55 research outputs found
Synthesis and thermal reactivity of pyrrolidine- and 2-pyrrolidinone-fused cyclic enediynes
No full textVarious bicyclic enediynes containing pyrrolidine and pyrrolidinone moieties were synthesised. Thermal reactivity studies indicated the lowering of the onset temperature for Bergman cyclisation upon fusion of these heterocyclic systems onto the cyclic enediyne
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No full textThe donor–acceptor (D–A) type dipolar fluorophores, an important class of luminescent dyes with two photon absorption behaviour, generally emit strongly in organic solvents but poorly in aqueous media. To understand and enhance the poor emission behaviour of dipolar dyes in aqueous media, we undertake a rational approach that includes a systematic structure variation of the donor, amino substituent of acedan, an important two-photon dye. We identify several factors that influence the emission behaviour of the dipolar dyes in aqueous media through computational and photophysical studies on new acedan derivatives. As a result, we can make acedan dyes emit bright fluorescence underone- and two-photon excitation in aqueous media by suppressing the liable factors for poor emission: 1,3-allylic strain, rotational freedom, and hydrogen bonding with water. We also validate that these findings can be generally extended to other dipolar fluorophores, as demonstrated for naphthalimide, coumarin and (4-nitro-2,1,3-benzoxadiazol-7-yl)amine (NBD) dyes. The new acedan and naphthalimide dyes thus allow us to obtain much brighter two-photon fluorescent images in cells and tissues than in their conventional forms. As an application of these findings, a thiol probe is synthesized based on a new naphthalimide dye, which shows greatly enhanced fluorescence from the widely used N,N-dimethyl analogue. The results disclosed here provide essential guidelines for the development of efficient dipolardyes and fluorescence probes for studying biological systems, particularly by two-photon microscopy.14
Sustainable Net Metering Model for Diversified India
No full textAbstractWith the increase in deployment of solar PV in India, a feasible net metering policy is need of the hour. In this paper, an analysis of data has been carried out for studying the feasibility of net metering in India. It is found that simple net metering policy is unable to accommodate various categories of consumers. A new model is proposed for making net metering more scalable, feasible and financially viable in India. The simulation results of model indicate that the proposed model is able to serve varied consumers leading to a sustainable net metering model which is economically acceptable
An Investigation of the Interaction of DNA With Selected Peptides and Proteins
No full textabstract: The communication of genetic material with biomolecules has been a major interest in cancer biology research for decades. Among its different levels of involvement, DNA is known to be a target of several antitumor agents. Additionally, tissue specific interaction between macromolecules such as proteins and structurally important regions of DNA has been reported to define the onset of certain types of cancers.
Illustrated in Chapter 1 is the general history of research on the interaction of DNA and anticancer drugs, most importantly different congener of bleomycin (BLM). Additionally, several synthetic analogues of bleomycin, including the structural components and functionalities, are discussed.
Chapter 2 describes a new approach to study the double-strand DNA lesion caused by antitumor drug bleomycin. The hairpin DNA library used in this study displays numerous cleavage sites demonstrating the versatility of bleomycin interaction with DNA. Interestingly, some of those cleavage sites suggest a novel mechanism of bleomycin interaction, which has not been reported before.
Cytidine methylation has generally been found to decrease site-specific cleavage of DNA by BLM, possibly due to structural change and subsequent reduced bleomycin-mediated recognition of DNA. As illustrated in Chapter 3, three hairpin DNAs known to be strongly bound by bleomycin, and their methylated counterparts, were used to study the dynamics of bleomycin-induced degradation of DNAs in cancer cells. Interestingly, cytidine methylation on one of the DNAs has also shown a major shift in the intensity of bleomycin induced double-strand DNA cleavage pattern, which is known to be a more potent form of bleomycin induced cleavages.
