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35-545: NNK can be produced by standard methods of organic synthesis . NNK is both found in cured tobacco and is produced during its burning (pyrolysis). The amount of NNK delivered in cigarette smoke ranged from 30 to 280 ng/cigarette in one study and 12 to 110 ng/cigarette in another. Sun-cured tobaccos (a.k.a. "Oriental") contain very little NNK and other TSNAs due to low-nitrate soil, lack of nitrate fertilizer, and sun-curing. Flue-cured tobacco (a.k.a. "Virginia" tobacco), especially when using an open flame, contains most of

70-429: A Grignard reagent , and carboxylation . In the synthesis of Ibuprofen proposed by Kjonass et al ., p -isobutylacetophenone, the starting material, is reduced with sodium borohydride (NaBH 4 ) to form an alcohol functional group . The resulting intermediate is acidified with HCl to create a chlorine group. The chlorine group is then reacted with magnesium turnings to form a Grignard reagent. This Grignard

105-401: A mutagen , which means it causes polymorphisms in the human genome. Studies showed that NNK induced gene polymorphisms in cells that involve in cell growth, proliferation and differentiation. There are multiple NNK dependent routes that involve cell proliferation. One example is the cell route that coordinates the downregulation of retinoic acid receptor beta (RAR-β). Studies showed that with

140-590: A retrosynthetic framework , a type of synthetic design developed by Elias James Corey , for which he won the Nobel Prize in Chemistry in 1990. In this approach, the synthesis is planned backwards from the product, obliging to standard chemical rules. Each step breaks down the parent structure into achievable components, which are shown via the use of graphical schemes with retrosynthetic arrows (drawn as ⇒, which in effect, means "is made from"). Retrosynthesis allows for

175-669: A 100 mg/kg dose of NNK, several point mutations were formed in the RAR-β gene, inducing tumorigenesis in the lungs. Other genes affected by NNK include sulfotransferase 1A1 (SULT1A1), transforming growth factor beta (TGF-β), and angiotensin II (AT2). NNK plays a very important role in gene silencing , modification, and functional disruption which induce carcinogenesis . Chemical compounds derived from cruciferous vegetables and EGCG inhibit lung tumorigenesis by NNK in animal models . Whether these effects have any relevance to human health

210-459: A given compound, and comes in many forms. Examples of common characterization methods include: nuclear magnetic resonance (NMR), mass spectrometry , Fourier-transform infrared spectroscopy (FTIR), and melting point analysis. Each of these techniques allow for a chemist to obtain structural information about a newly synthesized organic compound. Depending on the nature of the product, the characterization method used can vary. Organic synthesis

245-505: A much more diverse choice of enantiomerically pure materials. Using techniques developed by Robert B. Woodward paired with advancements in synthetic methodology, chemists have been able synthesize stereochemically selective complex molecules without racemization. Stereocontrol provides the target molecules to be synthesized as pure enantiomers (i.e., without need for resolution). Such techniques are referred to as stereoselective synthesis . Many synthetic procedures are developed from

280-426: A new synthetic route can be developed and tested. For practical, industrial applications additional reaction conditions must be considered to include the safety of both the researchers and the environment, as well as product purity. Organic Synthesis requires many steps to separate and purify products. Depending on the chemical state of the product to be isolated, different techniques are required. For liquid products,

315-416: A racemic mixture. Early examples include stereoselective hydrogenations (e.g., as reported by William Knowles and Ryōji Noyori ) and functional group modifications such as the asymmetric epoxidation by Barry Sharpless ; for these advancements in stereochemical preference, these chemists were awarded the Nobel Prize in Chemistry in 2001. Such preferential stereochemical reactions give chemists

350-417: A reaction mixture using filtration techniques. To obtain solid products a vacuum filtration apparatus can be used. Vacuum filtration uses suction to pull liquid through a Büchner funnel equipped with filter paper, which catches the desired solid product. This process removes any unwanted solution in the reaction mixture by pulling it into the filtration flask and leaving the desired product to collect on

385-442: A very common separation technique is liquid–liquid extraction and for solid products, filtration (gravity or vacuum) can be used. Liquid–liquid extraction uses the density and polarity of the product and solvents to perform a separation. Based on the concept of "like-dissolves-like", non-polar compounds are more soluble in non-polar solvents, and polar compounds are more soluble in polar solvents. By using this concept,

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420-421: Is 3'-phosphoadenosine-5'-phosphosulfate (PAPS). In the case of alcohol as acceptor, the product is a sulfate ( R−OSO − 3 ): whereas an amine leads to a sulfamate ( R−NH−SO − 3 ): Both reactive groups for a sulfonation via sulfotransferases may be part of a protein , lipid , carbohydrate or steroid . The following are examples of sulfotransferases: This biochemistry article

