Trichloroacetimidates as Alkylating Reagents and Their Application in the Synthesis of Pyrroloindoline Natural Products and Synthesis of Small Molecule Inhibitors of Src Homology 2 Domain- Containing Inositol Phosphatase (SHIP)

Trichloroacetimidates are known to be excellent alkylating agents when activated by a catalytic amount of a Brønsted or Lewis acid. Work described herein involved taking advantage of the favorable reactivity of trichloroacetimidates to establish several different synthetic protocols, including the application of these reagents in the synthesis of pyrroloindoline based natural products, 3,3\u27-disubstituted indolenines and benzylic trichloroacetamides. Initial investigations on the utilization of the reactivity of trichloroacetimidates found that diphenylmethyl trichloroacetimidate, which is a precursor to a highly stabilized carbocation, undergoes facile displacement with carboxylic acids providing the ester product without the need of any exogenous catalyst. Both hindered and unhindered carboxylic acids were esterified with high yields, with no preference for aromatic or aliphatic carboxylic acids. Carboxylic acids with unprotected hydroxyl groups or β-lactam rings were esterified efficiently. Substrates that are highly prone to elimination or retro-aldol were also esterified in high yields. Carboxylic acids with highly enolizable α-stereocenters were esterified without any racemization. Mechanistic studies indicate that the carboxylic acid substrate itself is acidic enough to be effective at promoting the esterification reaction. During our studies on esterification with imidates it was found that these imidates also showed a tendency to undergo rearrangement to the corresponding trichloroacetamides. Two different sets of conditions, thermal and Lewis acid catalyzed, were established which provided these rearranged products with high yields. Various benzylic trichloroacetimidates were shown to undergo these transformations under the established conditions. Based on the observations discussed in this work a cationic mechanism is proposed. After the preliminary studies on alkylation of benzylic trichloroacetimidate with different nucleophiles, this chemistry was applied towards the synthesis of natural products and their analogs. The pyrroloindoline ring system is found in many alkaloids and cyclic peptides which mainly differ in the substitution at the C3a position. To provide rapid access to these natural products a diversity-oriented strategy was established via displacement of C3a-trichloroacetimidate pyrroloindoline. Carbon, oxygen, sulfur and nitrogen nucleophiles were all shown to undergo substitution reactions with these trichloroacetimidates in the presence of a Lewis acid catalyst. In order to demonstrate the utility of this new method it was applied towards the synthesis of arundinine and a formal synthesis of psychotriasine. Current investigations involve the application of this method towards the synthesis of a complex pyrroloindoline natural product kapakahine C and the progress made therein has been discussed. The reactivity of trichloroacetimidates was also investigated for the selective C3-alkylation of 2,3-disubstituted indoles to provide indolenines. Indolenines serve as useful intermediates in the synthesis of many complex alkaloids. Different benzylic and allylic trichloroacetimidates were shown to provide 3,3’-disubstituted indolenines with high yields in the presence of catalytic amounts of Lewis acids. Various substituted indoles were evaluated under these reaction conditions. This methodology was also applied towards the synthesis of the core tetracyclic ring system found in communesin natural products. In addition to the above work, synthesis of small molecule inhibitors of Src Homology 2 Domain-Containing Inositol Phosphatase (SHIP) has also been described. Aberrations in the phosphoinositide 3-kinase (PI3K) cellular signaling pathway can lead to diseased cellular states like cancer. Herein we have reported stereoselective synthesis of two quinoline based small molecule SHIP inhibitors. The lead compounds and their analogs were tested for their activities against SHIP by Malachite green assay and the discoveries made therein are discussed. In addition to this synthesis of a tryptamine based SHIP inhibitor has also been reported

Routing algorithms classification & Proposed Routing Algorithm for DTN

This paper provides an introduction to Delay Tolerant Networks (DTN)alogorithms and would touch upon some basic classification. Continuous connectivity is difficult in today�s wireless world. The data preservation and security in challenged and intermittent network, is of paramount importance. In this paper, we will see how DTN provides detail classification and discription for further studies & application.an effective alternative. Security of data becomes important in disrupted networks; this paper would also discuss Praposed Routing algorithms with DTNs

Simulation for proposed DTN algorithm & Analysis

There are different simulation tools available for simulating the algorithms of mobile ad-hoc networks, and these tools are user friendly, means easy to work upon. In case of DTN algorithm implementation, these tool cannot work properly because of the frequent disconnection environment of nodes in DTN. We have used The ONE simulator [33] for implementing our proposed DTN algorithm

Search for intermediate mass black hole binaries in the first and second observing runs of the Advanced LIGO and Virgo network

Gravitational-wave astronomy has been firmly established with the detection of gravitational waves from the merger of ten stellar-mass binary black holes and a neutron star binary. This paper reports on the all-sky search for gravitational waves from intermediate mass black hole binaries in the first and second observing runs of the Advanced LIGO and Virgo network. The search uses three independent algorithms: two based on matched filtering of the data with waveform templates of gravitational-wave signals from compact binaries, and a third, model-independent algorithm that employs no signal model for the incoming signal. No intermediate mass black hole binary event is detected in this search. Consequently, we place upper limits on the merger rate density for a family of intermediate mass black hole binaries. In particular, we choose sources with total masses M=m1+m2ϵ[120,800] M and mass ratios q=m2/m1ϵ[0.1,1.0]. For the first time, this calculation is done using numerical relativity waveforms (which include higher modes) as models of the real emitted signal. We place a most stringent upper limit of 0.20 Gpc-3 yr-1 (in comoving units at the 90% confidence level) for equal-mass binaries with individual masses m1,2=100 M and dimensionless spins χ1,2=0.8 aligned with the orbital angular momentum of the binary. This improves by a factor of ∼5 that reported after Advanced LIGO's first observing run

