Britney Spears or Spear Britney

â€Å"Manufactured bands have brought us some fab solo acts in the way of Mr Keating, and Robbie. Where would the screaming girlies be with out them?† J17 magazine. The truth is as long as they aren't screaming and waving their underwear anywhere near me I don't honestly have a problem with teeny-boppers. Of course I enjoy the occasional joke about some larger than life band with a talent count of minus 50 but they don't aggravate me as much you might think. Ignorance is bliss! But if I HAD to rant about anything it would be about manufactured and their music. And so to make the rant really good I might as well exaggerate some of my views and thoughts to make me appear like a true cynic and hater of all that is pop. So I sat in my room staring at my CD collection, tossing away the couple that don't do me proud. So with my ‘Ricky Martin' and ‘Spice Girls' album on one side (carefully poised on the desk, teetering dangerously over the bin) and my ‘System Of A Down' and ‘Blink 182' on the other I sat down to write this article. OK. Ever stop to think about how much hormonally-charged energy you put into the quick quips and biting banter? Your life would be considerably more productive if you took some, what's that word again, oh that's it — action. I'm not suggesting that you incinerate some fresh teeny-boppers. There are laws against it. Yep even in that state of the US. But if you're so fed up of manufactured bands and this article awakes the rebel in you, then I say ‘Go Forth, join a band and top the charts!' OK fine maybe its not that easy but its more productive than bitchin about the manufactured lot with your mates. In this world of MTV soundbites (we are not worthy) and insanely uncreative lyrics, the manufactured band and the manufactured singer run rampant They are people who are pooled together, not because they excel musically, but because their looks and personality can be pigeon-holed to fit a â€Å"type† : cute, funny, naughty, or sexy. It's just that simple. Musical passion is generally becoming a fading art, with most people in it for nothing more than the money and the quick-fix of fame. Fame, you see, very rarely comes from the strength of the music. A few years ago, Britney Spears exploded onto the scene. Her virginal yet strangely flirty lyrics had paedophiles across the world intrigued. Here was a 16 year old girl who loved Jesus Christ, sung about ‘being hit' and claimed to be a virgin. It was all so†¦fan-bl**dy-tastic. Britney went on to sell lots of records, preach Satan's teachings and get to wear increasingly skimpy outfits in her music videos. With this much success, the clones were bound to follow. And, lo and behold, they did. Christina Aguilera was the first to jump on the pink-coated bandwagon, and one of many to ride Carson Daly's gear-stick to TRL glory. The girl could certainly sing, but she was the blondest Hispanic in history, and the most annoying anorexic this side of â€Å"Ally McBeal†. They became more and more annoying. â€Å"Is that humanly possible?† I hear you say but as I say if in doubt turn to the merry U S of A. Enter Mandy Moore. Moore was about 12 and could barely even screech well. She sang a song about missing a guy â€Å"like candy†, which is just plain sad. Nobody misses anyone like candy. I wonder what I'd miss my pin-ups like after my brains are gobbled by the undead teeny boppers. Mmmm†¦.. The manufactured craze is continuing as I write this dread-filled article. Oily men across the industry are lining their pockets and making an absolute mint from girls who dream about â€Å"cute guys† and â€Å"Dawson†. Why is it so big? Well its not because its so cutting edge. It's because girls are insecure. And popular culture capitalises on that. Girls think — maybe if I go out and buy that new lipstick, I'll fit in. Or maybe if I watch this show or listen to that music, I'll be popular. I mean, look around you now (that's right just blatantly stare at them!), every one of these girls is incredibly insecure. You can't even speak your mind anymore without stomping on somebody's feelings. You make a ‘Five' break up joke and the teeny-boppers have a fit. You make a Two Pac (deceased) joke and the Hip-Hop posse kindly raise their middle finger. And any comments of Marilyn Mansons femininity will have Satanists swarming around threatenin to send the forces of evil to your abode. In the States, songs about coming on over and getting hit in the face are all the rage. In Britain, the flavour is love. If you're ever making a boyband, be sure they sing songs about â€Å"love† and â€Å"sex†. If you're planning on making a girl group, make sure they sing songs about â€Å"love† and â€Å"sex†. Really its not that hard. The dudes on ‘Popstars' make it look so hard. However, if you plan on plucking an underage girl from school (and there are laws against it) in the hopes that you'll create the next Britney, make sure she sings songs about â€Å"genies in bottles† and being unvirginised. As I was surfin the wonderful net and followin the proverbial ‘yellow brick road' to all that is fake†¦(with a capital F ladies and gentlemen) I discovered that Britain is just as bad as the States in terms of manufactured bands. There's a deep-seated history involved in the art of making boybands. In the seventies, the Bay City Rollers were all the rage. Essentially, they were ugly Scottish dudes who wore Tartan costumes (kilt-like but not quite) and sang really badly (they have sound clips on the site†¦.sayin they sing badly is like saying ‘o the arctic is a bit chilly'). But the teenyboppers loved them, simply because the machine trained them to love them. It's like that mind-washing scene in â€Å"A Clockwork Orange†. Impressionable kids are force-fed a cocktail of bland music, and few of them have the intellectual tools or inquisitive nature, and think to themselves ‘er†¦why'. Well, it's very simple. These guys make money, and the formula is easy to reproduce. And people will buy anything if it's well-packaged. Sheep. BAAAA! Best not to think about it too much. It hurts my b r a i n! Fact is, these bands make great money for their producers, all by living up to a fallacious image. It's easy money, and while the fat cats grow obese, we're the ones who are losing out. Because when genuinely talented performers fail to find a niche in the busy marketplace, we'll be overcome with these beasts. I'll be honest, though. I like a wide range of music. Sometimes I'll be blown away (OK, hooked) by a boyband tune or maybe I'll even shock myself and buy the track†¦(id like to stress that this is not a frequent occurrence, and any tracks I do waste my money on tend to be incinerated by some Satanist folk that hang around these parts.) OK, let me be completely honest: I prefer rock/punk music to virtually any other type of music (yes, even opera). Now, I like a lot of â€Å"respected† artists as well and I think I have fairly good taste when it comes to rating music, but there's something alluring about Pop. I'm not saying the music is necessarily good, but it is very effective. I realise that it's manufactured, that it's sugary and the song lyrics are dud, but tell me you yourself haven't caught the Pop bug at some point. These songs linger in your mind, even more so than Papa Roach screaming about how much life sucks and how we should all die. Not dissin P'Roach or anything†¦Coby, Dude, You Rule! That strange mixture of superficial positivity and cynical marketing works for some. Not me, but it does for some†¦ahh an outcast yet again. But while I won't admit too vehemently that I enjoy cheesy pop ballads, I'd like to celebrate some of the manufactured â€Å"artists† here in this article – where no-one â€Å"in real life† will ever know. Our group up for discussion is†¦ Westlife, or using their pronunciation, â€Å"Westloife†. Flying without Wings Everybody's looking for a something One thing that makes it all complete You'll find it in the strangest places Places you never knew it could be Some find it in the face of their children Some find it in their lovers eyes Who can deny the joy it brings When you've found that special thing You're flying without wings This is Westlife's entry into the â€Å"we condone drug usage† halls of chart history. I know that I'm only flying without wings after ten too many beers (so that's 10 beers in total yea). It's obvious that these depraved young men are either promoting illegal substances (S club Seven wannabe's) or singing about love. Whichever way you look at it, the song is pretty damn kooky. All right, it's sweet and touching. This sucks. And to conclude†¦.o wait someone's at the door. ::Abruptly stands knocking Ricky and Spice-eys into the bin. Looks out window:: And now I've been called away by a knock at my door. And the person knocking is a God-lover telling me I need the light of God. I've been thinking†¦God is a lot like a boyband. People go on about him 24/7 and plaster his posters on their bedrooms, but has he ever written his own tracks?