455-404: Is also an important contributor to NNK-induced cellular transformations and metastasis. This process ensures the proliferation and survival of tumorigenic cells. The ERK1/2 and Akt pathways show consequential changes in levels of protein expression as a result of NNK-activation in the cells, but further research is needed to fully understand the mechanism of NNK-activated pathways. NNK is known as

490-467: Is an important chemical process that is integral to many scientific fields. Examples of fields beyond chemistry that require organic synthesis include the medical industry, pharmaceutical industry, and many more. Organic processes allow for the industrial-scale creation of pharmaceutical products. An example of such a synthesis is Ibuprofen . Ibuprofen can be synthesized from a series of reactions including: reduction , acidification , formation of

525-513: Is carboxylated and the resulting product is worked up to synthesize ibuprofen. This synthetic route is just one of many medically and industrially relevant reactions that have been created, and continued to be used. Sulfotransferase In biochemistry , sulfotransferases ( SULTs ) are transferase enzymes that catalyze the transfer of a sulfo group ( R−SO − 3 ) from a donor molecule to an acceptor alcohol ( R−OH ) or amine ( R−NH 2 ). The most common sulfo group donor

560-412: Is complete; the chemical compounds made in each step are called synthetic intermediates . Most often, each step in a synthesis is a separate reaction taking place to modify the starting materials. For more complex molecules, a convergent synthetic approach may be better suited. This type of reaction scheme involves the individual preparations of several key intermediates, which are then combined to form

595-438: Is important to understand the chemical reactions , reagents , and conditions required in each step to guarantee successful product formation. When determining optimal reaction conditions for a given synthesis, the goal is to produce an adequate yield of pure product with as few steps as possible. When deciding conditions for a reaction, the literature can offer examples of previous reaction conditions that can be repeated, or

630-408: Is necessary to be familiar with the methodology, techniques, and applications of the subject. A total synthesis refers to the complete chemical synthesis of molecules from simple, natural precursors . Total synthesis is accomplished either via a linear or convergent approach. In a linear synthesis —often adequate for simple structures—several steps are performed sequentially until the molecule

665-599: Is unknown and is a subject of ongoing research. Organic synthesis Organic synthesis is a branch of chemical synthesis concerned with the construction of organic compounds . Organic compounds are molecules consisting of combinations of covalently-linked hydrogen , carbon , oxygen , and nitrogen atoms. Within the general subject of organic synthesis, there are many different types of synthetic routes that can be completed including total synthesis , stereoselective synthesis , automated synthesis , and many more. Additionally, in understanding organic synthesis it

700-475: The CYP family NNK can also be activated by metabolic genes, like myeloperoxidase (MPO) and epoxide hydrolase (EPHX1). NNK can be activated by two different routes, the oxidative path and the reductive path. In the oxidative metabolism NNK undergoes an α-hydroxylation catalyzed by cytochrome P450 . This reaction can be done by two pathways namely by α-methylhydroxylation or by α-methylenehydroxylation. Both pathways produce

735-581: The NNK in American blended tobaccos although Marlboro's "virginia blend" had the lowest levels of NNK per nicotine out of many tested with the exception of Natural American Spirit. e-Cigarette do not convert nicotine to NNK due to their lower operating temperatures. The amount of NNK delivered by e-cigarettes reaches 2.8 ng per 15 puffs (approximately 1 cigarette). NNK was found in 89% of Korean e-cigarette liquids . Concentrations range from 0.22 to 9.84 μg/L. For

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770-457: The carcinogenic metabolized isoform of NNK, NNAL. In the reductive metabolism NNK undergoes either a carbonyl reduction or a pyridine N-oxidation, both producing NNAL. NNAL can be detoxified by glucuronidation producing a non-carcinogenic compounds known as NNAL-Glucs. The glucuronidation can take place on the oxygen next to the ring (NNAL-O-Gluc), or it takes place on the nitrogen inside the ring(NNAL-N-Gluc). The NNAL-Glucs are then excreted by

805-458: The desired product. Robert Burns Woodward , who received the 1965 Nobel Prize for Chemistry for several total syntheses including his synthesis of strychnine , is regarded as the grandfather of modern organic synthesis. Some latter-day examples of syntheses include Wender's , Holton's , Nicolaou's , and Danishefsky's total syntheses of the anti-cancer drug paclitaxel (trade name Taxol). Before beginning any organic synthesis, it