All-sky search for short gravitational-wave bursts in the second Advanced LIGO and Advanced Virgo run

We present the results of a search for short-duration gravitational-wave transients in the data from the second observing run of Advanced LIGO and Advanced Virgo. We search for gravitational-wave transients with a duration of milliseconds to approximately one second in the 32-4096 Hz frequency band with minimal assumptions about the signal properties, thus targeting a wide variety of sources. We also perform a matched-filter search for gravitational-wave transients from cosmic string cusps for which the waveform is well modeled. The unmodeled search detected gravitational waves from several binary black hole mergers which have been identified by previous analyses. No other significant events have been found by either the unmodeled search or the cosmic string search. We thus present the search sensitivities for a variety of signal waveforms and report upper limits on the source rate density as a function of the characteristic frequency of the signal. These upper limits are a factor of 3 lower than the first observing run, with a 50% detection probability for gravitational-wave emissions with energies of ∼10-9 Mc2 at 153 Hz. For the search dedicated to cosmic string cusps we consider several loop distribution models, and present updated constraints from the same search done in the first observing run

Search for Eccentric Binary Black Hole Mergers with Advanced LIGO and Advanced Virgo during Their First and Second Observing Runs

When formed through dynamical interactions, stellar-mass binary black holes (BBHs) may retain eccentric orbits (e > 0.1 at 10 Hz) detectable by ground-based gravitational-wave detectors. Eccentricity can therefore be used to differentiate dynamically formed binaries from isolated BBH mergers. Current template-based gravitational-wave searches do not use waveform models associated with eccentric orbits, rendering the search less efficient for eccentric binary systems. Here we present the results of a search for BBH mergers that inspiral in eccentric orbits using data from the first and second observing runs (O1 and O2) of Advanced LIGO and Advanced Virgo. We carried out the search with the coherent WaveBurst algorithm, which uses minimal assumptions on the signal morphology and does not rely on binary waveform templates. We show that it is sensitive to binary mergers with a detection range that is weakly dependent on eccentricity for all bound systems. Our search did not identify any new binary merger candidates. We interpret these results in light of eccentric binary formation models. We rule out formation channels with rates ⪆100 Gpc-3 yr-1 for e > 0.1, assuming a black hole mass spectrum with a power-law index ≲2

A comparative study between the use of the combination of trichloroacetic acid peeling with hydroquinone and hydroquinone alone in patients with melasma

Background: Melasma is a common acquired pigmentary disorder that is aesthetically displeasing. Kligman’s and Modified Kligman’s formula using topical steroids, hydroquinone and retinoids, and various other depigmenting agents is being widely used all over for melasma with varying results. Chemical peeling is newly added to the therapeutic armamentarium and is showing encouraging results worldwide in patients with melasma. However, comparative studies are lacking in abundance in our part of the world. Aims and Objectives: To determine if serial trichloroacetic acid peels provide additional benefits when combined with time-tested topical therapy with hydroquinone 4% in patients with melasma. Materials and Methods: Fifty melasma patients were divided into two groups of 25 each. One group received serial trichloroacetic acid peel combined with topical hydroquinone 4%. The other group only received topical hydroquinone 4% cream. The results were evaluated by a clinical investigator both subjectively and with photographs taken at baseline, 12 weeks, and 21 weeks. For clinical evaluation, the melasma area and severity index (MASI) was used. Results: A significant decrease in MASI score from baseline to 21 weeks was observed in both groups (P<0.001). The group receiving the trichloroacetic acid peel 20% showed a trend toward more rapid and greater improvement, with statistically significant results (P<0.001). Only a few side effects were observed in the peel group. Conclusion: This study demonstrates that serial trichloroacetic acid peels provide an additional effect to a topical regimen of 4% hydroquinone cream for treating melasma in Fitzpatrick skin types III and above if used judiciously and under supervision. It demonstrates that superficial chemical peels can be used as an adjunct with better efficacy to treat patients with melasma

An analysis and evaluation of the WeFold collaborative for protein structure prediction and its pipelines in CASP11 and CASP12

Every two years groups worldwide participate in the Critical Assessment of Protein Structure Prediction (CASP) experiment to blindly test the strengths and weaknesses of their computational methods. CASP has significantly advanced the field but many hurdles still remain, which may require new ideas and collaborations. In 2012 a web-based effort called WeFold, was initiated to promote collaboration within the CASP community and attract researchers from other fields to contribute new ideas to CASP. Members of the WeFold coopetition (cooperation and competition) participated in CASP as individual teams, but also shared components of their methods to create hybrid pipelines and actively contributed to this effort. We assert that the scale and diversity of integrative prediction pipelines could not have been achieved by any individual lab or even by any collaboration among a few partners. The models contributed by the participating groups and generated by the pipelines are publicly available at the WeFold website providing a wealth of data that remains to be tapped. Here, we analyze the results of the 2014 and 2016 pipelines showing improvements according to the CASP assessment as well as areas that require further adjustments and research