Peer Evaluation Example Essay

The first speech I am going to evaluate is Jane Doe’s speech about why music is good for people and the positives effect of it. Jane started out very well by giving a personal example of using music in her own life which got the audience’s attention. I liked it when she started off with a story and example because it helped me understand what she was trying to say to the class. She then introduced her topic and stated her reasons of why everybody should have an iPod and listen to music. This was a good strategy because it was well organized and simple which helped her keep the audience’s focus. Being too complicated would have caused the class to lose sight of her argument. I enjoyed the outline of her speech because it was simple and straight to the point. Although her outline was well thought out, the way she presented her argument could have used a little work. Jane wrote out a paper to explain her arguments so that she would not miss anything important that she wanted to say. This is a good way to be organized; however, she kept her head down most of the time and read off her paper word-by-word. This affected her voice which made her sound ‘monotone’. Also, an important thing about giving speeches and attracting the audience’s attention is to looking at the audience, making contact with them like you are speaking directly to them. I did not feel as if she had any contact with anyone since she was reading from her paper. I think if she would have had more eye contact, the audience would have been more interested and accepted her arguments. Another thing that affected her speech presentation was that she was very quiet and it was difficult to hear her. It did not seem like she was very passionate about her topic because she stayed at one level with her tone and her dynamics throughout the speech did not seem to change. In other words, she could have used more vocal variety and projection. Overall I think Jane picked a great topic that everybody could relate to and she used great points to explain her stance. However, I think if she would have been more excited about her topic and had contact with the audience, the speech would have been even better.

Accounting Theory and Development Essay Example for Free

Accounting Theory and Development Essay ? The methodology is often be â€Å"going from the general to the specific† as the research must develop a logical structure for accomplishing the objective then, which based on the definition and assumptions. The validity of any theory developed through this process is highly dependent upon the ability of the researcher to correctly identify and relate the various components of the accounting process in a logical manner. Induction is a method of reasoning by which a general law or principle is inferred from observed particular instances. Inductive approach emphasis making observations and drawing conclusions from it and is often be â€Å" going from specific to general, because the research generalizes about the universe on the basis of limited observations of specific situations. The inductivist is to draw theoretical and abstract conclusion from rationalizations of accounting practice. Applied to the accounting, the inductive approach begins with observations about the financial information of business enterprises and proceeds to construct generalizations and principles of accounting from those observations on the basis of recurring relationship. Reading 1. 2 – Accounting theory and development Accounting Theory Construction with Inductive and deductive approach Normative theory vs. Positive theory Normative theory attempts to justify what ought to be, rather than what is. The major criticism of normative theories is that they are based on value judgments. Positive (Descriptive) theories attempt to find relationships that actually exist. Deductive systems are normative and inductive systems attempt to be descriptive. The deductive method is basically a closed, non-empirical system. Theory verification Theory verification or validation is an integral part of theory construction. According to Popper, the testing of deductive theories could be carried out along four lines. There is the testing of the theory by way of empirical applications of conclusion, which can be derived from. This step is necessary to determine how the theory stands up to the demand of practice. If its predictions are acceptable, the theory is said to be verified otherwise, the theory is said to be falsified. Aspects of theories, their construction and verification Figure 2 Distinguishing features Accounting Theory and Development. (2018, Nov 13).

