Ozone Depletion (Alison)

It has been known for a long time that the depletion of the ozone layer is accelerated by the use of chlorofluorocarbons, or CFC's. This reaction is cyclical, as it leaves a chlorine radical in the 6th step of halogenation to destroy more ozone molecules. This can be seen in the reaction below:

The reaction begins when UV light strikes a CFC, creating a carbon radical and a chlorine radical. The chlorine radical then collides with an ozone molecule, removes an oxygen atom, and forms chlorine monoxide and an ordinary oxygen molecule. A free oxygen atom then collides with chlorine monoxide, thus creating an oxygen molecule and freeing the chlorine radical to destroy more ozone molecules.

Beyond the obvious environmental effects of this, there are many health effects which have also been documented. The article I read focused on these health effects, mainly skin cancer, cataracts, and immune deficiencies.

Click here for CiteULike reference.

Click here for full-text of article.

Biotinylation (Elizabeth)

Biotinylation is a reaction that is utilized in numerous biochemical experiments and processes. The value of biotinylation lies in the fact that biotin, a B-complex vitamin, forms strong bonds with streptavidin. This biotin-streptavidin complex can then be linked to numerous other biomolecules that function in various applications. Biotin is also readily available (it can be purchased from many different sources) to be used in these applications. The image shown here depicts the biotinylation of spermine, a polyamine that functions in many metabolic processes in eukaryotic cells. Jeon, Kim, Shin et al. utilized this reaction in research that they discussed their paper Differential incorporation of biotinylated polyamines by transglutaminase2 . The biotinylated spermine was used in this experiment to learn more about the intracellular actions of an enzyme, transglutaminase 2. It is believed that this enzyme may cause cell adhesions and apoptosis (cell death). Spermine served as a substrate for transglutaminase 2 so that researchers could better understand how this enzyme functions.

Researchers performed the pictured reaction by combining N, N –di-TFA spermine 2, biotin, 1,3-dicyclohexylcarbodiimide, and 1-hydroxybenzotriazole in anhydrous dimethylformamide (DMF). These substances were combined in a flask and stirred for twenty-four hours at room temperature.

One clinical application of biotinylation is seen in a new wound dressing that was recently created by a German laboratory. This bandage has insulin-like growth factor-1 (IGF-1) attached to the dressing material via biotinylation. The IGF-1 is bound to a biotin-steptavidin-biotin complex, which is connected to amines on the polyurethane gauze. IGF-1 is a hormone, similar in structure to insulin, that stimulates cell growth and reproduction. It is therefore beneficial to use this unique dressing on patients with severe wounds or ulcers, as it will promote healing and epithelial tissue regeneration.

Synthesis of Taste-Free Erythromycin B

In terms of antimicrobial compounds, erythromycin belongs to a family of agents known as macrolides, which includes azithromycin (Zithromax) and clarithromycin (Biaxin). It is used to treat individuals with streptococcal pharyngitis at a dose of 20-40mg/kg/day and also for the secondary prevention of rheumatic fever (250mg twice a day). Since erythromycin is commonly prescribed to children, it is formulated as a tasteless powder that is reconstituted in distilled water to create a suspension (Pharmacopoeia 2005, Tarascon Publishing) Unfortunately, following reconstitution, erythromycin hydrolyses at a measurable rate in the medicine bottle resulting in an extremely unpleasant taste when taken orally. In order to address this problem, researchers have proposed the use of erythromycin B derivatives which were found to be almost completely insoluble in water (i.e., hydrolysis is undetectable in medicine bottles). Ultimately, the commercial distribution of the taste-free prodrug should improve patient compliance.

The synthesis of one such erythromycin B derivative, Erythromycin B Enol Ether 2’- Ethyl Succinate, by erythromycin B 2'-ethyl succinate is shown below.