DNA secondary structures are known to play important roles in gene regulation. Chapter 4 demonstrates a structural change of the BCL2 promoter element as a result of its dynamic interaction with the individual domains of hnRNP LL, which is essential to facilitate the transcription of BCL2. Furthermore, an in vitro protein synthesis technique has been employed to study the dynamic interaction between protein domains and the i-motif DNA within the promoter element. Several constructs were made involving replacement of a single amino acid with a fluorescent analogue, and these were used to study FRET between domain 1 and the i-motif, the later of which harbored a fluorescent acceptor nucleotide analogue.Dissertation/ThesisDoctoral Dissertation Chemistry 201
Hairpin DNA sequences bound strongly by bleomycin exhibit enhanced double-strand cleavage
No full textABSTRACT: Clinically used bleomycin A5 has been employed in a study of double-strand cleavage of a library of 10 hairpin DNAs originally selected on the basis of their strong binding to bleomycin. Each of the DNAs underwent double-strand cleavage at more than one site, and all of the cleavage sites were within, or in close proximity to, an eight-base-pair region of the duplex that had been randomized to create the original library. A total of 31 double-strand cleavage sites were identified on the 10 DNAs, and 14 of these sites were found to represent coupled cleavage sites, that is, events in which one of the two strands was always cleaved first, followed by the associated site on the opposite strand. Most of these coupled sites underwent cleavage by a mechanism described previously by the Povirk laboratory and afforded cleavage patterns entirely analogous to those reported. However, at least one coupled cleavage event was noted that did not conform to the pattern of those described previously. More surprisingly, 17 double-strand cleavages were found not to result from coupled double-strand cleavage, and we posit that these cleavages resulted from a new mechanism not previously described. Enhanced double-strand cleavages at these sites appear to be a consequence of the dynamic nature of the interaction of Fe·BLM A5 with the strongly bound hairpin DNAs. The antitumor agent bleomycin is the prototypic sequence-selective DNA cleaving agent. That property has been studied intensively for decades in the belief that it must form the basi
The Effects of Wide-Angle Scattering on Coherent Diffraction Imaging
No full textDe potensielle negative effektene av vidvinkel-spredning på fasegjenvinningsprosessen i koherent røntgendiffraksjonsavbildning (CDI) har blitt undersøkt ved bruk av numeriske beregninger.
CDI er avbildningsmetode som kan lage en digital, tredimensjonal kopi av en prøve fra et sett med småvinkel Fraunhofer-diffraksjonsmønster. Metoden er særlig ettertraktet da den kan finne de tredimensjonale detaljene av prøven, med en oppløsning på rundt et titalls nanometer, uten å kutte den opp. Teknikken har allerede vist at den kan bidra med nyttig informasjon på tvers av mange fagfelt, og med tidsoppløst CDI på trappene kan man se for seg en rekke nye bruksområder.
Det finnes derimot et problem med dagens fasegjenvinningsalgoritmer, og det er at de antar at all den innkommende intensiteten vil bidra til småvinkel diffraksjonsmønstrene for hver orientering av prøven. Denne antagelsen vil sannsynligvis være riktig for ikke-krystallinske prøver, som teknikken først ble utviklet for å avbilde, men for krystallinske prøver måler man derimot et sterkt signal ved vidvinkel-detektoren. Spørsmålet blir derfor hva forholdet mellom denne spredte intensiteten og den innkommende intensiteten er, og hvordan forholdet påvirker resultatene i et CDI-eksperiment. Tidligere har jeg i en prosjektoppgave vist ved bruk av numeriske simuleringer at vidvinkel-spredning kan ha en betydelig innvirkning på rekonstruksjonskvaliteten, opp til et punkt hvor fasegjenvinningsalgoritmene ikke klarte å gjenskape prøven.
I disse beregningene ble det derimot antatt en forholdsvis stor intensitetsreduksjon. Det var derfor nødvendig å undersøke om de negative effektene fortsatt ville være til stede hvis en mer realistisk fordeling av vidvinkel-spredningen ble brukt i simuleringene. For å bestemme denne fordelingen ble såkalte rocking curves av ulike simulerte aragonitt krystallitter beregnet. Dessverre klarte jeg ikke å normalisere den spredte intensiteten mhp. den innkommende strålen. Jeg fant derimot et nytt anslag på hvor stort vinkelspenn av prøveorienteringer som vil gi en målbar mengde spredning.