Economic Globalisation and Developing Nations Essay

Economic Globalisation and Developing Nations - Essay Example The goal within evolution, or what animals see as "good," is the ability to survive and promulgate their genetic code. What economists see as "good," within the world of finance is for wealth to accumulate, for products and services to increase in value and for all to profit and live happily ever after. This is the goal of financial evolution. It sounds so very, very simple, doesn't it Ah, but there is a catch. Given human tendencies, it is impossible for anybody to really have "enough." By its very nature, wealth is not a matter of what one has, but rather what one has in comparison to what everyone else has. We really don't want to have enough. Enough does not exist. We want to have more. This notion is fairly across the board for all cultures. Further, the animal kingdom is equal to the economic world concerning the degree of competition that is involved. However, over time, the competitors have less and less of an advantage over one another, and the playing field is leveled somewhat. Should one introduce a foreign element that has an unfair advantage-an animal with no natural predators and an unlimited food source, for example- soon the delicate balance of power between species is torn asunder. Similarly, such an idea can be presented regarding financial globalisation. Financial globalisation is nothing new. ... Enabling framework of financial globalization essentially includes liberalization and deregulation of the domestic financial sector as well as liberalisation of the capital account. As economies progressively integrate globally, pari passu the financial structures of markets and the world of finance change. Financial globalisation cannot be considered a novel phenomenon. Trans-country capital movements are centuries old." (Das, "Globalization in the World of Finance") Arguably, the very first European pioneer into the area of global finance is Jakob Fugger, son of a wealthy, self-made merchant of textiles. Jakob Fugger used his toehold in the textile industry to expand into finance, with trade posts that stretched from the Mediterranean to the Baltic. (familybusiness.com) Later, the rest of Europe caught on, and The Royal Exchange was created in London, providing a center for English financiers to trade both locally and internationally. By the nineteenth century, it became fairly evident that money in the form of paper currency had much less stability in terms of its trading power against foreign currency. The gold standard was therefore established, the reasoning behind it being that gold was much less likely to fluctuate in value; notes were redeemable for gold, both within a country's borders and internationally. This was intended to act as a guarantee that paper currency could be used anywhere, with a fairly similar value, provided these same countries both agreed to the gold standard and operated under it. (This was prefaced by the Bank Charter Act of 1844, under which the Bank of England declared itself the only legitimate source from which paper money was to be issued.) This standard is no longer used,

Proof reading Essay Example | Topics and Well Written Essays - 500 words

Proof reading - Essay Example The system I developed is more suitable for hot-dry climate area. Now I am looking forward to expanding my experience by getting relevant employment.   I have completed two years job contract as a project engineer for Knowledge Transfer Partner (KTP) Association; this was a joint program between Cooper Technology and University of Nottingham. I have handled a project with a budget of ?200,000, which entailed designing and manufacturing of a new unbound material tester which called Precision Unbound Material Analyzer (PUMA). I carried out this project by myself; starting from market awareness, project management, designing and manufacturing of the product to testing the product, promotion and selling of the product. My educational background is in engineering only, however with the help of my KTP job I have had the opportunity to learn management as well. This opportunity was provided by KTP when they enrolled me in a number of training courses including those for project management , marketing, finance and leadership, software package training course, etc. I have had the opportunity to learn the process to request the UK Patent for the PUMA. Currently, the UK Patent Application No. of the PUMA is 1014471.5.

The Notion of A Living Constitution Essay Example | Topics and Well Written Essays - 500 words

The Notion of A Living Constitution - Essay Example The clear understanding or meaning of the word may not be contextual to the current situation in one approach thereby creating a conflict of interest. Substitution of some of the value of the living constitution that may be derived from the framers’ language and intents is not argued in many words to create the contextual meaning. Rather it is argued on few words which create a wide opening in the textual approach of interpretation. The living approach demands the understanding and the concept of the common people with the present contextual understanding which varies widely depending on the present environment from the original one (Rehnquist, 2010). Social problem may be addressed by the federal judiciary of nonelected members simply because branches of government are unable to come to a precise conclusion of the matter. This arises in the understanding of framed constitutional words in the textual approach. Therefore the living approach is required through â€Å"the voice and conscience of contemporary society† under the judges. The interpretation has to be done with the basic understanding of the ultimate source of authority that is the people and not the Supreme Court or government. Constitution being not a one worded document that is specific, the couched general phraseology cannot be placed into the textual approach without reference to the historical understanding and applications. This application brings in a foreign environment to the literal present environment hence results to an interpretation that favors government, state or congress and not the people. Textual approach gives wider room for opinion differences that are honest over the meaning of general constitutional phrases. The living constitutional concept requires justice decision in case of arising questions on the general phrases in relation to

Importance of skin moisturizers Essay Example | Topics and Well Written Essays - 1250 words