Here is a reference with the synthesis

Throughout most of my years in high school and college, I have worked as a compounding specialist in a pharmacy located on a medical school/hospital campus in South Jersey. It my experience, the custom formulation of antibiotics significantly improves patient compliance. Consequently, we are often asked by physicians and other health care professionals to create customized medications for their patients. I will now share with you a “trick of the trade” that is a specialty in our practice. If you think that it is difficult to get people to take medicine, try giving antibiotics to birds!

If you are a veterinarian or pharmacist who happens to come across this blog, I hope that the following formulas will be useful to you. This is certainly not the type of information that you will find just anywhere, and I very much doubt that any compounding pharmacist who has been using it in his/her practice would ever share it with you.

Disclaimer: I make no claims with regard to the safety or efficacy of this product.

________________________________________________________________________

Amoxicillin/Clavulanic Acid (Augmentin) 175mg/mL Oral Suspension (Avian)
100ml
________________________________________________________________________
n.b. Even though sterile conditions are not required for the preparation of this drug, I usually compound it in a laminar flow hood for good measure. It is just a personal policy of mine that maximizes my confidence in terms of quality assurance. As with all pharmaceutical compounding procedures, proper attire (gloves, labcoat, goggles) should be worn by the compounder during the entire drug preparation process.
________________________________________________________________________

* Amoxicillin/Clavulanic Acid 17.5g
Stevioside 90% Powder 0.75g
Acesulfame Potassium 0.50g
Flavor, Apple, Artificial 3.00ml
Potassium Sorbate NF 0.20g
**Hypromellose USP 1% Stock Suspension q.s. 100ml


*Pharmacy Stock (Source: 20 – 875mg tablets)

**See Formula to Follow for Making Hypromellose 1% Stock Suspension

(1) Crush Amoxicillin/Clavulanic Acid 875mg tablets to a fine powder.
(2) Triturate Step (1), Potassium Sorbate, Stevioside 90% Powder, and Acesulfame Potassium.
(3) Wet Step (2) with enough Hypromellose USP 1% Stock Suspension to make a thick paste.
(4) Add the Flavor to Step (3) with mixing.
(5) Bring to final volume (100ml) with Hypromellose USP 1% Stock Suspension.

Label Medicine Bottle: Shake well. Keep refrigerated.

Expiration Date: 14 days
________________________________________________________________________
** Hypromellose USP 1% Stock Suspension
100ml

________________________________________________________________________


Hypromellose USP 1% Stock Suspension 1.0g
Purified Water, USP q.s. 100ml


(1) Divide the Purified Water; put half in refrigerator.
(2) Heat the other half with stirring until it just becomes steamy (65-70ºC)
(3) Slowly sift the Hypromellose into Step (2) using a strainer.
(4) When Hypromellose is dispersed and free of clumps, take off the heat and add the refrigerated Purified Water and stir or 15 seconds. Place in refrigerator for 45 minutes and allow complete gelling.

Note: Store in refrigerator.

Expiration Date: 30 days
________________________________________________________________________

The same compounding procedure that I just outlined can be applied to creating suspensions with many other types of antibiotics, including erythromycin.


All drugs and additives listed in the above formulas can be purchased from Medisca Inc. (1-800-932-1039) by a licensed pharmacist.

L-ascorbic Acid Derivative with Activity Against Malignant Tumor Cells

The reaction below shows the synthesis of the 6-chloro derivative of 2,3-di-O-benzyl-L-ascorbic acid, by reacting ditosylate with diazobicycloundecane and tetraethyl-ammonium chloride. This particular compound was found to be extremely cytostatic against malignant human tumor cells in vitro. It is thought that the ditosylated compound goes through a two-step reaction pathway in which an E2 elimination reaction (step 1) produces an exocyclic allylic tosylate, that then proceeds through an SN2 reaction (step 2) with the corresponding nucleophile to produce the L-ascorbic acid derivative (please click on reference for more details).



