26: Temozolomide

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Nanoparticle for Anticancer Drug Delivery

Zhou J. Deng, Stephen W. Morton, Elana Ben-Akiva, Erik C. Dreaden, Kevin E. Shopsowitz, and Paula T. Hammond, Layer-by-Layer Nanoparticles for Systemic Co-delivery of an Anticancer Drug and siRNA for Potential Triple-Negative Breast Cancer Treatment, ACS Nano2013 7 (11), 9571-9584.

Glioblastoma multiforme is a deadly form of brain cancer. Until recently, it was treated with Temozolomide, whose structure is shown below.

Screen Shot 2019-03-23 at 3.52.25 AM.png

Determine the formula for Temozolomide.
Determinethehybridizationofeachofthethreeconsecutivenitrogensinthesix- membered ring. Write them next to each of the atoms in the ring.
Provideanameforthecircledfunctionalgroup.

That functional group can be considered to represent a three atom conjugated system.

Draw a Huckel MO diagram (pi MO diagram).
1. Show the energy levels for this part of the molecule.
2. Place the proper number of electrons into the diagram.
3. For each MO show how the p orbitals are phased.
Now look at the molecule again. Find the longest consecutive set of conjugated atoms and circle them.
Draw one resonance structure for the molecule.

In order for a molecule to be an effective pharmaceutical, it has to be at least somewhat water soluble so that it can pass though the bloodstream.

Ontheoriginalmolecule,showthe2-3strongestinteractionsbetweenwater molecules and the temozolomide. Draw the waters interacting with the appropriate atoms in the molecule.

Assume that Temozolimide is made from molecule A. (Both are shown below.) Before it can be used as a pharmaceutical, Temozolimide must be separated from any molecule A that remains, and silica gel column chromatography is a likely way to do it. The mixture is placed on top of the silica column, and a mixture of ethyl acetate and hexane is used to wash the components down the column.

Screen Shot 2019-03-23 at 3.57.55 AM.png

Draw the Lewis dot structures for ethylacetate (CH₃COOCH₂CH₂) and hexane.
Which is more polar, the ethylacetate/hexane mixture or silica gel(recall that silica gel has Si-OH groups on it)?
Which compound will come off the column first, Temozolimide or molecule A? Explain briefly.

One of the problems with Temozolomide is that it is not able to cross the blood-brain barrier very effectively so it is difficult to get the pharmaceutical to the tumor. Thus, a new class of treatments has been developed. They are called called SNAs (spherical nucleic acids) in which portions of RNA, DNA or other molecules are attached to gold nanoparticles, as shown below.

Screen Shot 2019-03-23 at 4.00.28 AM.png

A gold nanoparticle is a very small piece of gold metal. The crystal structure of gold is face-centered cubic. On the skeleton above draw a unit cell. How many gold atoms are in the unit cell? Show your work.
Assume pieces of DNA are attached to the surface of an SNA. What would the charge on the particle be (positive, negative or neutral)? Explain briefly.
The authors note that SNA nanoparticles (at least some of them) can cross the blood-brain barrier. They accumulate in tumors rather than healthy brain tissue. Why? (Hint—tumors have unusually distorted blood vessels.)

Scientists found that a certain gene is overexpressed in this type of tumor. By attaching an SNA that interferes with that gene to the nanoparticle, tumor growth can be stopped.