Importance of skin moisturizers - Essay Example It includes assuring an optimal functioning of the vital organs to caring about the body parts that were conveniently ignored just a couple of decades ago. Human skin is one such body organ that has found a new found respect and focus in the last few decades and it goes without saying that skin moisturizers are one such health aid, which immensely add to the human sense of well being by assuring the much needed proper skin care. Perhaps most of the people don’t know that skin tends to be the largest human organ. In an average human adult, the skin comprises of a total area of about 1.5 to 2.0 square meters (Baumann 17). No other organ happens to be so large and extensive. Besides, skin performs many important functions in the human body. It is the body’s first line of defense against any damage caused by pathogens and the external environment. The nerve endings embedded in the skin are responsible for registering sensations of heat and touch. The blood vessels and sweat glands in the skin are responsible for heat regulation. Skin also helps store fats, water and aids the synthesis of vitamin D. It facilitates the excretion of body wastes like sweat and urea. It also helps in the absorption of many vital elements and health aids like ointments and medicines. It prevents the loss of vital nutrients from the body. Last but not the least; skin is an indispensible component of body aesthetics and c ommunication. Considering the multifarious relevance of skin in the human health, there is no denying the fact that skin care ought to command a pivotal place in human well being and health. Once it is agreed upon that skin care is important, one needs to delve upon as to what constitutes the salient features of skin care. Good nutrition is the first step in assuring a healthy and robust skin. Not to mention that high stress levels do negatively impact skin as other organs. So, adequate rest and relaxation are of

The Burgelman Case Study Essay Example | Topics and Well Written Essays - 1000 words

The Burgelman Case Study - Essay Example Surveys and exploratory studies are examples of descriptive research designs, which are more quantitative than qualitative and have more aspects of this type of theory. Quantitative studies tend to rely on hard data and statistics that can provide generalizable results about a population, whereas qualitative studies could be more of a case example or subjective viewpoint. Bergemann's case study states having a qualitative method in place: â€Å"A qualitative method was chosen as the best way to arrive at an encompassing view of ICV project development has a ten- to twelve-yeartime horizon (Biggadike, 1979), and a truly longitudinal study was thus beyond the available resources† (Burgelmann, 2009). In terms of statistics, the single case study is not very representative. Another disadvantage in reference to flexible designs could be their lack of scientific credibility when compared to fixed designs using inferential statistics, which Burgelmann addresses explicitly as a possib le drawback. Of course, it is fitting at this level of research for authors to be forward with possible limitations of the study; however, this admission does not make the study more statistically or empirically viable, just because of this admission.   #2 Since this is a qualitative study, it tends to focus more on theory forming, rather than theory testing.

The low-cost Airline Ryanair Essay Example | Topics and Well Written Essays - 750 words

The low-cost Airline Ryanair - Essay Example In any industry, several forces in conjunction form the success or failure of any firm that operates in it. These forces include those factors, which affect a business from outside its immediate environment, which is the macro environment. Porter’s Five Forces Model makes it easier for one to analyze these various factors in relation to any industry, as it outlines the basic factors, which one should observe to understand a company’s chances for success and market attractiveness. Ryanair, an airline in the transportation industry, forms an interesting choice of company which one can analyze using this model. To start, one needs to have a brief idea about Ryanair. It is a low-cost airline, which is the second largest airline in Europe, and belongs to the transportation sector of the tourism industry. The reason it forms such an interesting choice is that it is one of the largest in the world in terms of international passenger number and the second largest (Amason, 2010) in terms of passenger number. This success of the airline is intriguing, and leads one to wonder whether the success can be explained by the recent deregulations that happened in the aviation industry in Europe in 1997 or whether it is due to the low-cost business model that Ryanair operates under. Either way, it is an intriguing case for anyone interested in studying companies from a business management aspect (Amason, 2010). Porter’s Five Forces Model includes firms, which study the competitive environment of the firm. ... In relation to the competition it faces from other firms, Ryanair competes against several rivals. These include another low-cost Irish airline Aer Lingus, which came into direct competition with Ryanair ever since it switched to a low-cost business model. Other competitors include MyTravelLite and Go (Hoffman, 2007), both of which were at a point in time, in competition with Ryanair, although it was not long before Ryanair was able to beat them due to its low cost strategies. Aer Arann and CityJet are some more examples of competition, which Ryanair faces, while EasyJet is this airline’s largest competitor (Hoffman, 2007). The airline industry is one where no one firm can hold monopoly, because each successful firm has different strategies and different core competencies, which earn them a fair share of market share. In addition, it is a large industry, which automatically means there will be several competitors. As for the power of customers, it is not a strong force in this particular industry. The customers are more or less price takers in the airline industry, as there are dozens of airlines, which cater to customers belonging to each price category. While it is true that these airlines use low-cost strategies due to the customers only, it does not mean that the customers have the power to influence the rates of fares of these airlines. Similarly, the power of suppliers is also not very relevant to this industry. The start-up costs as well as any materials and services the airlines use for their planes or operations make a large proportion of their costs. However, their magnitude is what influences the airline’s decisions, not the wishes or demands of the suppliers, which makes the power

