Molecule with Anti-Cancer Kick

In 2013, medical researchers found a molecule that fights cancer in animals by boosting the cell's production of a powerful natural antitumor protein known as TRAIL. The Researchers referred to this anti-cancer molecule as TIC10, short for TRAIL Inducing Compound number 10.
The structure of this molecule, as confirmed by mass spectroscopy, was published at this time as is shown below:

Chemists at The Scripps Research Institute (TSRI) found a way to synthesize this molecule in the laboratory. However, when the Chemists gave their molecule to Biologists to test on cancer cells, this molecule failed to show any anti-cancer activity!
So, the Chemists asked the Biologists to supply some of the TIC10 that had shown anti-cancer activity. The Chemists spent months analyzing both TIC10 molecules to determine their exact molecular structure. And they discovered that the molecule the biologists had shown to fight cancer did not have the structure that was originally published, so the molecule that the Chemists had synthesized in their laboratory would not fight cancer cells,.
However, the Chemists found that the molecule that DOES fight cancer cells has a very similar structure. The structure of the active molecule is shown below:

Note that the structure originally published for TIC10 had the three nitrogen containing rings in a straight line. This new, correct, structure for TIC10 has two of the nitrogen containing rings in a straight line, but the third ring sticks out at an angle from the other two. Only this "angular" isomer (the molecule with a kick) shows any anti-cancer activity.

Kim D. Janda, the Ely R. Callaway Jr. Professor of Chemistry and member of the Skaggs Institute for Chemical Biology at TSRI has been quoted as saying, "One lesson from this has got to be: don't leave your chemists behind".
(http://www.sciencedaily.com/releases/2014/05/140519184505.htm)

Reference:
Nicholas T. Jacob, Jonathan W. Lockner, Vladimir V. Kravchenko, Kim D. Janda. Pharmacophore Reassignment for Induction of the Immunosurveillance Cytokine TRAIL. Angewandte Chemie, 2014; DOI: 10.1002/ange.201402133

Further Reading
Molecular Formula  
Condensed Structural Formula 
2-Dimensional Structural Formula
Skeletal Formula
Percent Composition
Functional Groups
Benzene
Mass Spectroscopy for Structural Determination

Suggested Study Questions:

1. Refer to the structure of TIC10 as shown above. In one molecule, how many
   • carbon atoms are present?
   • hydrogen atoms are present?
   • oxygen atoms are present?
   • nitrogen atoms are present?
2.  Write the molecular formula for a molecule of TIC10.
3. For the TIC10 molecule, calculate the percent by mass of
   • carbon
   • hydrogen
   • oxygen
   • nitrogen
4. Convert the skeletal structure for the active anti-cancer molecule into a 2-dimensional structural formula.
5. Circle one benzene ring in the structure of the active anti-cancer molecule.
6. Circle and name the functional group containing an oxygen atom on the active anti-cancer molecule.
7. What value do you expect for the mass-to-charge (M/Z) peak on a mass spectrum of the anti-cancer TIC10 compound ?
8. Do you think mass spectroscopy alone could be used to distinguish between the two structures proposed for TIC10 above? Explain your answer.

Paracetamol

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Salts of Drugs a Health Risk

Many studies have shown that excess salt is harmful to heart health, but many commonly prescribed medicines have sodium added to improve their absorption into the body, but the effect of doing this has not been known. For example, 1 Alka-Seltzer tablet contains 324 mg of aspirin (the drug) and 445 mg of sodium.
University of Dundee and College of London researchers have found that a person taking the maximum, daily dose of some medicines would exceed the recommended daily dietary intake limits for sodium. In Australia, the total maximum recommended limit of sodium for adults should be less than 2300 mg per day (less for children). The label on the Alka-Seltzer tablets carries a warning that you should not take more than 8 tablets per day.
In the study, the researchers found that patients taking the sodium-containing medication had a 16% increased risk of a heart attack, were 7 times more likely to develop high blood pressure, and, were 28% more likely to die, compared with patients who took the non-sodium containing versions of the same drug.

So why do we add sodium to drugs if it is potentially harmful?

We do this because many drugs are actually insoluble in water. The cells in your body are made up mostly of water, so if you want to be able to transport a drug around the body, and have it absorbed into cells, it is beneficial if the drug is soluble in water.

How do we add sodium to drugs?

If the drug is, for example, a weak acid like aspirin, then it is not very soluble in water.
Being a weak acid, though, aspirin can undergo a proton transfer (neutralisation) reaction with a base such as sodium hydroxide. The product of a neutralisation reaction are salt and water.
acid + base → salt + water

aspirin + sodium hydroxide → sodium salt of aspirin + water

The sodium salt of aspirin readily dissolves in water by dissociating into positive sodium ions and negative "aspirin" ions.


Reference:
BMJ-British Medical Journal (2013, November 26). High salt levels in medicines increase risk of cardiovascular events. ScienceDaily. Retrieved November 28, 2013, from http://www.sciencedaily.com­ /releases/2013/11/131126191557.htm 

Further Reading
aspirin
mass conversions 
ppm
molarity
neutralisation
proton transfer reactions
acid dissociation constants

Suggested Study Questions: 

1. Convert these masses in milligrams to masses in grams
• 324 mg
• 445 mg
2. The label on the Alka-Seltzer packet recommends dissolving 2 tablets in water. For these two tablets, calculate the mass in milligrams of
• aspirin
• sodium
3. If you were to take the maximum number of tablets, 8, in a day, how much of each of the following substances would you be ingesting?
• aspirin
• sodium
4. Would you be exceeding the recommended daily dietary intake limits for sodium in Australia? Explain your answer.
5. A low salt food is one that contains less than 120 mg of sodium per 100 g of food. If Alka-Seltzer were to be considered a low salt food, what would the mass of each tablet need to be?
6. Aspirin has the molecular formula C₉H₈O₄. What is the molar mass of aspirin?
7. The sodium salt of aspirin has the molecular formula C₉H₇O₄^-Na⁺. What is the molar mass of the sodium salt of aspirin?
8. Calculate the mass of sodium in 1 Alka-Seltzer tablet due to the sodium salt of aspirin.
9. Compare the mass of sodium calculated above to the actual mass of sodium present in 1 Alka-Seltzer tablet according to the package. How would you explain the difference in the two masses?
10. If a person dissolved 2 Akla-Seltzer tablets in 150 mL of water, what is the concentration of sodium ions in the water in
    • mol/L
    • mg/L
    • ppm
11. Recommendations for the daily intake of potassium are higher than those for sodium at 4700 mg day, so one way to alleviate the sodium problem in aspirin tablets might be to replace the sodium with potassium. Describe one way that you could produce the potassium salt of aspirin.

 

Relenza Synthesis

Relenza, a pharmaceutical drug used to fight influenza (flu), went into production in 1999.

The synthesis of Relenza is a multi-step process involving a number of chemical reactions that should be familiar to High School Chemistry students.

The June 2012 issue of AUS-e-NEWS outlines the steps used to sythesise Relenza from commercially available N-acetyl-neuraminic acid.

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