840-457: The filter paper. Liquid products can also be separated from solids by using gravity filtration . In this separatory method, filter paper is folded into a funnel and placed on top of a reaction flask. The reaction mixture is then poured through the filter paper , at a rate such that the total volume of liquid in the funnel does not exceed the volume of the funnel. This method allows for the product to be separated from other reaction components by

875-530: The force of gravity, instead of a vacuum. Most complex natural products are chiral, and the bioactivity of chiral molecules varies with the enantiomer . Some total syntheses target racemic mixtures, which are mixtures of both possible enantiomers . A single enantiomer can then be selected via enantiomeric resolution .   As chemistry has developed methods of stereoselective catalysis and kinetic resolution have been introduced whereby reactions can be directed, producing only one enantiomer rather than

910-493: The glass against gravity. This flow of water cools any escaping substrate and condenses it back into the reaction flask to continue reacting and ensure that all product is contained. The use of reflux condensers is an important technique within organic syntheses and is utilized in reflux steps, as well as recrystallization steps. When being used for refluxing a solution, reflux condensers are fitted and closely observed. Reflux occurs when condensation can be seen dripping back into

945-487: The kidneys into the urine. Once NNK is activated, it initiates a cascade of signaling pathways (for example ERK1/2 , NF-κB , PI3K/Akt , MAPK , FasL , K-Ras ), resulting in uncontrolled cellular proliferation and tumorigenesis. NNK activates μ en m-calpain kinase which induces lung metastasis via the ERK1/2 pathway. This pathway upregulates cellular myelocytomatosis ( c-Myc ) and B cell leukemia/lymphoma 2 ( Bcl-2 ) in which

980-523: The layers, the product-containing layer can be isolated and the other layer can be removed. Many reactions require heat to increase reaction speed. However, in many situations increased heat can cause the solvent to boil uncontrollably which negatively affects the reaction, and can potentially reduce product yield. To address this issue, reflux condensers can be fitted to reaction glassware. Reflux condensers are specially calibrated pieces of glassware that possess two inlets for water to run in and out through

1015-434: The product that had the highest amount, if 1 ml is equivalent to 20 cigarettes, there would be 9.84/20 = 0.5 ng NNK per e-cig cigarette dose. Cigarettes with 1 gram of tobacco average about 350 ng. NNK is initially a procarcinogen that needs activation to exert its effects. The activation of NNK is done by enzymes of the cytochrome pigment (CYP) multigene family. These enzymes catalyze hydroxylation reactions. Beside

1050-442: The reaction flask from the reflux condenser; 1 drop every second or few seconds. For recrystallization , the product-containing solution is equipped with a condenser and brought to reflux again. Reflux is complete when the product-containing solution is clear. Once clear, the reaction is taken off heat and allowed to cool which will cause the product to re-precipitate, yielding a purer product. Solid products can be separated from

1085-543: The reaction to produce a higher yield . Previously, this type of reaction was reserved for large-scale industrial chemistry but has recently transitioned to bench-scale chemistry to improve the efficiency of reactions on a smaller scale. Currently integrating automated synthesis into their work is SRI International , a nonprofit research institute. Recently SRI International has developed Autosyn, an automated multi-step chemical synthesizer that can synthesize many FDA -approved small molecule drugs. This synthesizer demonstrates

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1120-407: The relative solubility of compounds can be exploited by adding immiscible solvents into the same flask and separating the product into the solvent with the most similar polarity. Solvent miscibility is of major importance as it allows for the formation of two layers in the flask, one layer containing the side reaction material and one containing the product. As a result of the differing densities of

1155-619: The two oncoproteins are involved in cellular proliferation, transformation and apoptosis. Also NNK promotes cell survival via phosphorylation with cooperation of c-Myc and Bcl-2 causing cellular migration, invasion and uncontrolled proliferation. The ERK1/2 pathway also phosphorylates NF-κB causing an upregulation of cyclin D1 , a G1 phase regulator protein. When NNK is present it directly involves cellular survival dependent on NF-κB. Further studies are needed to better understand NNK cellular pathways of NF-κB. The phosphoinositide 3-kinase (PI3K/Akt) pathway

1190-421: The versatility of substrates and the capacity to potentially expand the type of research conducted on novel drug molecules without human intervention. Automated chemistry and the automated synthesizers used demonstrate a potential direction for synthetic chemistry in the future. Necessary to organic synthesis is characterization . Characterization refers to the measurement of chemical and physical properties of

1225-506: The visualization of desired synthetic designs. A recent development within organic synthesis is automated synthesis . To conduct organic synthesis without human involvement, researchers are adapting existing synthetic methods and techniques to create entirely automated synthetic processes using organic synthesis software . This type of synthesis is advantageous as synthetic automation can increase yield with continual "flowing" reactions. In flow chemistry , substrates are continually fed into

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