Jacqueline Kennedy Onassis Essay Example for Free

Jacqueline Kennedy Onassis Essay â€Å"Many people called her the American Queen. † (Mattern) Jacqueline Kennedy Onassis was by far the most iconic fashion figure of the 1960’s. She shaped fashion especially for women in her own time, but more than just being a significant influence on how women dressed in the 1960’s her style has transcended the boundaries of time and the modern women even looks to her on matters of fashion. Jackie, as she was fondly called, did not remain as a potent fashion figure only in the 60’s but continued to shape the fashion industry worldwide, even after her days of glory as the First Lady of America. The influence of Jackies style can still be seen now on the catwalks, every designer shows a look inspired by her. She was very classic, but with a modern twist. (Reuters) Nevertheless, it would be presumptuous to just make this conclusion without looking at how this lady was able to change the way women dress. Jackie was highly instrumental in the fashion scene of the 60’s as well as in modern eras because she instilled a sense of courage into fashion, she equated fashion with personality, and she pioneered the concept that simplicity was in fact stylish, elegant and fashionable. The baroque and almost boisterous fashion sense of women in the 60’s were a basis for Jackie’s influence in making women bolder and more unique in their choice of clothing. Note that during this period discreet strain between American and French relations, and despite of this, Jackie rose above the rest and refused to be influenced by this. Oleg Cassini, Jackie’s designer, â€Å"created her wardrobe for the 1961 inauguration. Jackie told him she wanted to dress as if Jack were President of France. Jacobs) While this remark may be considered as un-patriotic at that time, it simply shows how Jackie chose to ignore political and social constructs in delivering her message of fashion. She was also known for quite radical fashion decisions such as when she â€Å"kicked off a craze for the one-shoulder dress, encouraged women to ditch their high, pointy heels, endorsed chain belts, oversized sunglasses, and YSL midi skirts. † (Mathai) All these changes in the way women dress all speak of the boldness Jackie which was what women of the time wanted to acquire. Fashion was almost secondary to women of this period; what were more important to them were the decisiveness, innovation, and courage that riddled decision making among the feminine gender. For instance, â€Å"Jackie had been forced by her public role into wearing hats, as called for by formal protocol†¦She made fashion history, however, by choosing to wear the hat tipped to the back of her head rather than straight on top. (CAVF) This is an illustration of how Jackie set the example for women to remain undaunted by male dominated policies and so take flight; she did this in a language that all women would easily understand – fashion. Jackie was never one to follow what was ‘in’ during the moment because she believed in the value of individualism and unique style. Her penchant for seeking what was most comfortable to her was the best indication that she was not about to sacrifice her comfort for trendiness, and this worked for her as a result. â€Å"Trends and fads never dictated Jackies fashion choices†¦she had the courage of her convictions to reject it if she didnt feel it was right for her. Flaherty) Her courage in fashion rubbed off on all women of the time and even on the modern woman and to this day, people will remember how she breathed new life into the American fashion scene even making the industry more competitive when compared to its global rivals. â€Å"At that time, most high fashion clothes were made in Europe. However, the first lady decided to promote American designers. † (Mattern) Jackie also exercised her influence over women of the 60’s and on today’s fashionable female by showing that clothing was not everything and that what one wore was in fact a reflection of one’s personality. Jackie understood the power of clothing and image and used it to reflect the internationalism of the Kennedy Administration and the promise of the 1960s. † (Leight) So, Jackie always made sure that what she wore made a statement, if not about her, at least about the country she was in. Nevertheless, she also insisted that it was not really the clothing that one wore that made the person, rather, this was just the extension of the ideals and principles that a particular person stood for. As much as Jackie loved fashion, she was much more than the clothes she wore. Although appearances clearly counted, how she lived her life mattered most. † (Flaherty) Jackie was not the kind of person who would as she pleased while compromising the image of her family and of her husband’s administration. Through her many women all around the world realized how important it was for a person to use fashion as a means of conveying a message either about oneself or about the society that he/she was in, but more importantly about one’s beliefs and convictions. Jackie chose clothes that played to both her athletic sensibility and her Vassar-educated, Francophile refinement, notes Bowles. †(Tauber) This meant that Jackie was always on top of her style, that her outfit almost usually reflected not the designer, not the luxury of the attire, but the sensibilities and the principles of the wearer. This had to mean wearing clothes that were not only practical but also simple and Jackie did not destroy the concept of simplicity in the process, in fact, she even re-invented simplicity at a time when artistic expression was at its noisiest. Jackie had left her legacy on the woman of the 60’s as well as on contemporary fashion trends by making women see that simplicity can in fact be fashionable, stylish and elegant. Her passion for simplicity â€Å"took America out of the staid and conservative 1950s and into the world of classy international elegance. † (Leight) Jackie knew what it meant to make an impression and she believed that a lasting impression was possible even with the simplest white dress. She knew that she did not have to be overly verbose about her dressing styles to make people want to turn and have a second look. Her clothes were informed with an understated modern elegance, characterized by cleanliness, solid colors, and ease of movement. † (Leight) So again, one sees here that Jackie found convenience in simplicity in that other than being overly numbered, her fashion sense was fluid and responsive to the needs of the contemporary woman. Nothing went wrong with fashion when Jackie was in the limelight because her style was almost a nude expression of the feminine psyche. â€Å"Years before she became Jackie O, Kennedy was a first lady with impeccable style. (Shih) Simplicity, however, did not come without a price because appearing simple meant that she had to carefully plan her wardrobe so that she achieved the kind of impression that she wanted to get; and so for Jackie, fashion was never unintentional, it was always a conscious effort like poetry and literature; â€Å"Jackie put an enormous amount of work into appearing effortlessly elegant. † We look at her and think, How simple! â€Å"says Hubert de Givenchy†¦But it was deliberate. She was very conscious of her style, her body, her face. (Tauber) A woman of the 90’s can look at Jackie and like the woman of the 60’s still say that she was in fact right in deciding to look simple amid the fame and glory that she was in because it was this simplicity in her fashion sense that gave her authority over the world of fashion and a healthy appreciation for the elegance that came with a piece of clothing. Jackie was nevertheless quite innovative as she always believed that simplicity could be expressed in a thousand different ways, and even with this ironic contradiction, women of the 60’s were able to identify with the effortlessness of Jackie’s fashion. It is this that transcended the trends of the 60’s and began a whole new movement in contemporary dressing, now even known as Jackie O fashion. Jackie was aware that she was changing the world of fashion little by little and building a monument to the element of feminism that is almost non-existent to the opposite sex. So, to date, the world fondly recalls â€Å"the elegant simplicity of Jacqueline Kennedys style that would come to influence fashion all over the world. † (CAVF) It is not always that a woman is able to change the world by being herself; but the fact remains that Jackie sparked a revolution or more appropriately a renaissance in how women dressed in the 60’s and in the new millennia. Of course, some would say that fashion is just a small piece of the bigger picture depicting world shattering issues but how comforting it is to have someone slink back once in a while and remember that there is nothing that one does not have that one can give to the world. Making a difference means having that difference initiated within oneself and through fashion Jackie was able to make this bold and courageous statement. History will forever remember Jackie as the woman who was able to put policy into fashion; as the women who through her humility and respect for the female persona was able to take the fashion of the 60’s and the contemporary era and mold it to perfection by making women understand that fashion meant courage and conviction, that fashion was an extension of oneself, and that fashion does not need to be loud and un-moderated for it to be elegant, fashionable, and more importantly, stylish.