Here is a Reference for the Synthesis

Characteristics of Malignant Tumors: Malignant tumors invade surrounding tissue and/or metastasize. In terms of cell morphology, malignant tumors are often abnormal in size with large and misshapen nuclei (in some cases this may be due to dedifferentiation of cells). Mitotic divisions are often irregular and mitotic chromosomes may be abnormal. Growth rates of malignant cells are often, but not necessarily, higher than benign; growth rates of malignant tumor cells frequently do not plateau in culture. In cell culture, malignant cells often lose contact inhibition. With normal contact inhibition, cells stop dividing and thus stop proliferating when they reach a certain density. This occurs as a result of contacting, and receiving signals from, other cells.

Malignant tumors are often highly vascularized (i.e., they are surrounded by many blood vessels). Tumors secrete compounds called angiogenesis factors, which cause blood vessels to sprout and proliferate around the tumors. The sprouting and proliferation of blood vessels is known as angiogenesis (Adapted From Lecture Notes "Characteristics of Tumors and Metastasis" Biology of Cancer (Bio 210) Drexel University Department of Bioscience and Biotechnology. Jeremy Lee, Ph.D. Winter 2006).

If you are a student at Drexel University and have an interest in studying cancer, I highly recommend Dr. Jeremy Lee's Biology of Cancer Course (Bio 210).

Variation of the Claisen Condensation

Researchers at Kwansei Gakuin University developed a better way of synthesizing β-keto esters from esters and acid chlorides as well as from esters and carboxylic acids. It is based on the Ti-self-Claisen condensation performed in a previous study. The new method is a Ti-crossed-Claisen condensation with a high yield of the desired product and a low yield of the undesired self-condensed reaction. In the previous study, the catalyst used was TiCl₄-Bu₃N. In this study, a co-catalyst, N-methylimidazole, was used to prevent self-condensing in the ester/acid chloride reaction. During the reaction, the acid chloride condenses with the N-methylimidazole to form an electrophilic acylammonium intermediate. An example of the reaction is shown below:

In the reactions between esters and carboxylic acids, the researchers developed a new procedure using mixed anhydrides to react with the ester and create an intermediate. The mixed anhyrides are formed in situ between sodium carboxylates and Cl3CCOCl. An example is shown below:

In order to show that these new methods are easier and work better than previous procedures, the researchers synthesized cis-Jasmone and (R)-Muscone. The resulting yields were 46% and 53% respectively. This reaction is a useful new method particularly because products of Ti-crossed-Claisen condensation reactions are useful reagents for organic syntheses, especially those that involve asymmetric transformations.

More information is available here.

Wittig Reaction (Thomas Dursch)

In the near future, perfection of Organic Light Emitting Diode (OLED) technology will create an alternative to LCD screens, revolutionizing the display market. Problems associated with the emission of blue light in OLEDs currently inhibit their mass production. According to Wikipedia.com, organic compounds that emit blue light have a lifespan of only 1,000 hours, whereas, the red and green emitting compounds have a lifespan of roughly 500,000 hours. Improvements upon the longevity of blue emitters will open a new door to display technology.

According to the article “Reliability and Degradation of Small Molecule-Based
Organic Light-Emitting Devices” in the IEEE Journal of Quantum Electronics, the cause of this limited lifespan is an undesirable reaction between oxygen molecules and the organic emitting layer. Due to the permeability of the glass substrate, oxygen molecules are able to diffuse into the organic emitting layer. During the operation of an OLED, singlet oxygen is formed due to the energy transfer from the excited organic molecules to oxygen molecules. The singlet oxygen molecules, known as radicals, then attack the structure of the organic compound eventually destroying the organic layer.

