previously reported; it also ensures a backgroundless measurement of the THz Kerr effect in pure liquids. For liquid diiodomethane, we observe a quantum beat at 3.66 THz (122 cm^-1), in exact agreement with the fundamental transition frequency of the υ4 vibration of the molecule. This result provides new insight into dipolar vs. Raman selection rules at terahertz frequencies.

To conclude we discuss future directions for the nonlinear THz spectroscopy in the Blake lab. We report the first results from an experiment using a plasma-based THz source for nonlinear spectroscopy that has the potential to enable nonlinear THz spectra with a sub-100 fs temporal resolution, and how the optics involved in the plasma mechanism can enable THz pulse shaping. Finally, we discuss how a single-shot THz detection scheme could improve the acquisition of THz data and how such a scheme could be implemented in the Blake lab. The instruments developed herein will hopefully remain a part of the groups core competencies and serve as building blocks for the next generation of THz instrumentation that pushes the frontiers of both chemistry and the scientific enterprise as a whole.

Homologs of eukaryotic Ras superfamily proteins in prokaryotes and their novel phylogenetic correlation with their eukaryotic analogs

Ras superfamily proteins are key regulators in a wide variety of cellular processes. Previously, they were considered to be specific to eukaryotes, and MglA, a group of obviously different prokaryotic proteins, were recognized as their only prokaryotic an

functional monomers and polymers.CXXXVI.effect of metal ions on the interaction of synthetic nucleic acid analogs

The effect of metal ions on the conformation of thymine-containing poly-D-lysine was studied by CD spectra in aqueous solution. Of the metal ions studied,only copper(Ⅱ)ion affected the conformation of mucleic acid analogs .copper(Ⅱ)ion also affected the specifically interacting system made up of thymine-containing poly-D-lysine and polyadenylic acid.

NMR studies on synthesized diosgenyl saponin analogs

The identification of six synthesized diosgenyl saponin analogs with up to five sugars was accomplished by NMR studies. A combination of homo- and heteronuclear two-dimensional NMR techniques was utilized to achieve the complete H-1 and C-13 NMR assignments. Copyright (C) 2000 John Wiley & Sons, Ltd.