Synthesis of Isatin Based Caspase Inhibitors

Synthesis of Isatin Based Caspase Inhibitors DESIGN AND SYNTHESIS OF ISATIN BASED CASPASE INHIBITORS FOR RUTHENIUM CAGING APPLICATIONS KASUN CHINTHAKA RATNAYAKE ABSTRACT Apoptosis is the energy dependent programmed cell death. Improper function of apoptosis could lead to diseases such as cancers, strokes, alziemer’s disease. Caspases are the enzymes involved in the later stage of this process. Peptidyl and non-peptidyl caspase inhibitors have been synthesized recently. One of these non-peptidyl compound classes which consist of pyrrolidinyl-5-sulfo isatins have showed a greater potency against executioner caspases, caspase-3 and -7. According to literature and for further caging studies, two compounds were designed, synthesized and evaluated their inhibition against caspase-3 in this study. The analog in which its N-1 position alkylated with a 4-methyl pyridine moiety (7) showed a higher inhibition than the analog in which its N-1 alkylated with cyanoethyl group (8). Thus, the compound  7  was selected for further caging studies with ruthenium. Chapter 1: Introduction 1.1 Apoptosis and Caspases Apoptosis is the process of programmed cell death. This is a significant cellular process which is directly co-related with embryogenesis, immune system, ageing and various diseases including cancers, stroke, myocardial infarction and neurodegenerative disorders.1 Caspases (cysteinyl dependent aspartate directed specific proteases) are the enzymes involved in the later stage of apoptosis. Caspases are divided to different classes according to their role played in the signaling cascade of apoptosis. Caspases 6, 8, 9 and 10 are involved as initiators and caspases 2, 3 and 7 are identified as executioner caspases in the signaling cascade.2The caspases 1, 4 and 5 are found to be non-active in the cell death process. 1.2 Caspase inhibition and modified isatin sulfonamides as caspase inhibitors Caspases play a significant role in both inflammation and apoptosis. Extensive researches have been conducted on caspases and their functions because they act as potential targets in drug discovery. Various inhibitors of Caspase have been made. These inhibitors could be categorized as non-peptidyl and peptidyl based compounds. A greater selectivity could be achieved when non-peptidyl inhibitors are used for different types of caspases. Isatin sulfonamides have showed inhibition on executioner caspases (caspase-3 and -7) in recent studies. In 2000, Lee and researchers reported the x-ray structure of caspase-3 with an isatin analog, 1-methyl-5-(2-phenoxymethyl-pyrrolidine-1-sulfonyl)-1h-indole-2,3-dione (a) bound to the active site of the enzyme (Figure 1).3 Modifying isatin sulfonamide analogues with pyrrolidine groups have shown significant effect on caspase inhibition.4 For example, various pyrrolidinyl-5-sulfo isatins have been shown inhibition to caspases, 3 and 7 (Figure 2). These isatin sulfonamide analogs are modified using structure activity relationships and performed these biological assays. The following isatin sulfonamides have shown to be inhibit caspase-3. The stereochemistry of substituted pyrrolidine moiety, cyclic vs acyclic ring structures and ring sizes have been examined for these inhibition studies (figure 3).5 1.3 Ruthenium complexes for caging applications Ruthenium compounds have been reported as significant candidates for caging applications. Light activation of these metal complexes has been extensively studied. Recently, neuroactive biomolecules as well as small molecular enzyme inhibitors have been reported to be caged with these ruthenium complexes. Spatial and temporal release of these caged molecules upon light activation gives insight to develop new tools that could be used to treat various diseases in biological systems. In this study Ruthenium polypyridyl compounds are used in future studies since they have been considered as excellent candidates for caging application of small molecules. Chapter 2: Results and Data 2.1 General considerations All reagents were purchased from commercial suppliers and used as received. Varian FT-NMR Mercury-400 Spectrometer was used to record all NMR spectra. IR spectra were recorded on High resolution mass spectra were recorded on.Melting points were recorded on .Enzyme inhibition assays were done on 2.2 Designing of Caspase inhibitors Recent studies show that various 5-pyrrolidinylsulfonyl isatins act as caspase-3 inhibitors. Several factors were considered in the designing process of these analogs. First, higher caspase inhibition was considered. Use of