Currently, my freshman design group is working on a solution to lengthen the lifespan of the blue emitting compound. Since it is very difficult to find a blue emitting compound that does not react with oxygen at all, we decided to find a compound that reacts with oxygen, but extremely slowly. Our group is currently investigating a class of compounds known as the triarylamines, specifically, a triphenylamine-based conjugated polymer known as MPa (chosen due to MPa’s high thermal stability, low t_g, and high quantum yield of nearly 64 %). In order to create MPa we must use the Wittig Reaction. According to Organic-chemistry.org, the Wittig Reaction allows the preparation of an alkene by the reaction of an aldehyde or ketone with the ylide generated from a phosphonium salt. MPa is created by a reaction of an aldehyde group found on PFT with benzyltriphenylphosphonium bromide and THF under N₂. For a detailed description of the reaction please refer to “Macromolecules” by the Tokyo Institute of Technology.

Esterification Reaction of Phenylacetic acids

Esterification reactions are condensation reactions between alcohols and carboxylic acids in the presence of an acid catalyst to form esters. According to a Wikipedia article, esterification is commonly used in substances such as lotions or perfumes, as they tend to give off various scents and flavors. Phenylacetic acids are found in plants, as a type of hormone known as auxin, which is generally used in the plants’ fruits. Phenylacetic acids tend to possess a honey-like odor in smaller concentrations and may be used in perfumes. Esterification reactions of carboxylic acids create esters that are excellent solvents and can then be used in soaps and lotions (“Intro to General, Organic, and Biological Chemistry,” Solomon).
In an experimental setting, an esterification reaction, as shown above, was tested using a catalyst, cerium (IV) ammonium nitrate (CAN), and simple primary and secondary alcohols in order to increase the efficiency of basic esterification reactions. A link to this experiment can be found here.
The synthesis of aspirin, also known as acetylsalicylic acid, also uses an esterification reaction. For more information on the uses of aspirin, please see the class blog.

Aspirin - Acetylsalicylic Acid (Thomas Dursch)

Since the time of Hippocrates, there have been written records of pain relief treatments, including powder obtained from the insides of willow trees. According to From a Miracle Drug written by Sophie Jourdier for the Royal Society of Chemistry, “It was not long before the active ingredient in willow bark was isolated; in 1828, Johann Buchner, professor of pharmaceuticals at the University of Munich, isolated a tiny amount of bitter tasting yellow crystals, which he called salicin”.

According to Wikipedia, an online encyclopedia, salicin undergoes a “Kolbe-Schmitt reaction and the final product is an aromatic hydroxyl acid known as salicylic acid”. Minimally, what happens in a Kolbe-Schmitt reaction is a sodium phenolate is heated with carbon dioxide, then the final product is treated with sulfuric acid, eventually producing salicylic acid. Today, scientists recognize salicylic acid as being harmful when ingested. Instead of using salicylic acid, the commonly used pain reliever is acetylsalicylic acid, now known as aspirin. The newly discovered acetylsalicylic acid is what is known as an “acetyl ester” formed through a process known as esterification. According to Wikipedia, for this esterification, “a carboxylic acid reacts with the phenol group of salicylic acid to produce the acetyl ester”. Simply, an ester can be thought of as a product of a condensation reaction of an acid usually an organic acid and an alcohol or phenol.

Aspirin helps cure headaches, reduce fevers, and reduce swelling to minor injuries, and since the time of its discovery, has risen to one of the leading over-the-counter drugs. According to Paul May at the University of Bristol School of Chemistry, “each year, more than 40 million pounds of aspirin is produced in the United States alone, a rate that translates to about 300 tablets per year for every man, woman and child”.

To further supplement this information and for a complete reaction/experiment, please refer to the following link.

Rigid-Rod Polyquinolines – the Creation of New Polymers (Zakiya)

Poly(2,2’-(p,p’-diphenylacetylene)-6,6’-bis(4-phenylquinoline) or PBAPQ is one of the group of polyquinolines used to create multilayer organic (thin film, polymer based) solar cells.

While now available commercially, this polymer was originally synthesized manually using the time intensive process described here and is an example of an enol/imine condensation.

For more information on how these polymers are used in organic solar cells click here.