Ved å bruke dette nye spennet på pluss-minus 0.1 grader, som var betydelig smalere enn spennet som ble antatt i prosjektoppgaven, samt de samme intensitetsreduksjonene som i prosjektoppgaven, avtok de negative effektene betraktelig. Små forverringer i rekonstruksjonskvaliteten ble observert for de største intensitetsreduksjonene, men alle rekonstruksjonene var kvalitativt lik den originale prøven, og det var kun mindre lokale variasjoner som skilte de ulike rekonstruksjonene. Jeg anser det derfor som usannsynlig at vidvinkel-spredning har en betydelig påvirkning på fasegjenvinningsprosessen.
Selv om effektene av vidvinkel-spredning sannsynligvis er små, om merkbare i det hele tatt, må det gjennomføres ytterligere beregninger på det absolutte intensitetstapet før man kan trekke noen endelige konklusjoner. Hvis det viser seg at energitapet er på høyde med det som ga forverrede rekonstruksjonsresultater i denne masteroppgaven, dvs. fra og med 30%, bør det gjennomføres forsøk hvor man måler det nøyaktige forholdet mellom intensiteten til den innkommende og den spredte strålen for å se om forholdet virkelig kan bli så stort.The effects of wide-angle scattering on Coherent X-ray Diffraction Imaging (CDI) have been explored numerically to decide whether the intensity lost due to Bragg scattering might have a negative impact on the phase retrieval process.
CDI is a nondestructive, three-dimensional imaging technique utilising phase retrieval algorithms to digitally reconstruct an object from a set of its small-angle diffraction patterns measured in the Fraunhofer limit. The technique is routinely able to resolve features down to tens of nanometers, and with the development of in situ CDI, several new applications can be envisaged.
However, today's phase retrieval algorithms assume that all the incoming radiation will contribute to the small-angle diffraction pattern for all the orientations of the sample. This assumption is well-founded for non-crystalline samples, for which the technique initially was developed. However, for crystalline samples, there will be a measurable signal at the wide-angle detector, meaning that some of the incoming intensity has been scattered off the sample. If a sufficiently large portion of the incoming beam is scattered, the author has previously shown in a project work that these losses might have serious negative impacts on the reconstruction quality, up to a point where the applied phase retrieval algorithm could not reconstruct the examined object.
It was however necessary to assume a large amount of scattered intensity, i.e. approximately 50% of the incoming beam, to see the negative effects. Therefore, it remained to see whether the negative effects still could be seen if the intensity losses were the same as in a real CDI experiment. To decide how much of the incoming intensity is lost due to the wide-angle scattering, rocking curves of simulated aragonite crystallites, with diameters ranging from approximately 75 nm to 500 nm, have been calculated using the kinematical approximation. No absolute intensity reduction could be decided, but the range of sample orientations which gave a wide-angle signal was found, and this range was significantly narrower than what had been assumed in the previous work.
Building on the new range of plus-minus 0.1 degrees, the effects of Bragg scattering on CDI were examined anew. By calculating the diffraction pattern of a known object and reducing the intensity for some projections, the effects of the phase retrieval process were studied. A reduction in the reconstruction quality was observed given that the intensity reduction was large enough. However, the phase retrieval algorithm was able to reconstruct the sample for all the intensity reductions, and only minor deviations were observed. It is therefore unlikely that Bragg scattering will have a significant negative effect on the phase retrieval process.
However, before drawing any final conclusions, further analysis of the absolute intensity reductions must be performed. If the reductions appear to be of the order which gave a reduced reconstruction quality in this thesis, i.e. 30% or more, it would be advisable to design an experiment which could accurately measure the relation between the incoming beam and the beam scattered to the wide-angle detector
Synthesis of highly strained enediynes and dienediynes
No full textEnediynes continue to fascinate scientists working in various domains because of their structural complexity and fascinating biological mode of action. They represent a masterpiece of nature's ingenuity. Besides the warhead which is the enediyne moiety, these molecules are equipped with a locking device, a delivery system and a chemical trigger for activation. Upon triggering, the molecules become active and undergo a thermal rearrangement that was disclosed in the early 70 by Masamune and Bergman and commonly known as Bergman cyclization. The reaction is believed to precede through a diradical benzenoid species (a p-benzyne). This review describes the various strategies employed for the synthesis of highly strained enediynes and dienediynes, both naturally occurring and the designed ones
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