specific stereochemistry in the pyrrolidine moiety is important since S-alkoxypyrrolidine is more potent than its R-stereoisomer which shows almost no potency against caspase-3. It is reported that methoxymethyl pyrrolidinyl analogs show higher cell toxicity than phenoxymethyl pyrrolidines, thus methoxymethyl pyrrolidine analogs were chosen for further studies. When considering the Ruthenium caging studies, the chosen analogs should contain a group which has a higher binding affinitiy towards Ruthenium. Therefore, pyridyl and cyano groups were selected to incorporate in these isatin sulfonamide analogs. These groups are chosen to be attached to N-1 position of isatin sulfonamide analog. It has been reported that higher alkyl chain on N-1 position could increase th e inhibition. Therefore 4-methylpyridine and cyanoethyl groups were selected to attach on N-1 position of these analogs and compounds 7 and 8 are designed (Figure 3). 2.3 Synthesis of designed isatin sulfonamide analogs The designed analogs were synthesized using literature and modified procedures5, 6, 7 (Scheme 1). The compound 5 was synthesized as the precursor for the final analogs 7 and 8. The compounds 7 and 8 were synthesized using modified and optimized procedures (Scheme 2 and Scheme 3). 2.4 Enzyme Inhibition Assay Caspase-3 inhibition assay was performed for compounds 6 and 7 according to the literature procedure.2 Compound 6 was found to be more potent (IC50 = .. ) of than compound 7 (IC50 = ..). Thus, compound 6 was selected for further caging studies with Ruthenium bipyridine complexes. 2.5 Experimental 2.5.1 Sodium 2,3-dioxoindoline-5-sulfonate (1) Isatin (10 g, 0.068 mol) was added carefully to a stirred solution of 20% SO3/H2SO4 (20 mL) at -15 °C. The reaction mixture was gently warmed up to 70  °C with stirring. Reaction mixture was stirred at 70  °C for another 15-20 min. The reaction mixture was carefully poured on to crushed ice and let ice to melt and then 20% NaOH was added to the reaction mixture (pH=7). The flask containing reaction mixture was kept in an ice bath to induce precipitation of the desired product. The solid was filtered, washed with ice-cold water and dried to give red-orange crystalline solid. The 1H-NMR data was compared and matched with literature data. Yield: 14.48 g (0.051 mol. 75%) 2.5.2 2,3-dioxoindoline-5-sulfonyl chloride (2) Sodium 2,3-dioxoindoline-5-sulfonate dihydrate (2 g, 70 mmol) was dissolved in tetramethylene sulfone (10 mL) under Argon environment at 60-70  °C and phosphorus oxychloride (3.36 mL, ) was added dropwise. The reaction mixture was stirred for 3 h. The reaction was cooled to room temperature and kept in an ice bath. Then ice-cold water was added to the reaction mixture carefully. A precipitate was formed, filtered, washed with ice-cold water and dried used without further purification. The desired compound is yielded as a bright yellow solid. The 1H-NMR data was compared and matched with literature data. Yield: 1.58 g (64 mmol, 92%). 2.5.3 Tert-butyl (S)-2-(methoxymethyl)pyrrolidine-1-carboxylate (3) To a solution of N-Boc-L-prolinol (5.0 g, 25 mmol) in THF (25 mL) at -78  °C, Sodium hydride (60% in mineral oil) (960 mg, 40.0 mmol) was added and stirred for 10 min. Then methyl iodide (2.65 mL, 42.5 mmol) was added dropwise and reaction was stirred for 4h at -78  °C and additional 16 h at RT. Then NH4Cl was added until all H2 evolved and EtOAc was added. The organic layer was washed with water and sat. NaCl, dried over anhyd. Na2SO4 and concentrated to give a pale yellow oil and purified with petroleum ether: ether (9:1) to give a colorless oil. The 1H-NMR data was compared and matched with literature data. Yield: 4.986 g (23.16 mmol, 92%) 2.5.4 (S)-2-(methoxymethyl)pyrrolidine (4) To a solution of tert-butyl (S)-2-(methoxymethyl)pyrrolidine-1-carboxylate (4.98 g, 23.07 mmol) in DCM (40 mL), TFA (25 mL) was added dropwise over 30 min at 0  °C. The reaction was warmed to RT and stirred for additional 1.5 h. The reaction mixture was added to 150 mL of 10% NaOH solution and extracted with DCM (50 mL x 3), dried over anhyd. Na2SO4 and concentrated to obtain a pale yellow oil. The 1H-NMR data was compared and matched with literature data. Yield: 2.657 g (23.07 mmol, 100%) 2.5.5 (S)-5-((2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)indoline-2,3-dione (5) The compound (1) was synthesized according to procedure reported by Harvan et al.1 To a stirred solution of 2,3-dioxoindoline-5-sulfonyl chloride (2 g, 8.153 mmol) in 1:1 THF/CHCl3 (80 mL), a solution of (S)-2-(methoxymethyl)pyrrolidine (1.033 g, 8.968 mmol) and DIPEA (2.84 mL, 16.310 mmol) in CHCl3 was added dropwise under Argon environment and stirred for 1 h at 0  °C. The reaction stirred for additional 1 h at RT. The reaction mixture was concentrated and purified using 1:1 EtOAc:Petroleum ether and isolated as bright yellow crystals. The 1H-NMR data was compared and matched with literature data. Yield: 1.185 g (36.53 mmol, 45%) 2.5.6 4-(bromomethyl)pyridine hydrobromide salt (6) Pyridin-4-ylmethanol (5.0 g) was dissolved in 48% HBr (50 mL) and refluxed for 24 h. (Reaction was monitored for completion using TLC). The reaction mixture was concentrated in vacuo until a thick gum appeared and treated with absolute Ethanol at 5  °C. The white crystalline solid obtained was filtered and washed thoroughly with cold absolute Ethanol. The 1H-NMR data was compared and matched with literature data. Yield: 4.74 g (18.7 mmol, 41%) 2.5.7 (S)-5-((2-(methoxymethyl) pyrrolidin-1-yl)sulfonyl)-1-(pyridin-4-ylmethyl)indoline-2,3-dione (7) To a stirred solution of (S)-5-((2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)indoline-2,3-dione (1) (168 mg, 0.518 mmol) in DMF, 60% NaH in mineral oil (51.8 mg, 1.295 mmol) was added at 0  °C under Argon atmosphere. The reaction was stirred for 30 min. Then a solution of 4-Bromomethyl pyridine (130.6 mg, 0.518 mmol) in DMF was added dropwise and stirred for 4 h at 0  °C. The reaction was diluted with EtOAc and washed with saturated NaCl (20 mLÃâ€"3). The organic layer was dried over anhyd. Na2SO4 and concentrated in vacuo. The crude product was crystallized using EtOAc:Hexanes and isolated as a yellow solid. Yield: 85.8 mg (0.207 mmol, 40%) mp = 172-174  °C, 1H NMR (400 MHz, CDCl3): ÃŽ ´ 8.64 (d, 2H, J = 6 Hz), 8.11 (s, 1H), 8.03 (d, 1H, J = 8.4 Hz), 7.27 (d, 2H, J = 3.6 Hz), 6.83 (d, 1H, J = 8.4 Hz), 4.99 (s, 2H), 3.74 (m, 1H), 3.55 (dd, 1H, J = 9.6 Hz, 4 Hz), 1H NMR (400 MHz, DMSO): ÃŽ ´ 8.51 (d, 2H, J = ..Hz), 8.01 (d, 1H, J = Hz), 7.84 (s, 1H), 7.46 (d, 2H, J = Hz), 7.07 (d, 1H, J = Hz), 4.99 (s, 2H), 3.67 (m, 1H), 3.41 (dd, 1H), 3.24 (s, 3H), 3.06 (m, 1H), 1.73 (m, 2H), 1.48 (m, 2H) 13C NMR (100 MHz, CDCl3): ÃŽ ´ 183.2, 160.8, 152.5, 150.5, 137.5, 134.9, 124.9, 122.1, 117.5, 110.8, 74.8, 59.2, 59.1, 49.3, 43.3, 28.8, 24.1 IR (ÃŽ ½max) (KBr): 3443, 2929, 2361, 2342, 1747, 1616, 1478, 1450, 1417, 1365, 1344, 1330, 1199, 1181, 1154, 1130, 1115, 1070, 1041, 994 MS (HRMS): 432 (M+Na+MeOH)+, 400 (M+Na)+ 2.5.8 (S)-3-(5-((2-(methoxymethyl) pyrrolidin-1-yl)sulfonyl)-2,3-dioxoindolin-1-yl)propanenitrile (8) To a stirred solution of (S)-5-((2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)indoline-2,3-dione (1) (200 mg, 0.620 mmol) in DMF (10 mL), KOH (4 mg, 0.062 mmol) was added and stirred for 10 min at RT. Then acrylonitrile (45  µL, 0.680 mmol) was added dropwise and stirred for 2 days under Argon environment at RT. The reaction mixture was added to H2O (30 mL), and extracted with EtOAc (20 mLÃâ€"3). The combined organic layer was washed with 10% NaCl (20 mLÃâ€"3). The organic layer was dried over anhyd. Na2SO4 and concentrated in vacuo. The crude product was purified with CH2Cl2: MeOH (99:1) to afford yellowish-orange solid. Yield: 63.6 mg (0.169 mmol, 27%) mp = 134-138  °C, 1H NMR (400 MHz, CDCl3): ÃŽ ´ 8.15 (d,1H,J=Hz), 8.11(d,1H, J=.Hz), 7.18(d,1H,J=.Hz), 4.10 (t,2H,J=), 3.77(m,2H), 3.57(dd, 2H, J= Hz), 3.43(m,H), 3.40 (s,..H), 3.38(d, H, J=Hz), 3.36 (s,3H,), 3.14(m,H), 2.98,2.96,2.94, 2.86(t,2H, J=Hz), 2.04(s,..H), 1.92(m,H), 1.69 (m,.H), 1.55(s,H) 13C NMR (100 MHz, CDCl3): ÃŽ ´ 180.8, 157.8, 152.3, 137.6, 134.7, 124.9, 117.5, 116.8, 110.4, 74.8, 59.3, 59.1, 49.4, 36.8, 28.8, 24.1, 16.7 IR (ÃŽ ½max) (KBr): 3422, 2921, 2852, 2361, 2251, 1742, 1717, 1647, 1612, 1558, 1542, 1508, 1475, 1456, 1418, 1373, 1364, 1340, 1314, 1268, 1234, 1195, 1175, 1153, 1133, 1063, 1046, 991, 970, 905, 877 MS (HRMS): 470 (M+Na+MeOH)+ Chapter 3: Conclusion and Future directions The compounds 7 and 8 were both potent for caspase-3 but compound 7 show more inhibition than that of compound 8. Thus compound 7 was selected for further ruthenium caging studies. The caged ruthenium complexes could be subjected for light activation experiments where IC50 of this complex under light and dark conditions could be determined and the dark to light inhibition ratio could be explored. Then cell toxicity studies could be done in order to explore the ability of these ruthenium complexes for prevention of apoptosis in biological systems. These combined experiments and results could lead to the final goal of this research study which is the development of novel tools to prevent apoptosis in biological systems.